Breakthroughs in 2022

There were lot of breakthroughs happened in the year 2022. Five prominent breakthroughs in the field of Medicine/ Biology in the year 2022 are listed here. Among the major breakthroughs, the drug discoveries for various disease conditions are really laudable. But how many of those drugs will get benefitted for the common patients around the globe is a big question? “Financial Toxicity” associated with all those new drugs is a real concern for the mankind!!

• Discovery in Human Evolution: Svante Pääbo, a Swedish geneticist who won Nobel prize for Physiology and Medicine, for pioneering studies of human evolution. He and his colleagues sequenced the genome of Neandertals and discovered a new hominin species, Denisovans. The research led to the surprising revelation that early humans interbred with these now extinct species. These primeval trysts gave us traits that persist in some people today, including an ability to survive at high altitude and a vulnerability to infections such as COVID.
• AI solved a biggest problem in biology: Predicting the three-dimensional structure of proteins from their amino acid sequence is a difficult task for biologists. In early 2022, an AI program was built by the Google-owned company DeepMind, called AlphaFold. AI can now predicts the shape of nearly all known proteins. These structures are already enabling scientists to unlock mysteries in biology, and they could help lead to new pharmaceutical drugs and more sustainable crops.
• Stem Cell - Gene therapy shows promise in Amyotrophic lateral sclerosis (ALS): An investigational therapy involving human neural progenitor cells transduced with glial cell line-derived neurotrophic factor (GDNF) differentiated to astrocytes protected spinal motor neurons. These cells were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study. They were able to show that the engineered stem cell product can be safely transplanted in the human spinal cord and after a one-time treatment, these cells can survive and produce an important protein for over three years that is known to protect motor neurons that die in ALS.
• Drug that delays the onset of type 1 diabetes: Teplizumab, a monoclonal antobody approved by FDA in November, could delay the onset of Type 1 diabetes. This drug is release under the brand name TZIELD. The treatment is for 14-days, 30-minute infusion for adult and children 8 years and older with Stage 2 Type 2 diabetes. Even though this drug could change the lives of lot of people, the financial toxicity is very high. (i.e., $13,850 a vial for a total of $193,000 over the 14-day treatment).
• Gene Therapy for Hemophilai B: FDA approved Hemgenix (etranacogene dezaparvovec), an adeno-associated virus vector-based gene therapy for the treatment of adults with Hemophilia B. Hemgenix is a one-time gene therapy product given as a single dose by IV infusion. Hemgenix consists of a viral vector carrying a gene for clotting Factor IX. The gene is expressed in the liver to produce Factor IX protein, to increase blood levels of Factor IX and thereby limit bleeding episodes. Again, the main issue with drug is the financial toxicity!! Developed by CSL Behring, Hemgenix is expected to cost $3.5 million per patient, the highest list price yet for a single-dose treatment!!

Strengthening of mitochondria to treat genetic disorders

An exciting results from an initial research suggests mitochondrial augmentation therapy can be used to treat patients with mtDNA disorders.

• Patients with single large-scale mitochondrial DNA deletion syndromes (SLSMDs) experience multisystemic disease, and no targeted therapies currently exist.
• Mitochondrial augmentation therapy in such patients as part of a compassionate use program, resulted in improved ATP content and thus shows some hope for the treatment of SLSMDs.
• SLSMDs usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life.
• Jacoby and colleagues applied mitochondrial augmentation therapy to six individuals with SLSMDs.
• Autologous CD34+ hematopoietic stem and progenitor cells were augmented with maternally derived healthy mitochondria - i.e. soaking patient’s blood cells in a soup of healthy mitochondria from their mothers and then reinfusing them.
• After mitochondrial augmentation therapy, heteroplasmy decreased in the peripheral blood in four of the six patients.
• An increase in 30% more mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months and produced one-third more ATP than before, after mitochondrial augmentation therapy as compared to baseline.
• Jacoby and co-workers noted some clinical improvement in aerobic function, measured in two patients by sit-to-stand or 6 min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment.
• Quality of life measurements as per caregiver assessment and physical examination showed improvement.

Together, this work lays the ground for clinical trials of mitochondrial augmentation therapy for the treatment of patients with mtDNA disorders. Early signs from this study suggest the intervention is safe and may improve the children’s health and development. Even though initial study shows some promise or a ray of hope, a clinical trial is warranted.

Smartphone Addiction Vs. Creative Cognition

Yet another negative effects of technology: Smartphone addiction leads to deleterious effect on individuals’ advanced cognitive abilities.

• Creative Cognition is a set of mental processes that support the generation of novel and useful ideas.
• In today’s world, smartphone usage has increased and this usage has become a popular behaviour in people’s lives. Many of them is finding difficulty in minimising the usage of smartphones. Thus, there is an emergence of smartphone-addictive behaviours about the people today.
• The COVID pandemic associated home isolation is also a contributing factor for the dramatic increase in the number of smartphone addicts.
• There are reports on smartphone addiction and its impact on individuals’ cognitive functions, such as attention (Choi et al., 2021; Lee et al., 2021), perception (Dong et al., 2014) and memory.
• The influence of smartphone addiction on individuals’ advanced cognition (creative cognition) was unclear. Will smartphone addiction has anything to do with creative cognition?
• Recently Li et al., did a functional near-infrared spectroscopy study and compared neural differences between smartphone addiction tendency (SAT) and healthy control (HC) individuals during creative idea generation. Especially by manipulating a key component of creative cognition, that is, overcoming semantic constraints, they explored whether SAT individuals could overcome semantic constraints.
• Both the addiction and HC groups completed the alternate uses task (AUT) in semantic constraint and unconstraint conditions.
• From the study Li and co-workers observed that the prefrontal cortex (PFC) and temporal regions were less active during AUT in the addiction group than in the HC group.
• In the addiction or SAT group, the PFC was less active under constraint than unconstraint conditions.
• Moreover, both task-related and resting-state functional connectivity analyses indicated weaker coupling between the PFC and temporal regions in the SAT than in the HC group.
• Furthermore, the left dorsolateral PFC mediated the effect of smartphone addiction on creative performance. These findings provide unprecedented neuroimaging evidence on the negative impact of smartphone addiction on creative cognition.

Thus it is clear that smartphone addicts exhibited reduced cortical activations and functional connectivities in the prefrontal cortex and temporal cortex, making it difficult to overcome semantic constraints and establish original associations during creative idea generation. The findings from this study revealed the deleterious effects of smartphone addiction on individuals’ advanced cognitive abilities. In today’s world were the usage of smartphone is rampant among the kids and younger people, the questions to ponder: Do we need to allow school kids to use smartphones? Can we restrict the usage of smartphones among younger people?, as these technologies reduce the creative thinking capability of the current generation!!

Potential biomarker for early detection of Alzheimer’s disease

Biomarker for the early stage detection of Alzheimer’s disease observed in urine

• A recent study by Wang and co-workers suggests that a simple urine test can reveal if someone has early-stage Alzheimer’s disease or not
• Normally Alzheimer’s disease may remain undetected until it is too late to treat
• Current diagnostic methods are too cumbersome and expensive
• In this study, wang and co-workers tested 574 participants. They divided the patient cohort in to five groups according to their diagnosis: 71 with normal cognitive, 101 with subjective cognitive decline , 131 with cognitive impairment without mild cognitive impairment, 158 with mild cognitive impairment and 113 with Alzheimer’s disease
• They identified formic acid as a sensitive urinary biomarker that can reveal early-stage Alzheimer disease. These investigators found that urinary formic acid is a sensitive marker of subjective cognitive decline that may indicate the very early stages of Alzheimer disease
• With the progression of the disease, urinary formic acid levels showed an overall upward trend
• The areas under the receiver operating characteristic curves (AUC) of urinary formic acid in distinguishing normal cognitive from Alzheimer’s disease was 0.797, which was similar to that of plasma neurofilament light chain (NfL; AUC = 0.768) and better than other plasma biomarkers (Aβ40, Aβ42, Aβ42/Aβ40, T-tau, P-tau181, and P-tau181/T-tau)
• Wang and co-workers also found that using urinary formic acid and formaldehyde levels could improve the accuracy of using plasma biomarkers to determine Alzheimer’s disease stage.

This study opens up a possibility of diagnosis of early-stage Alzheimer’s disease by looking at the urinary formic acid. The early stages of this disease occur before the irreversible dementia stage, and this is a golden window for intervention and treatment in Alzheimer’s disease

A leap in Precision Medicine

Breakthrough in HER2-targeted therapy for lung cancer. A slight ray of hope for Non-Small Cell Lung Cancer (NSCLC) patients

• HER2 mutations is observed in approximately 3% of non-squamous NSCLC patients and these patients often have a poor prognosis and an increased incidence of brain metastases.
• Till now there was no approved HER-2 targeted therapies available for patients with NSCLC, although HER2 gene targeting has transformed the treatment of patients with breast and gastric cancers.
• Previously, targeting HER2-mutant NSCLC had produced inconsistent results.
• A study was conducted by Li and coworkers on 91 patients from North America, Europe, and Asia with previously treated HER2-mutant NSCLC (May 2018 and July 2020). Patients were treated with trastuzumab deruxtecan for the phase 2 DESTINY-Lung01 trial. They published this study that highlighted the benefits of trastuzumab deruxtecan – a drug for treating people with HER2-mutant NSCLC.
• Trastuzumab deruxtecan (T-DXd or Enhertu®) is an antibody drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the topoisomerase I inhibitor deruxtecan.
• In this study, among the 91 patients enrolled, 50 patients had a confirmed objective response (54.9%) and nearly all patients showed disease control (92.3%) with a reduction in tumor size.

Thus on August 11, 2022, the U.S FDA approved trastuzumab deruxtecan for the treatment of advanced non-small cell lung cancer (NSCLC) driven by mutant HER2. Trastuzumab deruxtecan become the first antibody-drug conjugate for lung cancer. T-DXd become the first therapy targeting HER2 mutations in lung cancer as well as the first HER2-targeted therapy for lung cancer to have received a breakthrough. Hope this new accelerated approval of T-DXd by FDA will benefit lots of HER2-mutant NSCLC patients around the globe.

Pollution impairs immune regulation of lungs

Pollution is identified as a real culprit that impairs the immune function and architecture of human lung lymph nodes

• The lungs’ immune defenses can vanish with age, leaving elderly people more vulnerable to lung damage and severe spells of respiratory infections. Why this is happening was not clear till recently.
• Recent study by Ural and co-workers identified the reason why elderly people are vulnerable to lung damage.
• They identified that inhaled particulate matter from pollution over a period of time will lead to weakening of lungs’ immune system.
• Particulate matter is a type of pollution emitted from vehicle exhaust, power plants, wildfires and other sources. This has been linked to health harms including respiratory, cardiovascular and neurological diseases.
• Ural and co-workers analysed lung immune tissue from 84 organ donors aged 11 to 93 years old. The donors were non-smokers or had no history of heavy smoking.
• They found out that with age, the lungs’ lymph nodes, which filter foreign substances and contain immune cells, became loaded with particulate matter, turning them a deep onyx.
• They found a specific age-related decline in lung-associated, but not gut-associated,
• lymph nodes immune function linked to the accumulation of inhaled atmospheric particulate matter.
• Increasing densities of particulates were found in lung-associated lymph nodes with age.
• The lymph nodes are home to an array of immune cells, including macrophages.
• Particulates were specifically contained within CD68+CD169 macrophages, which exhibited decreased activation, phagocytic capacity, and altered cytokine production compared with non-particulate-containing macrophages.
• They also observed that the structures of B cell follicles and lymphatic drainage were also disrupted in lung-associated lymph nodes with particulates. If the lymph nodes build up with so much material, then they can’t do their job properly.

Thus this study unveil that the cumulative effects of environmental exposure and age may compromise immune surveillance of the lung through direct effects on immune cell function and lymphoid architecture. Pollution is a real threat to the health and livelihood of the humankind. Let every one of us should decide to save the earth from pollution.

How virus leak out from bats ?

Can we develop an ecological countermeasure to prevent pandemics in future? A recent study says “yes”. A landmark study reveals ‘spill over’ mechanism of rare and deadly virus from bats.

• A major health concern in the recent days is the pathogens originating from the bats and its potential in generating a pandemic. But how the “spill over” of pathogens happening from these bats is not known till now.
• Many correlational studies associate “spill over” with changes in land use or other anthropogenic stressors, although the mechanisms underlying the observed correlations have not been identified till recently.
• A study by Eby and co-workers recently published their 25 years of data (1996-2020) on land-use change, bat behaviour, and “spill over” of Hendra virus from Pteropodid bats to horses in subtropical Australia.

What is Hendra Virus?

• Hendra virus first identified in 1994, following an outbreak in horses and people in Brisbane, Australia. Studies confirmed later that the virus spreads from its bat reservoir-most likely the black flying fox (Pteropus alecto) to horses through faeces, urine and spats of chewed-up pulp the flying foxes spit out on the grass. Infected horses then spread the virus to people. Hendra virus, like Nipah, SARS-CoV-1 and SARS-CoV-2, is a bat virus that has spilled over into people.
• Eby and co-workers observed that bats are responding to environmental change by persistently adopting behaviours that were previously transient responses to nutritional stress. Interactions between land-use change and climate lead to persistent bat residency in agricultural areas, where periodic food shortages drive clusters of “spill overs”.
• This study observed that clusters of Hendra virus “spill overs” occur following years in which the bats experience food stress. And these food shortages typically follow years with a strong El Nino. But if the trees the bats rely on for food during the winter have a large flowering event the year after there’s been a food shortage, there are no spill overs!!
• They developed integrative Bayesian network models based on these environmental phenomena that accurately predicted the presence or absence of clusters of “spill overs” in each of 25 years.

This fantastic study by Eby and her colleagues can now predict Hendra virus “spill over” up to two years ahead!! They have determined how those events could be prevented. This study provides a framework for examining causes of bat virus “spill over” and for developing ecological countermeasures to prevent pandemics. This study may bring new insights to other pathogens, including Nipah, Ebola, their viral families and their “spill overs”.

In Utero treatment stave off organ damage in babies

Pediatric geneticist Cohen and co-workers of Duke University School of Medicine, USA reported recently the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a foetus with CRIM (cross-reactive immunologic material)–negative infantile-onset Pompe’s disease.

• Pompe’s disease (lysosomal storage disease) is a rare genetic disorder that cause organ damage especially heart and muscles and that begins before birth. Thus babies born with Pompe have enlarged hearts and weak muscles. If left untreated, most infants die before they turn 2.
• This disease is caused by genetic changes that either reduce levels of an enzyme called acid alpha-glucosidase or GAA, or prevent the body from making it at all.
• Inside the lysosomes, GAA turns the complex sugar glycogen into glucose. Without GAA, glycogen accumulates to dangerously high levels that can damage muscle tissue, including the heart and muscles that help people breathe.
• Normally treatment for Pompe’s disease begins after birth. This approach doesn’t stop the permanent and potentially deadly, organ damage that happens in utero.
• Recently as part of early-stage clinical trial a baby received treatment while still in the mother’s womb.
• The team began treating the baby by infusing GAA through the umbilical vein when the mother was 24 weeks pregnant. Mother received a total of six infusions, one every two weeks. After birth, the medical team has been treating the baby with now weekly infusions, and the baby need to continue treatment throughout her life.
• The toddler (currently 13 months old) has a normal heart and is meeting developmental milestones, including walking so far.

So far, two other patients with other lysosomal storage diseases have received treatment in this trialPatients are being treated and monitored in the current trial. Currently, it’s unclear whether this prenatal enzyme replacement therapy is fully safe and an effective option. But definitely this a great step forward !!

Previous research has shown an association between red meat consumption and increased risks to human health. Is that correct? Conflicting results are in front of us

• The Global Burden of Diseases, Injuries and Risk Factors study (GBD) 2019 estimated that 896,000 deaths and 23.9 million disability-adjusted life years were attributable to unprocessed red meat consumption globally in 2019.
• Such findings led to the recommendation of limiting red meat intake by the WHO, the World Cancer Research Fund (WCRF), the EAT-Lancet Commission and the US Departments of Health and Human Services and Agriculture.
• Recommended consumption targets were inconsistent, ranging from 14 g d−1 (EAT), to 50–70 g d−1 (WCRF), to unrestricted amounts (Nutritional Recommendations Consortium).
• At the same time, several studies have found no significant relationship between red meat consumption and risk of death as well, which has led to further questioning of the strength of evidence in these risk pair associations
• Recently, Lescinsky and co-workers did a systematic review and implemented a meta-regression relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes.
• Six health outcomes they analysed were breast cancer, colorectal cancer, type 2 diabetes, ischemic heart disease (IHD), ischemic stroke and haemorrhagic stroke.
• Their observations are (a) no evidence of an association between unprocessed red meat and ischemic stroke or haemorrhagic stroke (b) while risk for the six outcomes in their analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between study heterogeneity was very wide: from 0–200 g d−1.
• It is weak and insufficient to make stronger or more conclusive recommendations even though there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality.

More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.

Is it high time to ban Cigarettes?

Public and the health experts considered smoking as a major behavioural risk factor that leads to ascribed health burden worldwide. Then, why still cigarettes are made available for human use?

• In 2004, the first strong statistical proof of association between smoking and many diseases came out from a remarkable study on British doctors followed up for 50 years (1951-2001) - a paradigm for cohort studies !!
• In 2005, evidence of the health consequences of smoking stimulated the adoption of the first WHO treaty, the Framework Convention on Tobacco Control, in an attempt to drive reductions in global tobacco use and second-hand smoke exposure
• Even after these steps it is estimated that globally in 2020, 1.18 billion current smokers, 7 million deaths and 177 million disability-adjusted life-years were attributed to smoking
• A recent study re-estimated the dose response relationships between current smoking and 36 health outcomes by conducting systematic reviews employing a meta-analytic method that incorporates between study heterogeneity into estimates of uncertainty. (i.e. based on evidence from a total of 793 studies published between 1970 and 2022)
• In this study the 36 health outcomes were selected based on existing evidence of a relationship, which included 16 cancers, 5 cardiovascular diseases and 15 other diseases.
• Cancers included lung, oesophageal, stomach, leukaemia, liver, laryngeal, breast, cervical, colorectal, lip and oral cavity, nasopharyngeal, other pharynx , pancreatic , bladder, kidney and prostate.
• Cardiovascular diseases include ischemic heart disease, stroke, atrial fibrillation and flutter, aortic aneurysm and peripheral artery disease.
• Other diseases include COPD, lower respiratory tract infections, tuberculosis, asthma, type 2 diabetes, Alzheimer’s disease and related dementias, Parkinson’s disease, multiple sclerosis, cataracts, gallbladder diseases, low back pain, peptic ulcer disease, rheumatoid arthritis, macular degeneration and fractures.
• Out of 36 health outcomes, statistically 8 had strong to very strong evidence of an association with smoking. The average increased risk % is more for laryngeal cancer (374.95%), followed by aortic aneurism (149.73%), peripheral artery disease (136.53%), lung cancer (106.66%), other pharynx cancer (92.26%), COPD (72.11%), lower respiratory infection (54.45%) and pancreatic cancer (51.66%).
• 21 outcomes had weak to moderate evidence of association with smoking, which includes bladder cancer (40.18%), tuberculosis 31.04%), oesophageal cancer (29.36%), cervical cancer (23.53), multiple sclerosis (23.36%), rheumatoid arthritis (23.32%), lower back pain (21.84%), ischemic heart disease ((20.39%), peptic ulcer (19.84%), macular degeneration (19.44%), stomach cancer (17.39%), stroke (16.39%), Type 2 diabetes (15.76%), cataracts (15.47%), nasopharyngeal cancer (14.29%), alzheimer’s and other dementia (9.70%), gallbladder diseases (6.34%), atrial fibrillation and flutter (.5.67%), lip and oral cavity cancer (4.81%) and breast cancer (4.46%).
• 7 outcomes showed no evidence of association with smoking includes colon and rectum cancer, kidney cancer, leukaemia, fracture, prostate cancer, liver cancer and asthma.

These results once again reaffirm the importance of stopping the tobacco use globally. Why are our policy makers, law makers, smoking control team and public health professionals not coming forward to restrict or ban the usage of tobacco? Is it because of the huge income associated with these products and the multinational giants associated with this? Looks like the whole world is favouring a global killer- a true disaster for humankind!

Recent findings suggest a completely new way of how cancer cells spread around the body (metastasis).

• Recently, UK based researchers found out that blocking the activity of the sodium leak channel non-selective protein NALCN in cells in mice with cancer triggers metastasis
• Surprisingly, they discovered that this process is not only restricted to cancer, as this process was observed in normal healthy cells as well.
• When the researchers removed NALCN from mice without cancer they observed that the healthy cells leave their original tissue and travel around the body and joined other organs. Thus, healthy cells from the pancreas migrated to the kidney where they became healthy kidney cells. This suggests that metastasis isn't an abnormal process limited to cancer as previously thought, but is a normal process used by healthy cells that has been exploited by cancers to migrate to other parts of the body to generate metastases.
• Among human cancers, NALCN loss of function mutations were enriched in gastric and colorectal cancers.
• Deletion of NALCN from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumour incidence, but markedly increased the number of circulating tumour cells (CTCs) and metastases.
• Treatment of these mice with gadolinium, a NALCN channel blocker similarly increased CTCs and metastases.

NALCN controls cell shedding from solid tissues independent of cancer and this finding gives insight in to the processes that governs how cancer cells spread. This discovery has got a great potential in developing new target for antimetastatic therapies, that may help to prevent the mechanism from triggering cancer spreading in patients.

Evolutionary origin behind Laughter and Humour

Laughing brings a sense of well-being. Did you ever thought of what makes an individual laugh? and also why we are drawn to people who make us laugh?

There are several theories behind this phenomenon of what makes one laugh

• Theories include transgression (something prohibited), puncturing a sense of superciliousness or superiority (ridicule), and incongruity – the presence of two incompatible meanings in the same situation
• Recently Carlo Bellieni come up with an explanation based on his study that laughter is a tool nature may have provided us with to help us survive !!
• Main aim of his study was to determine what causes humour, and secondarily, to find out why rhythmic laughter is its expression.
• He analysed the characteristics of humour and laughter, their effects on health and social behaviour, their correlations with several areas of the brain and ultimately their health benefits.
• Then, he described the features of laughter, its rhythmic shape and its correlations with other rhythmic human behaviours
• According to him the most plausible theory for humour could be condensed into three main steps: (a) it needs a situation that seems odd and induces a sense of incongruity (bewilderment) (b) the worry or stress the incongruous situation has provoked must be worked out and overcome (resolution) and (c) a potential all-clear signal to alert bystanders (relief) that they are safe (or) not all incongruities provoke humour, but just those that introduce something stiff and stereotyped into a vital and fluid event
• Laughter could well be a signal people have used for millennia to show others that a fight or flight response is not required and that the perceived threat has passed. That’s why laughing is often contagious: it unites us, makes us more sociable, signals the end of fear or worry

Laughter is the stigmatization of this unnatural incongruity, through its loud and rhythmic shape, as a sort of signal of ceased alert after the shock induced by what seems hazardous to the fluidity of life. At the end of the day, laughter is life sustaining!!

Epigallocatechin gallate (EGCG) can disaggregate protein knots in the brain that cause Alzheimer’s disease.

• UCLA Scientists have used a molecule found in green tea, EGCG, to identify additional molecules that could break up protein (tau) tangles in the brain thought to cause Alzheimer's and similar diseases.
• A recent publication by Seidler and co-workers describe how EGCG cracks tau fibers layer by layer. They also show how they discovered other molecules likely to work the same way that would make better potential candidates for drugs than EGCG, which can't easily penetrate the brain.
• In this study Seidler and co-workers have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure.
• The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define Alzheimer’s disease.
• Treating the EGCG binding position as a pharmacophore, they computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro.

This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases. The finding opens up new possibilities for fighting Alzheimer's, Parkinson's and related diseases by developing drugs that target the structure of tau fibers and other amyloid fibrils.

A bioelectronic mask that can sense the presence of airborne virus has been developed.

• A new mask outfitted with electronics that can detect SARS-CoV-2 and other airborne viruses has been developed by Wang and co-workers and reported recently in the journal “Matter”
• For rapidly diagnosing respiratory infectious diseases, a wearable electronics capable of detecting viruses directly from airborne media is crucial.
• Wang and co-workers developed a wearable bioelectronic mask device integrated with ion-gated transistors for testing viral proteins
• A stretchable ionic gel synthesized by a two-solvent system works as a dielectric layer for the ion-gated transistors. This device can detect trace liquid samples and gaseous media samples
• Based on the sensitive gating effect of ion gels, the aptamer-functionalized transistors can measure trace-level liquid samples (0.3 μL) and even gaseous media samples at an ultra-low concentration
• The special sensor in the mask reacts to the presence of viral proteins in the air and attached it to a face mask. The sensor could detect just a fraction of a microliter of these proteins (eg: a cough might contain 10 to 80 times)
• Once a pathogen is detected, the sensor-mask combo will sent a signal to the researchers informing them of the virus’s presence
• Advantages of this device is that (a) it has a low detection limit (0.1 fg/mL) and (b) a rapid response time of 10 minutes
• Ultimately, researchers plan for such signals to be sent to a wearer’s phone or other devices

This technology facilitates real-time on-site detection of surrounding air. Face mask thus developed is light and wearable and which allows users to wear it anytime, anywhere. This bioelectronic mask is a versatile detection platform for various respiratory infectious diseases. Hope this mask may serve as an early warning system to prevent outbreaks of respiratory infectious diseases.

A Precision treatment for Pancreatic ductal adenocarcinoma is on the way!

Mayo Clinic researchers identified a gene marker that may lead to a more effective personalized treatment for Pancreatic ductal adenocarcinoma.

• Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal cancers.
• A promising FDA-approved treatment option for standard maintenance therapy for patients with metastatic PDAC who harbour pathogenic germline BRCA1/2 mutations is Poly-ADP-ribose-polymerase inhibitors (PARPi).
• Since only about 10 percent of patients with PDAC harbour pathogenic mutations of the homologous recombination (HR) genes, most of the patients miss out this promising treatment strategy.
• In a recent study Zeng and co-workers identified a protein - METTL16 that may be a new biomarker for PARPi treatment. They observed that PDAC with elevated expression of METTL16, may benefit from PARPi treatment.
• METTL16, belongs to a family of factors that regulate RNA methylation, whose function in DNA repair is still not clear.
• These researchers found that METTL16 expression correlated with accumulated DNA damage in a PDAC microarray. Thus elevated METTL16 may result in HR DNA repair defects, which may lead to accelerated aging, disease or increased risk of cancer.
• They showed in this study that METTL16 suppresses DNA repair via interaction with a key DNA repair nuclease called MRE11.
• METTL16 unexpectedly bound with MRE11 not through direct protein to protein interaction but through RNA.
• Because METTL16 is highly expressed in a subset of PDAC and inhibits HR, PDAC cells with high METTL16 expression showed increased sensitivity to PARPi in both cellular and mouse models, especially when combined with gemcitabine.

These findings suggests that in addition to PDAC with BRCA1/2 mutation, PDAC without BRCA1/2 mutation, but with elevated expression of METTL16, may also be a target for PARPi treatment. This observation opens up a ray of hope for lots of patients suffering with PDAC. Thus a combination of PARPi with gemcitabine could be an effective treatment strategy for PDAC with elevated METTL16 expression.

CAR-T therapy: Why only some patients respond well to this therapy?

CAR T_reg cells the real culprit !!

• Recently, in the last five years the treatment of blood cancers has dramatically improved by a new type of cancer immunotherapies called CAR-T (Chimeric antigen receptor T cells) cell therapy.
• CAR-T therapy involves engineering a patient’s own T cells in the lab to fight against cancer cells and then infusing them back into the patient.
• "axi-cel" and "tisa-cel", are the two CAR-T therapies approved by the FDA, in 2017 and 2018. They both target the CD19 protein on the surface of cancer cells, and have similar success rates in the clinic.
• However, this therapy cures only 40 percent of patients with otherwise incurable lymphoma. Rest of the 60% patients experience disease progression, and neurotoxicity remains a challenge in them

Why such difference in response was perplexing scientist for the last few years!!

• A recent study reported by using single-cell RNA-sequencing, Good and co-workers studied how the CAR-T cells from the therapies changed over time i.e. from before infusion to the patients' blood to a week after treatment
• They found out that most CAR-T cells in patient blood after the therapy originated from a particular variety of T cells that contribute to the immune system’s memory of specific antigens
• These T cells were also more abundant in patients who responded well to the therapy compared to those who didn’t. The therapy led to a greater mixture of T-cell types. This gave a clue now to the researchers about which cell type is playing a role in relapse. Those patients who did not respond to therapy, showed more of regulatory T cells
• Single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity
• Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells
• Thus there is a clear connection established between higher CAR TReg cells in circulation to clinical progression of the disease and less severe neurotoxicity

This study suggests CAR Treg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and the removal of CAR Treg from the engineered cells lower the chance of relapse. Thus we can hope that these findings will improve the outcome of CAR-T cell therapy

"Rules and Steps" to the genetic evolution of cancer cracked

• p53 gene mutation is known to be present in more than 50% of all cancers and the protein made from p53 are termed as “tumour suppressor” proteins and its overexpression is reported to have a twofold increased risk for malignant transformation
• Long since we considered p53 as the “guardian of the Genome”, there were lot of unanswered questions surrounding the p53, as how this p53 guards our genome and how its mutation leads to progression of cancer?
• p53 inactivation facilitates genomic chaos and the extrapolation of the order of events from bulk sequencing data frequently positions TP53 mutations early in progression time, earlier than other genomic rearrangements
• However, the sequence of events that happens after TP53 inactivation and their relationship with the biological alterations in sequential cancer progression has not been established
• Scientists so far could not fully understand the effect of p53 in cancer and predominantly the effect of p53 on genome, mainly due to the nonavailability of appropriate human cancer samples as well as due to the lack of good laboratory animal models
• To unravel this mystery, a recent study published in Nature by Baslan and co-workers developed an appropriate mouse model that allows detection of genetic changes as initial cancer cells conversion from a benign to a malignant state
• They observed a deterministic behaviour with four sequential phases in cells after p53 inactivation: (1) Trp53 loss of heterozygosity (2) deletion accumulation (3) doubling of genome (4) appearance of gains and amplifications
• This study clearly shows that the loss of p53 is not simply an opening of genetic chaos but, allows deterministic pattern of genome progression
• This observation of a set of "rules" to the genome progression of tumours suggests new strategies in treating cancer

Currently most of the targeting drugs for cancer aim at the amplified genes in tumours, which are acquired late in tumour progression, thus killing only some cancer cells and leaving others untouched. Thus a more effective way of treating cancers might be to target the initial step in cancer progression after p53 inactivation, i.e. gene deletions, than the late step of gains and amplifications. Since we know the sequential phases in cells after p53 inactivation, exploiting such “Rules and steps” associated with cancer development or genetic progression of tumours might ultimately help in checking the cancer progression.

Humans have more voice control: A progressive event in human evolution

A recent study reveals that humans do not have vocal membranes near their vocal cords!!

Crying baby, a blaring adult or a voice cracks of a teenager could have sounded shrill all the time, but that’s not the case in real world situation. Why?

• Human speech and language are extremely multifarious, comprising of a large number of sounds.
• It’s clear that the human phonal apparatus, the larynx, has developed the capability to generate a wider range of sounds.
• Previous studies revealed that there is similarity between the larynx of humans and other primates.
• In a recent study to characterize the sound production in the larynx, Nishimura et al. used a combination of anatomical, phonal and modelling approaches.
• They found out an interesting fact that our larynx are relatively simple than other primates and this simplified larynx allows clearer sound production with less aural chaos.
• According to their observation humans don’t have vocal membrane a small bits of tissue above the vocal cords. This unique anatomy of humans helps in controlling their voices well enough to produce the sounds.
• Vocal membrane act like a reed in a clarinet that makes some animals to shout loud and make sharp voice. In this study by using imaging techniques such as MRI and CT scans researchers revealed that vocal membrane is present in 43 different primate species, except for human beings.
• This finding points towards a progressive event in human evolution.

This evolutionary loss of vocal membrane allows humans to avoid the spontaneous nonlinear phenomena and acoustic chaos in their communication, which is a common phenomenon in other primates. This loss of vocal membrane helps human larynx to produce stable, harmonic-rich phonation.

Will Multiple sclerosis become a historical disease?

Recent studies points out the role of virus in instigating Multiple Sclerosis when the Central Nervous System (CNS) gets caught in the cross hairs of an immune response to the virus’s attack.

What is Multiple Sclerosis (MS)?

• MS is a potential debilitating disease of the brain and spinal cord affecting 3 million people globally.
• This is an auto-immune disease, which results in the demyelination. i.e. this disease causes damage to the protective covering (myelin sheath) that surrounds nerve fibres.
• There's no cure for multiple sclerosis. However, treatments can help speed recovery from attacks, modify the course of the disease and manage symptoms.
• The cause of multiple sclerosis is unknown.
• However, some factors are thought to increase the risk of developing MS. This include age (usually between 20-40), sex (woman are 2-3 time more likely than men), Family history, certain infections (including Epstein-Barr), race (high incidence among Northern European descents), climate (more in temperate region), Vitamin D and low exposure to sunlight, certain auto-immune diseases (thyroid disease, pernicious anemia, psoriasis, type 1 diabetes or inflammatory bowel disease) and smoking

Will Epstein-Barr virus infection instigates MS and How ?

• Recent studies throw light in to the role of Epstein-Barr virus in instigating MS.
• In March 2000, a Harvard epidemiologist Alberto Ascherio published research exploring the link between Epstein-Barr virus and MS. He and his collaborator Mette Munch (Denmark), analysed data from eight studies suggesting that MS patients are more likely to have had an Epstein-Barr infection than those without MS.
• But there was no proof for the role of virus as getting that proof is really difficult because nearly everyone has been infected with Epstein-Barr virus, yet very few have MS.
• The researchers got access to repeated blood samples from more than 10 million individuals and found such a group of individuals who had never been infected with Epstein-Barr virus from the US Military Department of Défense Serum Repository.
• Then over a 20-year span, 801 people whose blood was tested were diagnosed with MS. 35 of those people had no signs of Epstein-Barr virus infection in their first blood sample.
• People infected with the virus were 32 times as likely to develop MS as uninfected people.
• Lanz, Robinson and their colleagues found hints of how Epstein-Barr virus could spark nerve damage
• Antibodies from some MS patients attach to key viral protein, called EBNA1 as well as to a protein of CNS, GlialCAM. This helps Epstein-Barr virus persist in the body for life, hidden away inside B cells .
• From the study it is observed that, EBNA1 immunization exacerbates disease in a mouse model of MS and anti-EBNA1 and anti-GlialCAM antibodies were prevalent in patients with MS.

This study provide a mechanistic link for the association between MS and EBV. This findings could guide the development of new therapies for MS.

Langya virus: Another pathogen from China

A novel virus detected in dozens of people in eastern China, named Langya henipavirus. Currently, as per the experts opinion there is nothing to worry because the virus doesn’t seem to spread easily between people, nor is it fatal.

What is Langya henipavirus (LayV)?

• LayV belongs to a genus of viruses called henipaviruses, that are naturally harboured in fruit bats.
• LayV is closely related to two other henipaviruses known to infect people — Hendra virus and Nipah virus.
• Hendra virus was first identified in 1994 in Australia and is known to infect humans and horses. The Nipah virus was first identified in 1999 in Malaysia and is known to infect humans and cause high fatality rates.
• Recently a group of people with fever and a recent history of animal exposure were being monitored in eastern China. LayV – was identified in a throat swab sample from one individual and a subsequent analysis has revealed 35 known cases of LayV, mostly in farmers. These infected people is from the Shandong and Henan provinces of eastern China between December 2018 and May 2021.

Origin of Langya Virus

After testing 25 species of small wild animals for virus, researchers found out that 27% of the 262 shrews they surveyed had detectable levels of LayV, suggesting shrews may be the natural reservoir of these virus’. Researchers detected virus in other animals like dog (5%) and goats (2%) also .

Is Langya virus another trepidation?

• So far, with the smaller sample size, there is no evidence of close contact with an infected person being a reason for the transmission of the virus. This suggests that the virus doesn’t pass from person to person, but rather animal to person.
• No death reported so far from Langya virus infection.

All these findings are hinting to the fact that, there are lots and lots of undiscovered pathogens or large number of undetected infections spilling over from the wildlife to humans. Some of the questions that ponder now are (a) Is this new Langya virus and the infection risk currently concentrated in China alone? (b) Or is this infection risk - widespread ?

In my opinion studies are needed to establish the geographic rage of this virus in shrews as well as in humans. There need to be a systematic study to understand how humans gets infected with these viruses from the wild life?

A forgotten nutrient and a molecule that made the world

A statement of Polish alchemist Michael Sendivogius in 1604 is really striking: "Man was created of the Earth, and lives by virtue of the air; for there is in the air a secret food of life...". That means Sendivogius hypothesised the presence of oxygen much before its discovery.

The credit for the discovery of oxygen in the latter half of 18th century is to many. Few names that pops up in this context are (a) English chemist Joseph Priestley (b) Swedish druggist Carl Scheele and (c) French chemist Antoine Lavoisier, each contributing in different ways.

Appearance of Oxygen in atmosphere

About 4.54 billion years ago through accumulation from the solar nebula, Earth was created. That primeval atmosphere was devoid of oxygen. i.e. there was no free O2 at the time of the formation of earth.

The diatomic oxygen that was present was essentially locked up in rocks and in water, and some 4 billion years ago the atmosphere was thought to have contained oxygen at just one part in a million.

The initial single celled organisms existed under anoxic conditions and were overtaken by cyanobacteria, which appeared up to 3 billion years or more ago and, importantly, generated oxygen through photosynthesis.

Under anoxic condition, microorganisms that lived in deep seas survived through sulphur respiration – i.e. anaerobic respiration with sulphur

Approximately 2.45 billion years ago oxygen began to emerge in the atmosphere in significant quantities at what is termed the “Great Oxidation Event”.

Oxygen levels increased gradually, and possibly then fell, until around 700 million years ago when a further sharp increase occurred.

It is believed that the current oxygen level of 21% established since approximately 600 million years ago.

A forgotten nutrient

According to Oxford English dictionary, Oxygen is "a substance that provides nourishment for the maintenance of life and for growth”. This is confusing. Few questions pops up in my mind. (a) Is oxygen a nutrient? (b) whether oxygen has been included as a nutrient by the nutritionists? (c) what exactly is a nutrient according to the current concept?

Mitochondrial respiration and oxidative phosphorylation cannot take place without Oxygen. Thus gaseous oxygen is essential for all aerobic animals. Still oxygen is not considered as a "nutrient”.

According to Oxford English Dictionary, nutrient is defined as "a substance that provides nourishment for the maintenance of life and for growth”. Where as according to Webster’s dictionary a nutrient is "any substance or matter that is needed for the life and growth of living things”.

According to these definitions, there is no doubt that oxygen is definitely a nutrient. But the current concept about a nutrient is perplexing!! i.e. any substance that is consumed through the mouth and is absorbed from the GI tract is regarded as nutrients. Since oxygen is delivered through the nose and lungs (or gills in the case of aquatic animals), this is not regarded as a nutrient in humans and other higher animals.

Oxygen which is obtained from the air surrounding us enters through our nose constantly throughout our life time and doesn’t require any processing. Once when oxygen is deficient, various disease conditions may arise (deficiency at high altitudes, deep diving, ecological variations, lung diseases etc.). Deficiency may also lead to toxicity at normal levels and we can argue that a recommended dietary allowance (RDA) is there to potentially maintain the energy balance.

RDA is based on the need to set standards for the intake of nutrients and we may think that in case of oxygen this may not be possible. But "RDA" for oxygen can be determined essentially by the need (eg: level of physical activity, growth phase, pregnancy, lactation etc.) to maintain energy balance so that intake and expenditure are equal, especially in those of normal body weight.

We can conclude by saying that oxygen is an important nutrient and indeed an essential one needed in large quantities along with other conventional nutrients. Thus oxygen is really "A forgotten nutrient and a molecule that made the world".

A single shot of monoclonal antibody that could provide months-long protection against malaria has been developed. This monoclonal antibody at a low dose either subcutaneously or intravenously is reported to prevent Malaria.

What is Malaria?

• Female Anopheles mosquitoes-borne life threatening disease caused by Plasmodium parasites.
• There are 5 parasite species that cause malaria in humans. Out of the 5 parasite species, P. falciparum and P. vivax pose the greatest threat. P. falciparum is the deadliest and most prevalent malarial parasite on the African continent. P. vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa.
• Symptoms of malaria include fever, headache and chills, usually appear 10–15 days after the infective mosquito bite. If left untreated, P. falciparum malaria can progress to severe illness and death within a period of 24 hours.
• Infants, children under 5 years of age, pregnant women and patients with HIV/AIDS, as well as people with low immunity moving to areas with intense malaria transmission such as migrant workers, mobile populations and travellers are at considerably higher risk of contracting malaria and developing severe disease.
• The disease affected 241 million people and an estimated 627,000 deaths worldwide in 2020.
• Nearly 32 countries in Sub-Saharan Africa continues to bear disproportionately high share of global malaria burden with nearly 95% of all malaria cases and 96% of malarial deaths. Children under the age group of 5 accounted for about 80% of all malaria deaths.

Prevention of Malaria

• An effective vector control and the use of preventive antimalarial drugs are the WHO-recommended malaria prevention tools and strategies.
• The 2 core vector interventions include insecticide-treated nets and indoor residual spraying.
• Preventive chemotherapy is the use of medicines, either alone or in combination, to prevent malaria infections and their consequences.
• The RTS,S/AS01 vaccine (Mosquirix), recommended by the WHO in October 2021 for widespread use in infants, provides only partial protection against clinical malaria, with a reported vaccine efficacy of 36.3% after 4 years of follow-up
• Monoclonal antibodies offer a new approach to passive protection against malaria over a prolonged period. It has been shown to prevent Plasmodium falciparum malaria at the pre-erythrocytic stage that precedes clinical blood-stage infection by neutralizing the infecting sporozoites through binding to the major P. falciparum circumsporozoite protein, an essential mediator of infection.
• There was a previous report in Nature, on the safety and efficacy of a highly potent human antimalarial monoclonal antibody, CIS43LS. This antibody targets the junctional region of the P. falciparum circumsporozoite protein. CIS43LS provided protection against malaria and was reported safe in all the nine participants who received IV doses
• Recently The New England Journal of Medicine reported a next-generation antimalarial monoclonal antibody (L9LS), which was approximately three times more potent than CIS43, the parent antibody of CIS43LS, in preclinical models.
• In the current trial L9LS, a next generation antibody, was assessed for its safety, pharmacokinetics, and protective efficacy.
• In the clinical trial, 15 of 17 participants who received the monoclonal antibody L9LS did not become infected after being exposed to mosquitoes with malaria in the lab.
• L9LS targets highly conserved, minor NVDP repeats on the P. falciparum circumsporozoite protein and then achieves both cytolytic destruction of sporozoites and prevention of hepatocyte infection by limiting parasite (sporozoite) egress from liver sinusoids.
• In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns.
• L9LS has an estimated half-life of 56 days which is almost three times that of its predecessor, CIS43LS..

Thus sporozoites were unable to resist L9LS Juggernaut. This new approach in the prevention and elimination of malaria is a great boon. Hope this new drug can reduce the illness and death associated with malaria among infants and young children globally.

CRISPR Therapeutics: How safe is “safe” at the moment?

• CRISPR therapeutics and its agathokakological effect is in news a few days ago.
• A recent study reported an oncogenic risk, as a result of frequent aneuploidy and chromosomal truncations in human T cells targeted using CRISPR-Cas9 and clinical gRNA sequences. This finding accentuates the need for extenuation strategies in order to allow the safe application of nucleases in adoptive immunotherapy.

What is CRISPR?

• CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) allows genetic material to be added, removed or altered at particular locations in the genome. Several approaches to genome editing have been developed.
• Emmanuelle Charpentier and Jennifer Doudna was awarded the Nobel Prize (Chemistry) in 2020 for the discovery of this gene technology’s sharpest tools, the CRISPR/Cas9 genetic scissors.
• CRISPR-Cas9 was adapted from a naturally occurring genome-editing system that bacteria use as an immune defence. When infected with viruses, bacteria capture small pieces of the viruses’ DNA and insert them into their own DNA in a particular pattern to create segments known as CRISPR arrays.
• The CRISPR arrays allow the bacteria to “remember” the viruses or closely related ones. If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays that recognize and attach to specific regions of the viruses’ DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.
• This technology proved strikingly efficient in treating diseases including cancer, liver diseases, genetic syndromes etc.

What is adoptive immunotherapy?

• A type of immunotherapy in which T cells are given to a patient to help the body fight diseases, such as cancer. This therapy is also called as adoptive cell therapy and T-cell transfer therapy.
• In cancer therapy, T cells are usually taken from the patient's own blood or tumor tissue, grown in vitro or modified in vitro to make them better able to target the patient's cancer cells and then given back to the patient to help the immune system fight the cancer.
• Types of adoptive cell transfer include chimeric antigen receptor T-cell (CAR T-cell) therapy and tumor-infiltrating lymphocyte (TIL) therapy. A recent study published in Nature Biotechnology by Barzel and his team (30th June, 2022) reported an oncogenic risk and shed light on potential risks in the use of CRISPR therapeutics
• In 2020, University of Pennsylvania used this CRISPR technology for the first time on T-cells in an approved clinical trial.
• They took T-cells from a donor and expressed an engineered receptor targeting cancer cells, while using CRISPR to destroy genes coding for the original receptor. This technique becomes cheaper, more accurate and more efficient than other genome editing methods.
• However, the technique raises ethical concerns because of the potential of changing human genomes.
• Current study by Barzel and his team identifies risks in the use of CRISPR therapeutics. They investigated the impact of this technology on T-cells and found out that there is significant loss of genetic material (i.e. up to 10% of the treated cells). They made it clear that such loss can lead to destabilization of the genome, which might cause cancer.
• Barzel and his team examined whether the potential benefits of CRISPR therapeutics might be offset by risks resulting from the cleavage itself, assuming that broken DNA is not always able to recover.
• They repeated the 2020 Pennsylvania experiment to examine the extent of potential damage by cleaving the T-cells’ genome in exactly the same locations – chromosomes 2, 7, and 14 of the human genome’s 23 pairs of chromosomes.
• Then they analysed each cell separately and measured the expression levels of each chromosome in every cell by using single-cell RNA sequencing. They observed a significant loss of genetic material in some of the cells.
• Four days after transfection, they found loss of chromosome. For eg: when chromosome 14 had been cleaved, about 5% of the cells showed little or no expression of this chromosome. When all chromosomes were cleaved simultaneously, the damage increased, with 9%, 9.9% and 3% of the cells were unable to repair the break in chromosomes 14, 7 and 2 respectively. They validated the aberrations using fluorescence in situ hybridization and digital droplet PCR.
• Aneuploidy was associated with reduced proliferation, induced p53 activation and cell death. Aneuploidy and chromosomal truncations are, thus, frequent outcomes of CRISPR–Cas9 cleavage that should be monitored and minimized in clinical protocols.

Based on these findings, we need to be cautious that extra care should be taken when using CRISPR therapeutics. Further study is warranted to understand (a) how can we reduce the production of damaged cells or (b) how can we identify the damaged cells and remove them before the material is administered to the patient.

Men growing older may have a greater risk for heart failure and cardiac fibrosis

• It is observed that when men age, they can lose some of those Y chromosomes and such mosaic loss of the Y chromosome in blood cells is associated with various medical conditions such as Alzheimer disease and cancer.
• Normal males have 46 chromosomes with two sex chromosomes X and a Y (46, XY).
• Y chromosome is the smallest of the chromosomes and contains very few genes.
• Y chromosome’s function is not fully understood. It has been long considered as a "genetic wasteland" and beyond the biological sex determination, there is very little understanding of its functional role.
• Till now there was no reports suggesting the loss of Y chromosome and cardio vascular diseases.
• Recently (14^th July, 2022) Sano et al., published their work in Science found out that the loss of Y chromosomes in White Blood Cells is associated with increased risk of heart failure and cardiac fibrosis in men.
• Sano and co-workers modelled male mice who were reconstituted with bone marrow cells lacking the Y chromosomes. They found out that those mice had increased mortality and age-related profibrotic symptoms, including decreased cardiac function.
• Cardiac macrophages lacking Y chromosome exhibited polarization towards more fibrotic phenotype.
• They also observed that when those mice where treated with transforming growth factor ß1-neutralizing antibody they were benefited.
• Investigators also were able to validate the causal effect in mouse via epidemiological studies in humans and found that mosaic loss of the Y chromosome was a new significant risk factor for death from cardio vascular diseases in men.
• They found that men with mosaic loss of the Y chromosome in their blood at the start of the study displayed an approximately 30% increased risk of dying from heart failure and other types of cardio vascular diseases during the 11 years of follow-up.

Together with the mice study and the prospective study, its clear that hematopoetic loss of Y chromosome contributes to fibrosis, cardiac dysfunction and mortality in men. The connection between mosaic loss of the Y chromosome and fibrosis is really interesting, especially given the new treatment strategies for heart failure, pulmonary fibrosis and certain cancers that aim to counteract the onset of fibrosis. Men with such loss of Y chromosome could be a patient group that responds particularly well to such targeted therapies/treatments.

Orange blossom smell of Zika/Dengue infection lures mosquitos

• Mosquito broadcasted flaviviruses can influence host skin microbiota to produce a fragrance that attracts mosquitoes.
• Mice and humans infected with Zika and dengue emit acetophenone, a mosquito-attractor

What is Zika and Dengue Infection?

• Zika virus disease is caused by a virus transmitted primarily by Aedes mosquitoes, which bite during the day. Zika virus is a mosquito-borne flavivirus that was first identified in Uganda in 1947 in monkeys. It was later identified in humans in 1952 in Uganda and the United Republic of Tanzania.
• Symptoms of Zika virus infection are generally mild and include fever, rash, conjunctivitis, muscle and joint pain, malaise or headache.
• Dengue is a viral infection transmitted to humans through the bite of Aedes mosquitoes. This infection is caused by mosquito-borne flavivirus.
• Symptoms of dengue virus infection are high fever, severe headache, pain behind eyes, muscular pain, nausea.
• Severe dengue, first recognized in the 1950s during dengue epidemics in the Philippines and Thailand, is a potentially fatal complication resulting in plasma leakage, fluid accumulation, respiratory distress, severe bleeding, or organ impairment.

A recent study by Zang et al., (7th July, 2022) observed that a volatile - Acetophenone, from the skin microbiota of flavivirus-infected hosts promotes mosquito attractiveness.

• They found out that mice infected with dengue or Zika viruses and people infected with the virus emits an orange blossom smelling chemical- Acetophenone, that tempts hungry mosquitoes.
• Mice infected with dengue or Zika viruses give off approximately 10 times more acetophenone and attract more mosquitoes than uninfected animals.
• Aedes mosquitoes preferred to seek and feed on mice infected by dengue and Zika viruses
• Researcher’s found out that Bacillus bacteria on mice were the likely culprits producing the chemical- Acetophenone. An infection stops mice from making an antimicrobial protein called RELMa, allowing the acetophenone emitting microbes to flourish.
• Mechanistically, flaviviruses infection suppressed the expression of RELMa an essential antimicrobial protein on host skin, thereby leading to the expansion of acetophenone producing commensal bacteria and, consequently, a high acetophenone level.
• It is known that RELMα, can be specifically induced by Vitamin A.
• When the researchers fed the infected animals with a derivative of vitamin A -isotretinoin, the animals produced less acetophenone and become less attractive for mosquitos, thus providing a strategy of arboviral control.

This study opens up a possible strategy for reducing the transmission of Zika and dengue infection. Now we need to test the strategy of giving isotretinoin to patients and see whether there will be reduction of transmission in those areas with risk of Zika and Dengue

We are what we eat

The food we eat literally becomes who we are, and influences our physical, mental and even emotional well-being. The composition of the diet, even in the absence of undernutrition and overnutrition, may make a significant contribution to the causation and progression of a number of diseases. It is a known fact that diet is linked to lot of systemic diseases.

As we age there will be a functional shift of immune system towards a pro-inflammatory phenotype. This derangement has been associated with cognitive decline and has been implicated in the pathogenesis of dementia. Since diet has been known to modulate systemic inflammation, a proper diet may be a potential tool to counteract the associated risk for cognitive impairment and dementia.

A recent study by Scarmeas and his team from Columbia University, USA observed that there is a link between diet and the incidence of Dementia. They published this interesting finding in the journal ‘Neurology’

• They found out that people on a diet rich in anti-inflammatory foods like fruits, vegetables, beans and tea or coffee had a lower risk of dementia than those who ate foods that boost inflammation, such as sugar, processed foods, unhealthy fats and red meat

What is Dementia?

• Dementia is a syndrome in which there is deterioration in cognitive function beyond what might be expected from the usual consequences of biological ageing.
• This condition mainly affects elderly population.
• Dementia is not an inevitable consequence of ageing.
• According to WHO, 55 million people live with dementia worldwide, and there are nearly 10 million new cases every year.
• Dementia is currently the seventh leading cause of death among all diseases and one of the major causes of disability and dependency among older people globally.
• Dementia has physical, psychological, social and economic impacts, not only for people living with dementia, but also for their carers, families and society at large.

Scarmeas and his team aimed to explore the associations between the inflammatory potential of diet, assessed with an easily applicable, population-based, biomarker-validated diet inflammatory index (DII), and the risk for dementia in community-dwelling older adults.

• 1,059 individuals (mean age 73.1 years, 40.3% male, mean education 8.2 years) from Greece were included in the study and they completed a questionnaire to determine the inflammatory potential or score of their diet.
• No one had dementia when the study began. (i.e. those with baseline dementia or missing cognitive follow-up data were excluded from the analyses).
• The inflammatory potential of diet was assessed through a DII score that considers literature-derived associations of 45 food parameters with levels of proinflammatory and anti-inflammatory cytokines in the blood; higher values indicated a more proinflammatory diet.
• Consumption frequencies were derived from the detailed food frequency questionnaire.
• Analysis of dementia incidence as a function of baseline DII scores was performed by Cox proportional hazards models.
• Out of 1059 individuals included in the study, 62 of whom developed incident dementia (nearly six percent developed dementia during a follow-up of just over three years).
• Each additional unit of DII score was associated with a 21% increase in the risk for dementia incidence.
• Compared to participants in the lowest DII score tertile, participants in the highest one (maximal proinflammatory diet potential) were 3 times more likely to develop incident dementia.
• Individuals with the lowest dietary inflammation scores were less likely to develop dementia than those with higher ones.
• Individuals with the lowest scores consumed about 20 servings of fruit, 19 of vegetables, 4 of beans or other legumes, and 11 of coffee or tea each week.
• Individuals with the highest scores ate about 9 servings of fruit, 10 of vegetables, 2 of legumes, and 9 of coffee or tea per week.

Thus a higher DII scores (indicating greater proinflammatory diet potential) were associated with an increased risk for incident dementia.

Even though from this study, there is no proof that eating an anti-inflammatory diet prevents brain aging and dementia, but there's a link these researchers could establish between diet and dementia. A longer follow-up is needed to draw any firm conclusions on how inflammatory diet score affects brain health. The exact cause of how dementia is linked to the diet is still an enigma!!

• Recent investigation on the effects of light exposure during sleep revealed potential health hazards.
• The study pointed out that the exposure to light during sleep may likely impairs the cardiometabolic health.

Exposure to artificial light during the night time is a widespread phenomenon. Timing of behaviours and physiological functions of an individual is influenced by light and dark exposure patterns. It has been suggested that the exposure to light in the evening and night is detrimental for human health and well-being (Fonken and Nelson, 2011)

An observational study reported that the artificial light exposure in the bedroom during sleep is associated with obesity in women. This study pointed out that the incidence of obesity is high in those individuals who sleep with televisions or light on in the bed room (Park et al., 2019). This study suggests the negative influence of light during sleep on the metabolic regulation

So far three pathways /mechanisms were proposed to explain the relationship between night-time light exposure and altered metabolic function:

• Via the changes in subjective and objective sleep quality (indicated by actigraphy or polysomnography measures of reduced total sleep time, sleep efficiency, increased wake after sleep onset, reduced amount of slow wave sleep, or increased arousal index)
• via the light-induced changes to the endogenous circadian system, including suppression and phase shifting of the melatonin rhythm
• The effect of light exposure on autonomic nervous system activity, revealed by the increase in cortisol or heart rate (HR) associated with light exposure (during the morning and/or night-time hours as compared to evening hours)

All these previous studies have reported that light exposure during sleep increases HR and decreases HR variability, consistent with increased sympathetic activation. These studies either examined bright light (1,000 lx) over the entire sleep period or lower light levels (50 lx or dawn simulation) early or late in the sleep period

But there is no clear idea so far on how a single night of moderate room light exposure across the entire night-time sleep period on autonomic activation and its impact on metabolic function

Zee and her team in a recent study (14th March, 2022) hypothesized that the room light exposure (100 lx) during habitual night-time sleep is associated with increased insulin resistance the next morning and also there will be reduced sleep quality, suppression of melatonin level, and elevated sympathetic activation during the sleep period. The salient findings of the study are:

• 20 young adults took part in this study (n=20)
• One set of participants (n=10) were in the room light i.e. one night of sleep in dim light (<3 lx) followed by one night of sleep with overhead room lighting (100 lx)
• Second set of participants (n=10) were in the dim light situation. i.e. two consecutive nights of sleep in dim light
• Measures of insulin resistance (morning homeostatic model assessment of insulin resistance, 30-min insulin area under the curve [AUC] from a 2 h oral glucose tolerance test) were higher in the room light versus dim light condition
• Melatonin levels were similar in both conditions
• In the room light condition, participants spent proportionately more time in stage N2 and less in slow wave and rapid eye movement sleep
• Heart rate was higher and heart rate variability lower (higher sympathovagal balance) during sleep in the room light versus the dim light condition
• Importantly, the higher sympathovagal balance during sleep was associated with higher 30 min insulin AUC, consistent with increased insulin resistance the following morning
• These results demonstrate that a single night of exposure to room light during sleep can impair glucose homeostasis, potentially via increased sympathetic nervous system activation
• Finally this study pointed out that avoiding exposure to light at night during sleep may be beneficial for cardiometabolic health

Observations from this study serves as a caution for the many people living in industrialized nations, where light tends to be pervasive. No doubt, the findings from this study is very interesting and useful especially for young adults. By this study can we say for sure that sleeping in darkness will be beneficial for the well-being of all humans?? To me without addressing the following points we cannot say for sure that this will be applicable for everyone.

• Will these findings be applicable to all people with different age groups, as this study was done in 20 young health adults.
• What about people with other disease conditions or with comorbidities?
• What about the long term exposure to such room light condition? Will there be more health hazards?
• What about the artificial light at night on cardiovascular health of people belonging to different sex or ethnicity? Will they differ by sex or ethnicity?

• A recent study shed light on the striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and also in mouse models
• These novel finding provides a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers

What is metastases?

We know that primary tumors are responsible for approximately 10% of deaths from cancer. The remaining 90% of patients are smacked down by cancerous growths that are noticed at sites far aloof from the locations in their bodies where their primary tumors first arose. Thus, the spread of cancer from the place where they first formed to another site is termed ‘metastases’.

These metastases are formed by cancer cells (circulating tumour cells (CTCs) that have left the primary tumour mass and travelled by the body’s motorway i.e. blood and lymphatic vessels - to look for new sites throughout the body where they may found new colonies.

Such nomadic cancer cells are the most treacherous manifestations of the cancer process. When they succeed in founding colonies in distant sites, they often wreak great havoc.

Tumours of certain tissues have a high probability of metastasizing whereas those arising from certain tissues never metastasize. For eg: primary melanomas penetrate to the tissue underlying the skin and metastasize to distant sites in the body is a certainty, whereas basal cell carcinomas of the skin and astrocytomas (glial cell tumour) rarely metastasize.

The invasion-metastasis cascade involves seven distinct steps:

• localized invasiveness facilitating in situ carcinoma cells to breach the basement membrane
• the cells may intravasate into either lymphatic or blood micro-vessels
• transportation of these cancer cells, via the general circulation, to distant anatomical sites, where they may be trapped
• extravasation of cells
• formation of dormant micro-metastases
• micro-metastases may eventually acquire the ability to colonize the tissue in which they have landed
• finally the colonization and formation of a macro-metastasis

The metastatic spread of cancer is achieved by the haematogenous propagation of CTCs. However CTCs are mostly uncharacterized, and it is assumed so far that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults.

A recent study shed light on the striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and also in mouse models.

The research community has been discussing for decades how the body’s circadian rhythm influences cancer. Aceto and his team in a recent publication in Nature (22nd June 2022) highlighted that most spontaneous CTC intravasation events occur during sleep. With this study now it has become clear that “tumours get up when patients are sleeping”,

A person’s circadian clock, controlled by various genes that express specific molecules on a 24-hour timetable, influences many processes in the body, including metabolism and sleep. Since cancer cells are highly mutated, so far researchers believed that cancer cells wouldn’t comply with such a schedule.

Aceto and his colleagues noticed that levels of CTCs in mice with tumors varied depending on the time of day that their blood was drawn. Based on this interesting observation, they collected blood from 30 women hospitalized with breast cancer at two time points - 4 a.m and 10 a.m. To their surprise, they observed that the bulk of the CTCs in the blood samples of patients were almost 80% in the portion collected at 4 a.m., when the patients were resting.

Based on the observation in breast cancer patients, they developed a breast cancer mice model and checked the CTCs during day time and at night. Compared to humans, even though the mice have an inverted circadian rhythm they found that the concentration of CTCs was up to 88 times higher than baseline i.e. when the animals were in their resting state.

Key findings of the study

• Rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability.
• Single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase (patients and mouse models), enabling metastasis proficiency.
• Melatonin, testosterone and glucocorticoids, the key circadian rhythm hormones, dictate CTC generation dynamics. Thus, in consequence, insulin directly promotes tumor cell proliferation in vivo, yet in a time-dependent manner.
• Spontaneous generation of CTCs with a high tendency to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual.

Unusual temperature has been recognized as a sign of disease for millennia

Brain cell function is indisputably temperature-dependent. Direct measurement of brain temperature is difficult or rare due to invasiveness associated with determining. Common practice so far is to assume the temperature of brain to match the core body temperature (about 37°C), by overseeing the clinical importance of brain specific measurements. It is assumed that that brain temperature is maintained within a narrow range. Several reports suggest that a healthy brain temperature may vary over time and also vary between the regions in brain. Research on primates showed that the deep brain structures are warmer than the surface and the brain temperature varies across a 24 hour period.

It is recognized that absolute temperature of brain, its relationship to body temperature and the apparent temperature-sensitivity of brain tissue are frequently altered following injury.

From the studies of brain-injured patients using intracranial probes, direct measurement of temperature from a single locus of brain was known (±0.1–0.3°C). But a comprehensive reference data sheet is not available. Thus the relevance of temperature management in neurocritical care remains highly controversial. Even though there is indisputable clinical significance, the normal range of human brain temperature is unknown.

But now with the help of magnetic resonance spectroscopy (MRS), spatially resolved brain temperature data can be obtained non-invasively. Thus brain thermometry is a powerful research application of MRS.

A recent report by Rzechorzek et al., from MRC Laboratory of Molecular Biology, Cambridge, UK throws light into the temperature of brain. In a prospective study, they recruited 40 healthy adults (20 males, 20 females, 20–40 years) for brain thermometry using MRS. Participants were scanned in the morning, afternoon, and late evening of a single day. They measured the brain temperature variation of all participants during the day and also over the menstrual cycle in females.

• In healthy participants, brain temperature ranged from 36.1 to 40.9°C with a mean brain temperature (38.5±0.4°C) exceeded the oral temperature (36.0±0.5°C). i.e. an average of 2.5°C higher than the oral temperature. This observation logically makes sense, as the brain is more metabolically active.
• Temperature of brain increases with age, most notably in the deep brain regions. i.e. brain is much hotter in the core. The highest temperature readings came from the thalamus, one of the deepest parts of the brain, which may be less cooled by the organ’s blood vessels.
• The study also found that the brain is approximately 0.9°C cooler at night, which might be because there is greater blood flow to the organ when we sleep.
• Another interesting finding that came out of the study was that brain temperature is 0.36°C higher in luteal females relative to follicular females and males (P= 0.0006 and P < 0.0001, respectively). i.e. the brains of the women participated in the study were 0.36°C hotter during the second half of the menstrual cycle, between ovulation and menstruation, compared with the first half, and compared with men.
• The study pointing to a fact that the brain temperature is higher and varies more than what we previously assumed— by age, sex, menstrual cycle, brain region, and time of day.
• Now it is clear that what we were practicing till now may need a revision. Clinicians sometimes try to lower the body temperature of people with brain injuries because they are concerned that high temperatures are harmful, an approach that may need revising!!

The results from this study has major implications for temperature monitoring and management, with daily brain temperature rhythmicity emerging as one of the strongest single predictors of survival after brain injury.

Even though we are trying to study human brain with our own brain - More studies in this direction may help us understand a little bit more on how our brain works?

Monkeypox and things to know

People are concerned now that whether the world is on the verge of another pandemic - Monkeypox? This concern has been driven due to the widespread outbreak of the disease with more than 700 confirmed cases of Monkeypox picking up in 27 countries outside Africa since May 7, 2022.

Among the countries reported this disease so far, Spain, Portugal, Belgium, Canada and England have recorded most of the cases. US also reported few confirmed cases

Patients were presented with flu like symptoms, such as fever, headaches and body aches, as well as profound weakness, back pain, swollen lymph nodes, rashes that erupt into pus-filled blisters, genital and peri-anal lesions, and pain when swallowing.

Key Facts

• Monkeypox is a viral zoonotic disease. i.e., a virus transmitted to humans from animals.
• Symptoms of monkeypox is very similar to those seen in the past in smallpox patients, but clinically less severe.
• Monkeypox virus belongs to the Orthopoxvirus genus of the Poxviridae family.
• The term monkeypox was originated from the initial discovery of the virus in monkeys in 1958 at Statens Serum Institute, Copenhagen Denmark.
• First human case was reported in a child from the Democratic Republic of the Congo in 1970.
• This virus is transmitted from one person to another by close contact with lesions, body fluids, respiratory droplets and contaminated materials such as beddings.
• The incubation period of monkeypox : usually 6 to 13 days (can range from 5 to 21 days).
• Monkeypox typically presents clinically with fever, rash and swollen lymph nodes and may lead to a range of medical complications.
• Monkeypox virus is an endemic virus, especially in the West or Central Africa. (i.e. two clades- West African clade and the Congo Basin (Central African) clade).
• Various animals’ species have been recognized as susceptible to this virus.
• Natural history of the virus, its reservoirs and how virus is circulated in nature is still uncertain!!
• Eating poorly cooked meat/animal products of infected animals is a possible risk factor.

Current outbreak

• But the current concern is the reporting of monkeypox from non-endemic countries.
• According to WHO, between 13 May and 2 June 2022 there are 780 confirmed cases from 27 non-endemic countries.
• Endemic countries also reporting an ongoing monkeypox outbreaks between January to June 2022 (1408 suspected cases, 44 confirmed cases including 66 deaths were reported from seven endemic countries)
• To date, the clinical presentation of confirmed cases from non-endemic countries has been variable.
• Many cases are not presenting with classical monkeypox symptoms.
• Current presentation of patients with genital or peri-anal rash in many cases suggests close physical contact as the likely route of transmission during sexual contact.
• According to Dr. David Heymann, WHO expert, the leading theory behind the origins of the current cluster of cases is the sexual transmission at two festivals in Europe, which may have sparked the world’s escalating monkeypox outbreak
• So far, cases in this outbreak have been mild.

How to stop this outbreak? Any medication available?

• Best way to check the spread is by isolating infected people and tracing close contacts. Also avoid close contact with lesions, body fluids, respiratory droplets and contaminated materials of infected people.
• In Europe and the United States, close contacts of infected people may be vaccinated with either ACAM2000, an older vaccine against smallpox or with a newer vaccine called Jynneos, approved by US FDA in 2019 for smallpox and monkeypox.
• Two antiviral drugs, called brincidofovir and tecovirimat, developed against smallpox might be used to treat severe monkeypox cases
• Most of the evidence that the drugs will work against monkeypox come from animal studies. Even though some adverse effects of the drug brincidofovir has been reported from UK (May 24 in Lancet Infectious Diseases)
• People previously vaccinated against smallpox may still have some protection against monkeypox.
• This outbreak is really mild so far.

Dogs can detect COVID-19 within seconds

• A recent large study (n=335) by Grandjean et al., 2022 showed that trained detection dogs are as trustworthy as laboratory tests for detecting COVID-19.
• By rewarding them with toys (usually tennis balls), dogs from the French fire stations and from the Ministry of Interior, UAE were trained in coronavirus detection.
• Dogs were trained to pick out COVID-19 cases from sweat samples collected from the underarms of patients.
• Depending upon the dog’s experience with odour detection, it took nearly three to six weeks.to train a dog to sniff out COVID-19.

Experimental Testing Protocol used in the study

In dedicated rooms, line-up consisting of 10 olfaction cones was placed. Dogs were allowed to sniff each cones, were different samples were placed. Once the dogs had performed the line-up, the cones and the background were cleaned with high pressure vapor and new samples were placed. For each new sample placement, the person in charge had to wear new disposable gloves and a mask in order not to contaminate the olfactory environment. Each line-up was sniffed by at least two dogs in order to mimic a real operational situation. Positive marking by a dog is by sitting in front of a cone containing a positive sample.

Results

• This non-invasive procedure may be even better than PCR tests for recognizing patients without symptoms.
• Study included 143 symptomatic and 192 asymptomatic patients (A total of 335 patients with an age group between 25-49 years)
• 109/335 participants tested positive on nasopharyngeal RT-PCR either in symptomatic (78/ 143) or in asymptomatic participants (31/192).
• Overall sensitivity of canine detection was 97% and even reached 100% in asymptomatic individuals compared to nasopharyngeal swab RT-PCR. The specificity was 91%, reaching 94% for asymptomatic individuals.
• The sensitivity of canine detection was higher compared to nasopharyngeal antigen testing 97% versus 84%, (p = 0.006). But the specificity was lower (90% versus 97% p = 0.016).

Inhalation of nanoparticle can have huge impact in human health

• One nanometre is 10^-9m or one millionth of a millimetre. As a comparison: a human hair is approximately 70,000 nm in diameter, a red blood cell is approximately 5,000 nm wide
• Nanoparticles on exposure to tissues and fluids of the body, can immediately adsorb onto their surface (adsorption process will depend on the surface characteristics of the particles).
• Reduction in size to the nanoscale level results in an enormous increase of surface to volume ratio. Thus relatively more molecules of the chemical will be present on the surface, thus enhancing the intrinsic toxicity.

In early 2000 when Michael Crichton, one of my favourite authors, published ‘Prey’, I finished reading the whole novel in one sitting. After finishing the novel my thought was, when Steven Spielberg will adapt the book into another blockbuster film? My wish was to see that story in a movie but definitely not in the real world. But today I am sceptical….will that happen to us?

Let’s have a look at the atmospheric nanoparticles and its harmful effects on human health.

A particle with a diameter of 0.1–10µm can dwell in the atmosphere for approximately a week than coarser particle, which is removed by settling. Smaller particles can only be removed via diffusion and coagulation (Bakshi et al., 2015; Slezakova et al., 2013). Thus fine particles such as nanoparticles have a higher retention time in the atmosphere and this makes it difficult to remove from the atmosphere. The consequence of this is – HUMAN HEALTH HAZARD.

In nature nanoparticles originate from the exhaust of vehicles, combustion reactions, forest fires and industrial emission. Most of the anthropogenic nanoparticles are made up of carbon, silicon, metal, or metal oxides. Some of the reports are listed here:

• Other than tropospheric ozone, nanoparticles are reported to be toxic to plant species (Giorgetti, 2019).
• Sajid et al., 2015, reported the adverse effects of nanoparticles on human health as a result of its entry via skin, lungs and by ingestion.
• Nanoparticle exposure has direct relationship with the development of neuro-degenerative disorders and defects in apoptosis (Chen et al., 2016).
• Across the world, Asthma and COPD affects accounts to 300 and 210 million people respectively. Studies pointing out to exposure of atmospheric nanoparticles as a reason for such conditions in humans (Yhee et al., 2016).
• Nanoparticles cause acute and chronic problems ranging from asthma and metal fume fever to fibrosis, carcinogenesis, and other chronic lung maladies (Bakand et al. 2012).

Among the reported in vivo studies regarding the harmful effects of nanoparticles to almost all systems of the body, few of them are listed here:

• Affect Reproductive system: Nanoparticles affect the reproductive system by inducing cytotoxicity in ovarian cells, disrupts oogenesis and eventually causing sex-hormone imbalance in the body (Iavicoli et al., 2013)
• Affect Neural system: TiO2 nanoparticle cross the blood–testis barrier and exhibit genotoxicity and significant loss of sperm DNA integrity (Santonastaso et al., 2019). Nanoparticles gets accumulated in different regions of the brain and produce toxic effects of the brain which ultimately lead to impaired development and function of CNS (Yang et al., 2010). ZnO induce significant cytotoxicity (Valdiglesias et al., 2013) and silver nanoparticles cause oxidative stress and subsequent upregulation of oxidative stress-related genes in the cortex and hippocampus of mice (Haase et al., 2012; Feng et al., 2015).
• There are reports on adverse effects of nanoparticle exposure on various human systems including cardiovascular (Yu et al., 2016), endocrine (Leso et al., 2018); excretory (Pujalté et al., 2011) and digestive system (Jones et al., 2015).

The results reported so far on the exposure of natural and anthropogenic nanoparticle and its adverse health effects is really alarming. It is clear that the interaction of nanoparticles and biological systems are not fully elucidated. For those getting exposed to nanoparticles: Are we following any strict safety measures?? Do we know what safety measures to follow? Do we still know the toxicity associated with nanomaterials? Is our youngsters doing studies/research in the so called “nanotechnology” getting exposed to health hazards??

At last but not least, what will be the harmful effect when nanoparticle gets accumulated in our environment and ultimately what will happen to our Mother Earth? Are we heading to a disaster?

Will this new nuclear imaging modality revolutionize imaging of oncology patients in low-income countries?

• Globally, 40 million nuclear medicine procedures are executed every year.
• 1 in 50 people use diagnostic nuclear medicine per year in developing countries.
• Positron Emission Tomography (PET) a widely accepted diagnostic modality, is expensive and needs dedicated infrastructure.
  • 70% of deaths related to cancer occur in low-to-middle income countries. Only 30% of thes countries can offer treatment services.
  • Only 10% of these countries have a PET scanner in limited quantity - one scanner per one million people.
  • In the case of India, we have only 0.08 PET scanners per one million people, compared to approximately 7 PET Scanners per one million people in USA. Similarly among the developing countries, only 14% have at least one CT scanner per million people.

Apart from the availability, the cost involved in such diagnostic procedures is very high. Thus a cost effective isotope source and scanner is the need of the hour for nuclear clinical imaging world-wide.

Cerenkov luminescence imaging (CLI) is a budding mixed modality, that's invented 100 years ago, exploits the light emission from many commonly used medical isotopes. Cerenkov luminescence /radiation is produced by a charged subatomic particle travelling at a velocity exceeding the speed of light in a dielectric medium, like tissue. Recently Cerenkov Radiation (CR) has been used in biomedical applications. Due to the recent advances in camera technology and due to new probes that can convert Cerenkov emission to longer (red-shifted) penetrating wavelengths, CLI can achieve mesoscale resolution. These advances have enabled CLI to emerge as a proof-of-principle in clinical settings for potential tumour recognition. CR has been applied for biomedical imaging purposes.

A recent study reported in Nature Biomedical Engineering by Pratt et al., (April, 2022) from Memorial Sloan Kettering Cancer Center, New York, USA on the prospective testing of clinical CLI against the current standard-of-care nuclear imaging for detecting tumours. This study suggests an affordable new nuclear imaging modality for basic disease surveillance and therapy monitoring. Pratt and co-workers developed a clinical testing setup with a clinical CLI fiberscope with in a lightproof cabin for imaging patients. They did an observational prospective trial on 96 patients with existing or suspected tumours, scheduled for routine clinical FDG PET or 131I therapy. The results of CLI imaging when compared with PET, suggested an "acceptable" agreement with PET in capturing the presence and location of tumours for 90% of patients in the study cohort.

Even though the CLI images were not accurate as that of PET, CLI could be used as an initial diagnostic test to assess the tumour size of those patients undergoing treatments. Thus CLI could be a cost effective alternative that could expand access to nuclear imaging in hospitals. Thus this technology could possibly supplement radiological scans, especially when scanner capacity is limited in low-income/ developing countries.