Scientific Highlights of 2023

• Chandrayaan-3: Indian moon lander makes history as the first mission to successfully reach the lunar south pole on 23 August, 2023, with a much cheaper budget of $75m (£60m). Before sending to sleep during the lunar night-time, Chandrayaan-3 had been sent to (a) detect sulphur on the surface of the moon and (b) to show that lunar soil is a good insulator.
• ChatGPT: A sophisticated Artificial Intelligence (AI) went viral in 2023, dazzling users with its fluency and seemingly encyclopaedic knowledge. ChatGPT is very accessible and anyone with a web browser can access this sophisticated AI.
• CRISPR therapy for sickle cell disease and -thalassaemia: For the first time, UK medicines regulator has approved the Crispr-Cas9 genome editing tool called Casgevy, for the treatment of disease. The therapy has been shown to relieve debilitating episodes of pain in sickle cell disease and to remove or reduce the need for red-blood cell transfusions in thalassaemia for at least a year.
• Drug for Alzheimer’s: The Alzheimer’s drug lecanemab (brand name Leqembi) won full FDA approval in July. This drug removes the amyloid plaques that build up in the brains of people with Alzheimer’s. Lecanemab doesn’t stop the disease, but in a clinical trial, this drug slowed cognitive decline by about 30 percent over 18 months compared to a placebo.
• Chikungunya Vaccine: The chikungunya virus can cause fever and severe joint pain, and can be fatal to new-borns. In November, the FDA approved the first vaccine, Ixchiq, against the virus, which is transmitted by mosquitoes. Ixchiq was granted Fast Track and Breakthrough Therapy designations and the application was granted Priority Review by FDA.
• Glucagon-like peptide-1 receptor agonists: A breakthrough weight loss drug. This weight loss drugs has generally limited and manageable side effects. Clinical trials suggest that they improve heart health and kidney disease in people with obesity or diabetes, and they’re being tested in other conditions too, including drug addiction.
• Skin grafts for complex body parts: Team led by Dr. Hasan Erbil Abaci from Columbia University made 3D engineered skin in the shape of complex body parts. Such custom grafts could then be transplanted intact with minimal suturing. His research team tested their skin-culture system using models of human hands and the hindlimbs of mice.
• Erythritol and cardiac arrest: Erythritol is a common artificial sweetener. Low amounts occur naturally in fruits and vegetables. It is also made inside our cells as part of normal metabolism. But when used as a sweetener, erythritol levels are typically more than 1,000-fold greater than levels found naturally in foods. Research team led by Dr. Stanley Hazen at the Cleveland Clinic examined the relationship between erythritol and heart attacks and stroke. In an initial study with more than 1,000 people, the team looked for compounds in blood whose levels were linked to future cardiac risk. They tracked major adverse cardiovascular events over three years, including death and nonfatal heart attack or stroke.
• Blood test to detect Alzheimer’s: Research team led by Valerie Daggett at the University of Washington developed a method to detect toxic Aβ oligomers in patients’ blood. They tested the assay, called the soluble oligomer binding assay (SOBA). SOBA could detect toxic oligomers in the blood even before cognitive impairment occurs. It could thus form the basis for early diagnostic tests of Alzheimer’s disease and other neurodegenerative diseases.
• Gene therapy for muscular dystrophy: FDA approved the first gene therapy for children with Duchenne muscular dystrophy. Due to a faulty gene, people with this muscle-wasting disease don’t make the protein dystrophin, which helps keep muscle cells intact. The therapy helps the body produce a version of the missing protein.

Nanoplastics

Nano-plastics and Parkinson’s Disease

Recently scientists found that tiny plastic particles can enter nerve cells and harm certain regions in the brain of mice. These nanoplastics may set a stage for the development of parkinson’s disease.

• Parkinson’s disease, a disorder marked by the abnormal accumulation of the protein alpha-synuclein in the brain, have been on the rise worldwide.
• Earlier researches pointed towards the role of environmental factors in the build-up of alpha-synuclein.
• Throughout the environment small bits of plastics are widely present, especially nanoplastics which are less than 1 μm in size.
• Studies have already reported that particles of polystyrene and other plastics were detected in the blood of healthy adults.
• Recently Liu and co-workers, from both in vitro and in vivo studies, reported that interactions between alpha-synuclein and polystyrene nano-plastics precipitate the formation and propagation of α-synuclein protein fibrils.
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• They observed that nano-plastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein

This findings is pointing towards the molecular links between nano-plastics and Parkinson’s disease mechanisms. This study clearly established a link between nanoplastic pollution and α-synuclein aggregation associated with Parkinson’s disease and related dementias.

Clinical Trials 2024

Here are some of the clinical trials in 2024 that are likely to have a massive impact on medicine

• Malaria Vaccine: R21/Matrix-M vaccine against malaria. This trial checks long term vaccine efficacy in children 5-36 months of age in malaria-endemic areas of Burkina Faso, kenya, Mali and Tanzania. This will go for phase 3 trial for lead indication, malaria.
• Immunotherapy for melanoma NADINA trial is an international, open-label, two-arm trial that includes 420 patients in Australia, Europe and the USA with stage III cutaneous or unknown primary melanoma. This trial aims to compare the efficacy of neoadjuvant ipilimumab plus nivolumab with that of adjuvant nivolumab in macroscopic stage III melanoma. This will go for randomized phase 3 trial for lead indication, melanoma.
• Medicine for Hypercholesterolemia : VERVE-101, is an investigational in vivo, base-editing medicine, designed to be a single course treatment that durably decrease disease driving LDL cholesterol. VERVE 101 consists of mRNA that encodes an adenine base editor, plus a guide RNA, that are packaged within a lipid nanoparticle and can be delivered by intravenous infusion. This will be on a Phase 1b clinical trial for lead indication, Heterozygous familial hypercholesterolemia.
• T Cell vaccine for HIV: VIR-1388, a cytomegalovirus (CMV) vector vaccine for the prevention of infection with HIV. This vaccine induces strong, unique and sustained T cell responses that can potentially prevent acquisition of HIV. This will go for Phase 1 trial for lead indication, HIV.
• Early diagnosis of cancer Artificial Intelligence.(AI) will be applied to chest X-rays as soon as they are taken shortens the time to a CT scan and time to diagnosis. This is a Class IIa CE-certified deep learning algorithm to analyse chest X ray and computed tomography. This will be on randomised trial for lead indication, lung cancer.
• Stem cell therapy for Parkinson’s disease STEM-PD Trial, the first time a human embryonic stem cell therapy is being tested in Parkinson’s disease. In this trial dopaminergic neurons derived from human embryonic stem cells will be transplanted into the brains of patients with Parkinson’s disease. This will go for Phase 1 trial for lead indication, Parkinson’s disease.
• Machine learning for Patient triage A prospective validation of Artificial Intelligence model. This trial checks the implementation of machine learning algorithm in the emergency room. MARS-ED is a prospective multi-centre, randomized, open-label, non-inferiority pilot clinical trial of risk-score assistance to clinicians in the emergency department.

Latent virus getting reactivated in CAR-T cells

Modified T-cells, known as Chimeric Antigen Receptor-T (CAR-T) cells, are an FDA-approved treatment for different forms of cancer including acute lymphoblastic leukaemia, non-Hodgkin lymphoma, and multiple myeloma.

• CAR- T cells have been used to target specific antigens on blood cells and to cure leukaemia and lymphoma patients.
• The risk associated with these manipulated cells are not studied fully.
• Clinical trials reported encephalitis in patients receiving T cell therapies, caused by the reactivation of human herpesvirus 6 (HHV-6).
• But a comprehensive understanding of the mechanisms behind such toxicities is not known till recently.
• Lareau and co-workers through petabase-scale viral genomics mining examined the landscape of latent viral reactivation and confirmed that HHV-6B can get reactivated in cultures of CD4+ T cells
• They identified a rare population of cells (nearly 1 cell in 300-10000 cells) that possess high viral transcriptional activity among allogenic CAR-T cells.
• They also investigated single-cell sequencing data from patients who received cell therapy and recognized the presence of HHV-6 “super-expressor” CAR T cells in patients
• This study by Lareau and co-workers pointing fingers towards the use of genomic analyses in linking cell therapy products as potential source contributing to lytic HHV-6 infection that has been reported in clinical trials.

We need to have a clear understanding about the toxicities associated with these cell therapies and also should understand the mechanisms associated with such toxicities. According to the current understanding, a comprehensive genomic analyses may be useful in linking cell therapy products and their potential source to lytic infections and such analyses may influence the design and production of autologous and allogenic cell therapies as well.

Microbiota and Prostate Cancer

The human body holds an intricate and active population of trillions of microorganisms called microbiota.

• Microbiota influences the body in homeostasis and disease, including cancer.
• Studies have reported the association of urinary and gut microbial species and its risk in the incidence of prostate cancer.
• Nevertheless, the carcinogenesis remain indefinable.
• Studies demonstrated that a common and early oncogenic event during prostate carcinogenesis, is the bacterial generation of genotoxins with the occurrence of TMPRSS2–ERG gene fusions.
• Another study established the role of the gut microbiota in prostate cancer endocrine resistance, which occurs, at least partially, through the generation of androgenic steroids fuelling oncogenic signalling via the androgen receptor.
• These studies present mechanistic confirmation of how the host microbiota might be associated in prostate carcinogenesis and tumour progression.
• All these findings expose potential ways for the detection and treatment of prostate cancer through the profiling and modulation of the host microbiota.

These findings open up avenues for potential treatment options in prostate cancer. Treatments including faecal microbiota transplantation, prebiotics, probiotics, postbiotics or antibiotics on its own or in combination with current treatments regimens may help to reverse therapeutic resistance and thereby improve clinical outcomes in patients with prostate cancer.

CRISPR and Cholestrol

CRISPR based gene editing therapy helps in lowering cholesterol

• A new form of gene therapy called base editing shows the lowering of cholesterol levels.
• First clinical trial led by Verve Therapeutics done on 10 patients in UK and New Zealand who were prone to dangerously high levels of fat, a disease called heterozygous familial hypercholesterolemia (FH).
• FIH is caused by a defect in one copy of a gene that encodes a cell surface protein needed by the liver to clear the blood of low-density lipoproteins (LDLs).
• The new treatment, VERVE-101, uses a base editor to disable a gene encoding a liver protein that regulates cholesterol. A single infusion lowered the Cholesterol by up to 55 percent.
• Current treatment strategy for FIH patients is to control their cholesterol levels by taking statins and other drugs lifelong
• FH patients make some LDL receptors and the strategy of this new treatment is to keep those molecules around for longer by altering the liver’s gene for PCSK9, an enzyme that normally removes the receptors from cells.
• VERVE-101 uses lipid nanoparticle encapsulated mRNA that instructs cells to manufacture the gene editor’s protein components along with an additional RNA that guides the base editor to the gene for PCSK9.
• The combo makes a one base pair change so that cells can produce only shortened, non-functional versions of the enzyme.

Like a standard CRISPR, will this base editing make changes to other nontargeted genes? Even though the initial trial shows some benefit, more safety data is needed. Long-term safety and efficacy of the treatment is still unknown. A clinical trial with more patients and long term follow-up will answer these questions.

Probiotic guided CAR-T

Modified T-cells, known as Chimeric Antigen Receptor-T (CAR-T) cells, are an FDA-approved treatment for different forms of cancer including acute lymphoblastic leukaemia, non-Hodgkin lymphoma, and multiple myeloma.

• CAR- T cells have been used to target specific antigens on blood cells and to cure leukaemia and lymphoma patients.
• However, for solid tumours this approach have been more challenging to treat as there is diverse and unspecific expression of tumour associated antigens in solid tumours.
• Thus targeting solid tumours with CAR-T involves high risk due to fatal on-target or off-tumour toxicity, as CAR-T cells attack the targeted antigen on health tissues as well.
• A recent study by Vincent and co-workers demonstrated that a probiotic guided CAR-T (ProCAR) platform uses engineered bacteria to home in and produce synthetic antigen targets, thereby enabling CAR-T cells to locate, recognize, and obliterate tumor cells.
• By using synthetic gene circuit engineering on a well characterized strain of E. coli, they created a probiotic that could infiltrate and cyclically release synthetic CAR targets directly to the tumour core, effectively “tagging” the tumour tissue.
• Then, the probiotic-delivered synthetic antigen tags from the tumour cells will be identified by the generated CAR-T cells and kill tumour cells in situ.
• They also engineered probiotics to release chemokines that will enhance CAR-T cell recruitment to the tagged tumour cells, thereby increasing the therapeutic response.
• This study demonstrated efficacy and safety in in vivo mouse models of leukaemia, colorectal cancer, and breast cancer.

These findings is a proof of concept for a potential approach in treating diverse, immunologically cold, and poorly infiltrated solid tumours. I hope that day is not that far when we can cure almost all cancer patients with CAR-T cell therapy.

Hybrid Monkey

First live-born chimaeric primate developed by scientists.

• A hybrid monkey made from cells of two embryos have been developed by Cao and co-workers recently. Earlier chimaeric monkeys, just 0.1–4.5% of the cells in organs such as the brain, kidney and lungs were derived from donor stem cells
• The developed chimaeric primate have a high proportion of cells originating from donor stem cells.
• i.e. the generated foetus and liveborn chimeric monkey had high contribution (up to 90% in some tissues) from homologous naive Embryonic Stem Cells (ESCs).
• Cao and co-workers extracted ESCs from one-week old cynomolgus embryos and genetically edited the cells to display a green fluorescent signal.
• Then they injected up to 20 green embryonic stem cells into each of the recipient embryos, yielding 74 chimaeric embryos with a strong fluorescent signal.
• Embryos were implanted into 40 surrogate female monkeys, out of which 12 surrogates become pregnant.
• Finally only one gave birth to a live chimaeric monkey, a male and was later euthanized.
• The developed chimaeric monkey had to be euthanized when it was ten days old due to hypothermia and breathing difficulties.

Even though this research opens door to using chimaeric monkeys, which are more biologically similar to humans than chimaeric rats and mice for studying human diseases and developing treatments, there are lots of optimization needed in this area of research as well as some ethical concerns to address. This research is opening new avenues that might be used to grow human organs in pig or non-human primate tissues.

Metastasis

Metastasis is the movement or spreading of cancer cells from one organ or tissue to another. What drives metastasis?

• How spine metastasis happens in breast cancer patients was not clearly understood till recently.
• In early in 1940s it was proposed that forceful events such as coughs can momentarily reverse blood flow and jolt cancer cells into the vicinity of the spine, where they form new tumours.
• This classical dogma was being followed as a reason for metastasis till recently!!
• Breast cancer cells move to spine and not to long bones to cause metastatic cancer of spine, the reason behind this phenomenon is not elucidated till recently.
• A recent study by Sun et al., provided strong clues to why cancer cells move to spine and develop metastatic cancer there.
• A protein produced by the vertebral skeletal stem cells (vSSCs) lures breast cancer cells to the spine and there by helps in metastasis.
• A protein called Milk Fat Globule Epidermal Growth Factor 8 (MFGE8) or Lactadherin, secreted by vSSCs, could account for some of the unexplained patterns in cancer metastasis.
• They also observed that the human vSSCs secreting MFGE8 were more likely to interact with cancer cells than vSSCs that were not secreting the protein.

This study has opened up a Pandora’s Box. Even though this one protein play a key role in metastasis and seems to be an important component, it is clear that this one protein can’t explain the entire phenomenon of metastasis. Lots to unravel.

Mitochondrial protein Vs. Brain tumour

• Glioblastoma, a malignant brain tumour seen in adults, is incurable and notoriously lethal.
• Major challenge of this cancer is that it spreads invasively throughout the brain.
• Researchers led by Rex Gaskins, focused on the mitochondrial coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2), that has been reported to mediate mitochondrial respiration, nuclear gene expression and cell migration.
• This research team hypothesized that CHCHD2 may play a functional role in glioma cells expressing the constitutively active epidermal growth factor receptor variant III (EGFRvIII).
• Cancer Genome Atlas glioblastoma database analysis were done by this team to see whether they could spot any patterns that related CHCHD2 levels to cancer.
• Out of 577 samples, they found that the CHCHD2 genes had higher expression in tumour cells, compared to non-tumour tissue, and was higher in advanced cases of glioblastoma.
• The amplification of the CHCHD2 gene was found to be associated with a decreased patient overall and progression free survival.
• The CHCHD2 mRNA levels were increased in high vs. low grade glioma, IDHwt GBMs, and in tumour vs. non tumour tissues.
• They also observed that CHCHD2 protein expression was greatest in invasive, EGFRvIII expressing patient derived samples. By knockout of CHCHD2 in glioma cell line, they observed decreased cell growth and invasion as well as an enhanced sensitivity to cytotoxic agents.

The preliminary research pointing towards the role of CHCHD2 in Glioblastoma cell proliferation, mitochondrial metabolism, invasion and therapeutic resistance. CHCHD2 targeting might be a new significant way to improve clinical outcome.

Pig Donors – A possible Reality

• A pig donor has been engineered and its xenograft was successfully tested in monkeys by Anand and co-workers recently.
• A kidney grafts has been designed and created from a genetically engineered pig donor and transplanted in to a cynomolgus monkey model.
• The pig donor was engineered in such a way to carry out the genomic editing and eliminate glycan antigens, overexpress human transgenes and also inactivate pig endogenous retroviruses.
• Later the functional analysis done by the research team concluded that the kidney endothelial cells modulated inflammation. The extent of such modulation was identical to that of human endothelial cells.
• This observation by the team suggested the immune compatibility of the edited cells.
• When transplanted in cynomolgus monkeys, these organs with glycan antigen knockouts and human transgene expression survived for a significantly longer time. i.e. humanized pig renal graft, combined with a clinically relevant immunosuppressive regimen supported long-term survival of monkeys for up to 2 years (758 days).

This research paved the way for a potential clinical trial of genetically engineered pig renal grafts.

Resting HIV’s constant battle with immune system

Current understanding is that the antiretroviral therapy effectively wipes out active viruses but leaves behind infected cells that are imperceptible to the immune system till the treatment is over and the virus comes back afterwards.

• A recent study by Dube and co-workers as well as Takata and co-workers observed that the virus continues to put the immune system through a test.
• Both studies took blood cells from people on HIV antiretroviral therapy and looked for evidence of viral activity. They analysed the infected cells, searching for viral RNA and protein production
• They observed that some infected cells churn out bits of viral RNA and protein that elicit an immune response, While not infectious, those damaged viral particles appear to weaken the immune system.
• The discovery provides a possible explanation for what allows the virus to re-emerge with such vigour when people stop taking antiretroviral drugs.

The new results suggests two possible strategies for better treating people infected with HIV. First strategy may be the redoubling efforts to dramatically shrink the reservoir of infected cells, which could reduce the production of the problematic viral particles. Second strategy may be to figure out ways to reinvigorate T cells, perhaps by applying lessons from successes in boosting the immune response to cancer.

Corona virus puff out from COVID-19 individuals

Patients infected with COVID-19 breathe out dozens of copies of viral RNA per minute.

• How much virus people breathe out over the course of infection isn’t well-defined till recently.
• Lane and co-workers analyzed over 300 breath samples from 43 people with COVID-19 and following them for nearly three weeks.
• Levels varied between and within individuals, but some people shed a lot, releasing over 800 copies of viral RNA per minute at times.
• They found out that on average, participants breathed out 80 copies per minute for a full eight days after symptoms began.
• Only after that point (8 days) did the viral particles drop to nearly undetectable levels.
• They also found out that the levels of exhaled viral RNA did not differ across age, sex, time of day, vaccination status or viral variant.

Thus this study estimates that a high shedder could potentially breathe out enough virus to infect someone in a closed space in about 20 seconds. That means even an elevator ride may be risky!! With an average shedder, infection could take a little under four minutes.

Solution for Organ Transplantation

First time a human organ is created in another animal and this could eventually lead to the production of human organs for transplantation.

• Early-stage human kidneys, mesonephros, grown in pigs for first time.
• This approach could eventually yield organs for transplantation
• Wang and co-workers generated humanized mesonepros from iPS cells in pigs
• They produced human cells with superior intra-niche competitiveness, thus avoiding one of the major challenges i.e. the poor integration of human cells into the recipient tissues.
• They combined optimized pluripotent stem cell culture conditions with the inducible overexpression of two pro-survival genes viz. MYCN and BCL2.
• The resulting cells had substantially enhanced viability in the xeno-environment of interspecies chimeric blastocyst.
• The research team engineered SIX1/SALL1-null pig embryos.
• SIX1 regulates mesonephric tubule (mesonephroi) formation and ureteric bud branching for metanephrogenesis and SALL1 maintains nephron progenitors and nascent nephrons in the metanephric mesenchyme
• Thus they could produce a nephric-defective niche from early mesonephros to late metanephros, and this could allow human PSCs to fill in the whole renal development program
• Thus organized human-pig chimeric middle-stage kidney (mesonephros) structures were formed up to embryonic day 28 inside nephric-defective pig embryos lacking SIX1 and SALL1.
• Up to 65% of the cells in these organs were human, indicating the stem cells had spawned kidney cells in their porcine surroundings.

This finding opens up an exciting avenue in regenerative medicine. There is lot more to do before we can create a fully functional organ for transplantation, as this study grew only the early stage of kidney. Also the percentage of human cells in such organs developed in animals need to be increased. This attempt could bring pig-grown human organs closer to realism, at least in the next decade. This study thus offer a new solution and hope for many patients waiting for transplants.

Traces of giardia parasite from ancient toilets

Giardia duodenalis is a flagellated parasitic microorganism of the genus Giardia that colonizes the small intestine, causing a diarrheal condition known as giardiasis.

• Giardia was believed to be endemic to the Jerusalem region 2,600 years ago.
• Mitchell and co-workers have now uncovered the oldest known biological evidence of the giardia parasite in the remains of two roughly 2,600-year-old toilets, once used by the wealthy denizens of Jerusalem.
• The aim of Mitchell and colleagues was to determine if the protozoa that cause dysentery were present in Jerusalem during the Iron Age.
• Sediments from 2 latrines pertaining to this time period were obtained. (i.e. from the 7th century BCE and from 7th to early 6th century BCE).
• Microscopic investigations were not successful, as this protozoa are fragile and do not survive well in ancient samples in a form recognizable using light microscopy.
• Then they used ELISA kits to detect the antigens of Giardia duodenalis .
• Giardia was positive for both latrine sediments when the analysis was repeated three times.

This is the first microbiological evidence for infective diarrhoeal illnesses that would have affected the populations of the ancient near east.

Antidiabetic medication and reduction of alcohol addiction

Evidences suggest that an antidiabetic medication may be used for substance use disorders.

• Semaglutide, glucagon-like peptide-1 receptor (GLP-1R) agonist, is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management.
• Another fascinating job of this drug is its action in brain!!
• Some people consuming this drug have reported certain side effects such as diminished desire for alcohol, nicotine etc.
• These reports pointed towards the possibility of repurposing this drug toward treatments for substance use disorders.
• A recent study published by Aranäs and co-workers showed that those rodents that were subsequently dosed with semaglutide drank less alcohol than rodents that weren’t.
• These mice also drank less sweet non-alcoholic liquids and unsweetened calorie-rich liquids, which is a known effect of this drug. As this medication is approved already for obesity, for its ability to reduce appetite and food intake.
• They examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats.
• The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice.
• They also evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.
• The study found out that repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking and labelled semaglutide was detected in NAc of alcohol-drinking male and female rats.
• Semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice and also shown to have enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.

Resistance to Malarial drug

New study report came out suggesting partial resistance of Plasmodium falciparum to the artemisinin component of artemisinin-based combination therapies in South East Asia and East Africa.

• Malaria is caused by protozoan parasite, Plasmodium falciparum.
• The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria
• This disease remains a substantial health challenge, particularly in Africa, where approximately 95% of malaria cases and deaths occur.
• Partial resistance to the artemisinin component of artemisinin-based combination therapies, manifests as delayed clearance after therapy, which is mediated principally by mutations in the kelch protein K13 (PfK13).
• Conrad and co-workers performed annual surveillance among patients who presented with uncomplicated malaria at 10 to 16 sites across Uganda from 2016 through 2022.
• They sequenced the gene encoding kelch 13 (pfk13) and analysed relatedness using molecular methods.
• By 2021–2022, the prevalence of parasites with validated or candidate resistance markers reached more than 20% in 11 of the 16 districts where surveillance was conducted.
• The PfK13, 469Y and 675V mutations were seen in far northern Uganda in 2016–2017 and increased and spread thereafter, reaching a combined prevalence of 10 to 54% across much of northern Uganda, with spread to other regions.
• The 469F mutation reached a prevalence of 38 to 40% in one district in southwestern Uganda in 2021–2022.
• The 561H mutation was first seen in southwestern Uganda in 2021, reaching a prevalence of 23% by 2022.
• The 441L mutation reached a prevalence of 12 to 23% in three districts in western Uganda in 2022.
• Genetic analysis indicated local emergence of mutant parasites.
• The emergence of resistance was observed predominantly in areas where effective malaria control had been discontinued or transmission was unstable.

Postacute sequelae of SARS-CoV-2 infection

New study suggests that health hazard may persist for two years after SARS-CoV-2 infection

• Evidence suggests that SARS-CoV-2 infection can lead to postacute consequence in pulmonary and an array of extrapulmonary organ systems.
• Bowe et al., conducted the study and the result is based on the health records of about 140,000 U.S. veterans (n= 138,818) iinfected with SARS-CoV-2 early in the pandemic, compared with nearly 6 million (n= 5,985,227) more who did not test positive for the virus that causes COVID-19.
• They were followed for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection.
• Postacute consequence include cardiovascular risks, neurologic and mental health disorders, metabolic disorders, kidney disorders and gastrointestinal disorders.
• It was observed that Patients who were hospitalized during their initial COVID-19 cases were more likely to experience these health problems.
• Those people with milder initial infections were still at higher risk for about one-third of the medical issues that the scientists analyzed, compared with people who didn’t test positive.
• Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among non-hospitalized and hospitalized individuals, respectively.
• Cumulatively at 2 years, postacute sequelae of COVID-19 contributed 80.4 and 642.8 disability-adjusted life years per 1,000 persons among non-hospitalized and hospitalized individuals.
• 25.3% (18.9–31.0%) and 21.3% (18.2–24.5%) of the cumulative 2-year disability-adjusted life years in non-hospitalized and hospitalized were from the second year.
• They summarised their study with the finding that, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to postacute sequelae of COVID-19 calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

Even though this study observed some important health consequences, there were some limitations as well. Since the information was obtained from the electronic health data, post-exertional malaise commonly seen in such patients couldn’t be assessed. This chronic condition shares many symptoms with long COVID. Also this study were conducted in veterans (90% were men), health issues that are more common for women with long COVID, such as long-term neurological and endocrine symptoms, may be underrepresented.

Cardiorespiratory Fitness and Cancer

Cardiorespiratory fitness may decrease the risk of nine different forms of cancer by up to 40%!!

• Onerup and co-workers recently found out that cardiorespiratory (heart and lung) fitness decreased the risk of almost nine different kinds of cancer.
• This include head and neck, stomach, pancreas, liver, colon, rectum, oesophagus, kidney and lung cancers
• They used a Swedish population-based cohort study with register linkage of men who underwent military conscription in 1968 - 2005 was undertaken.
• They assessed Cardiorespiratory fitness by maximal aerobic workload cycle test at conscription.
• Only males with severe chronic conditions, functional disabilities, and imprisoned individuals were barred from conscription, limiting the cohort to healthy young men.
• Conscripts underwent standard physical assessments, including blood pressure, BMI, height and weight, and physical strength.
• In a massive observational study performed in 1,078,000 men, of whom 84 117 subsequently developed cancer in at least one site during a mean follow-up of 33 years.
• Higher Cardiorespiratory fitness was linearly associated with a lower hazard ratio of developing cancer in the head and neck (n=2738), oesophagus (n=689), stomach (n=902), pancreas (n=1280), liver (n=1111), colon (n=3222), rectum (n=2337), kidney (n=1753) and lung (n=1635).
• Surprisingly, researchers observed that two forms of cancer, skin cancer and prostate cancer, have a slightly increased risk associated with higher cardiorespiratory fitness.
• This study doesn’t give concrete answers to why skin and prostate cancer risk is higher in people with higher cardiorespiratory fitness.

The take home message from this study is that physical fitness is very important. The American Cancer Society recommends 150-300 minutes of moderate intensity exercise for adults each week.

Climate threatens moss survival in Himalayas

The genus Takakia has the highest number of fast-evolving genes of any moss. Takakia sports a genome whose length is average for a bryophyte - just over 27,400 genes.

• Takakia consists of just two species of moss. While they can be found individually in the United States and Japan, both species occur together only on the Tibetan Plateau in the Himalayas.
• A decade-long incredible study of Takakia (Takakia lepidozioides ) in the Himalayas shows that the moss is well-adapted to its high-altitude home, with resistance to extreme cold and intense ultraviolet light. But no matter how fast it can tweak its genes, the scientists Hu and co-workers found recently that the rapidly rising temperatures in the region were associated with a decrease in the moss’s range - a faster decrease than any of the mosses around it.
• Over 11 years, the researchers collected samples, analyzed genomes, collected data on the surrounding ecosystem and compared modern specimens with fossils from 165 million years ago.
• The new study showed the moss’s ability to withstand solar radiation. When the researchers exposed Takakia to a high amount of UV light, it was unharmed, while comparison mosses began to die within 72 hours.
• Researchers observed that the hardy moss produces high amounts of metabolites like flavonoids and polyunsaturated fatty acids to protect against radiation and also sports genes to enable more efficient DNA repair-essential protection against harmful rays.
• Takakia also adapted to the extreme cold, and can go dormant for eight months of the year while under snow, and gets all of its growth and reproduction done.
• The most extreme environments are the most vulnerable to transformation under a rapidly changing climate. These ecosystems harbour some of the most specialized species, which will likely suffer the highest extinction rates
• Following nearly 400 million years of evolution and resilience, Takakia species is now facing extinction.

Thymus: A mysterious organ

A very important discovery from the immunology point of view happened recently.

Thymus is an organ that’s believed to be play a valuable role in childhood might play a previously underappreciated role in adults.

• Thymus and its function in adult is not clear and this organ is removed in a variety of surgical procedures.
• Till recently, there was no direct evidence to establish the role of thymus and its importance in adults.
• Kooshesh and co-workers evaluated the risk of death, cancer, and autoimmune disease among adult patients who had undergone thymectomy as compared with demographically matched controls who had undergone similar cardiothoracic surgery without thymectomy.
• In this study, 1146 of the patients who had undergone thymectomy had a matched control and were included (from 1993 to early 2020).
• At 5 years after surgery, all-cause mortality was higher in the thymectomy group than in the control group. i.e. 8.1 percent of thymectomy patients died compared to 2.8 percent of patients whose thymus remained intact.
• It was also observed in this study that there was the risk of cancer (7.4% vs. 3.7%) in the thymectomy group.
• The risk of autoimmune disease did not differ substantially between the groups in the overall primary cohort.
• T-cell production and plasma cytokine levels were measured in thymectomy vs. control group and was observed that those who had undergone thymectomy had less new production of CD4+ and CD8+ lymphocytes than controls as well as higher levels of pro-inflammatory cytokines in the blood.

The observation of cancer among those patients undergone thymectomy might be due to the immune system’s compromised surveillance capabilities i.e. lack of producing new T cells or is there any less well-defined function of the thymus? Lots of questions still unanswered!! Any way this discovery pushes back on a long-held belief that the immune system organ, Thymus, is somewhat expendable in adulthood.

Umbilical cord “Milking”

Umbilical cord milking (UCM) increased cardiac output compared with early cord clamping in non-vigorous new-borns.

• UCM is a process of holding the umbilical cord of a new-born child between the thumb and forefinger, squeezing gently, and gradually pushing the contents of the umbilical cord into the new-born’s abdomen.
• Researchers reported recently that this process, relatively unknown and not without some controversy, may help protect some of the most at risk new-borns.
• During foetal development, the umbilical cord brings nutrients from the placenta, which also serves as a reservoir for blood, iron and stem cells.
• At birth, the standard recommendation is to wait at least 30 seconds to a minute before clipping that UC connection, allowing the baby to take in more of those essential nutrients.
• According to studies, for healthy babies, delayed cord clamping can improve some aspects of health, such as iron levels or fine motor skills (for months or years) where as those babies born with health problems, there’s no time to wait.
• There is a thought that for those babies born with health problems, quickly milking the cord might provide similar benefits as delayed cord clamping. But according to American College of Obstetricians and Gynaecologists there is “insufficient evidence to support or refute umbilical cord milking” in such cases till recently.
• In early 2023, researchers randomly assigned 10 medical centers in three countries to one of two groups. If an infant was born limp, with difficulty breathing or bluish skin, the cord was immediately clamped and cut in one group. In the other, the umbilical cord was milked four times before being cut. The hospitals then switched practices halfway through the study.
• After analysing outcomes for over 1,700 infants, researchers found that babies who had had their umbilical cords milked were less likely to need extra oxygen or other breathing assistance. The new-borns were also less likely to suffer from a brain injury (hypoxic encephalopathy) that’s caused by a lack of oxygen to the brain before or shortly after birth.
• Again a follow-up study done recently reported that the improved outcomes were probably due in part to increased blood volume and blood flow to the heart, lungs and brain in the infants who received the UCM.

These new-borns also had slightly higher levels of haemoglobin than babies whose cords were quickly cut. Overall increases in measures of cerebral and pulmonary blood flow may explain improved outcomes associated with UCM among non-vigorous new-born infants. Thus this new study shows promise in infants born in poor health at or near term.

New device to detect SARS-CoV 2 Virus

A proof-of-concept pathogen Air Quality (pAQ) monitor for real-time direct detection of SARS-CoV-2 aerosols have been developed.

• Puthussery and co-workers developed a new device that will takes only five minutes to detect as few as 7 to 35 viral particles per litre of air.
• This device is reported to be very sensitive (i.e. as sensitive as PCR nasal swab tests).
• The detector in this device can pulls in 1,000 litres of air each minute, that is sufficient enough to concentrate viral particles at detectable levels.
• For trapping the virus, Puthussery and his team created an artificial cyclone inside the sampler. That is the system synergistically integrates a high flow (~1000 lpm) wet cyclone air sampler and a nanobody-based ultrasensitive micro-immunoelectrode biosensor.
• Viruses will get trapped in the wall of the cyclone and concentrated for analysis.
• The biosensor consists of an electrode attached to a llama nanobody, a specialized immune system protein made by llamas and their relatives that fights infections much the way antibodies do but is smaller and perhaps tougher than human antibodies.
• The nanobody grabs any passing coronavirus by its spike protein.
• Electricity passing through the nanobody and spike protein causes tyrosine amino acids in the spike protein to oxidize, or lose electrons. Another device attached to the electrode detects that oxidation as a change in voltage, signalling that SARS-CoV-2 is in the air.
• This device demonstrated a sensitivity of 77–83% and a limit of detection of 7-35 viral RNA copies/m3 of air during lab experiments.
• According to the research group, this pAQ monitor is suited for point-of-need surveillance of SARS-CoV-2 variants in indoor environments.

According to the report these detectors cost about $1,400 to $1,900 to build in a research lab. Thus the commercial versions may be very expensive. Initially this device, if detecting with such high sensitivity and limit as these authors claimed in this publication, may be used in public areas including hospitals, airports etc. to detect the virus. Also this finding opens up the scope for detecting other respiratory viruses using llama nanobodies.

Treatment for diabetes-related nerve pain

Diabetes-related nerve pain is a complication that affects more than half of people with diabetes leading to tingling, numbness and stinging.

Faecal transplants alleviated nerve pain in people with diabetes, suggesting gut bacteria may play a role in causing such pain.

• Zhao and team from Rutgers University, USA analysed faecal samples from 86 people, 27 of whom had diabetes-related nerve pain and 30 of whom had diabetes without nerve pain. The rest did not have diabetes.
• Genetic sequencing revealed a greater abundance of 13 bacteria in people with diabetes related nerve pain than in those without it.
• On average, these species constituted almost 12 per cent of the gut microbiome in people with this neuropathy and less than 2 per cent in people without it, indicating that an altered gut microbiome may underlie nerve pain in people with diabetes.
• So, the team transplanted faecal samples from people without diabetes into a separate group of 22 participants with diabetic nerve pain. An additional 10 people with the condition received a placebo of pumpkin and potato powder.
• The researchers assessed participants before treatment and 84 days afterwards.
• On average, nerve pain decreased by about 35 per cent in those who received the transplant and about 5 per cent in those who didn’t.
• Additional genetic analysis found that improvements were associated with a distinct cluster of gut bacteria that reduces inflammation, which is known to underlie chronic pain.

Reversal of Aging: Will this be possible?

Aging is an inevitable multifactorial process. Aging related changes will lead to decline in organ functions, and increase the risk of disease and death.

Aging is associated with systemic changes in the concentrations of molecules such as metabolites.

However, whether such changes are merely the consequence of aging or whether these molecules are drivers of aging remains largely unexplored.

• Recent study by Singh et al., revealed that an ingredient common in energy drinks and baby formula, Taurine, can make mice, monkeys and worms healthier and extends its life span.
• Taurine or 2-aminoethanesulfonic acid, a semi-essential micronutrient, is a non-proteinogenic amino sulfonic acid that is widely distributed in animal tissues and other eukaryotes.
• Recent study shows that blood concentration of taurine declines with age in mice, monkeys, and humans.
• Singh and co workers orally fed taurine or a control solution once daily to middle-aged wild-type female and male C57Bl/6J mice until the end of life.
• They found that taurine-fed mice of both sexes survived longer than the control mice. i.e. median life span of taurine-treated mice (33 months) increased by 10 to 12% compared to control ((29 months). Taurine fed mice showed improved health status as well.
• Also they observed that taurine led to a similar life span boost for shorter-lived worms; C. elegans (median 20 days to about 23 days)

Even though this finding is quite interesting, lot of questions remain unanswered. What Singh and team used in mice experiments were equivalent to about 3 or 6 grams per day of taurine for an adult human? What taurine actually does in the body and whether it works similarly in different animals, including humans? We are not aware about the long term toxicity of taurine when taken at 3-6g/day levels in humans. Can we fight against such natural process?

Gene Therapy for Muscular Dystrophy

FDA approved Elevidys, the first gene therapy for the treatment of paediatric patients with Duchenne Muscular Dystrophy (DMD) with a confirmed mutation in the DMD gene.

• DMD is a rare and serious genetic condition which worsens over time, leading to weakness and wasting away of the body’s muscles.
• DMD is due to a defective gene that results in absence of dystrophin, a protein that helps keep the body’s muscle cells intact. This protein acts as a shock absorber to keep muscle cells intact.
• Patients with DMD don’t make this protein and damage their muscles themselves whenever they contract their muscles.
• FDA approved first gene therapy for children with DMD on June 22nd. The therapy can be used in 4 and 5year-old kids with this disease.
• The gene therapy is designed to deliver a shortened form of the dystrophin gene, that leads to production of Elevidys micro-dystrophin (138 kDa, compared to the 427 kDa dystrophin protein of normal muscle cells), packed into harmless viruses for delivery to muscle cells. The product is administered as a single intravenous dose.

Sarepta, the company who come up with this product, won approval by showing that children treated with the gene therapy make the shortened dystrophin protein. But Sarepta hasn’t yet completed an ongoing clinical trial to demonstrate whether the therapy actually works to restore muscle function. Results of that trial are expected this fall. If the data show that the therapy is safe and effective, its use could be expanded to children and people of other ages.

Ultrasound: A future treatment for inflammation?

Ultrasound usage in medical field is mainly for two reasons: Diagnostics as well as therapeutics. Most common usage is for non-invasive diagnostics to image inside the body. For therapeutic purpose, so far, ultrasound is used to interact with tissues in the body such that they are either modified or destroyed.

A slight twist in this ultrasound usage can lead to the treatment of various diseases.

• Focused ultrasound stimulation (FUS), an emerging method of non-invasive neuromodulation, activates mechanosensitive ion channels.
• In preclinical studies, FUS of the spleen (sFUS) activates an anti-inflammatory neural pathway which suppresses acute and chronic inflammation. But there are no reports so far on what will happen to humans.
• A recent study by Zanos and co-workers suggest that the use of ultrasound in stimulating spleen can lead to a brief reduction of inflammation
• They targeted the spleen of healthy human subjects (n=60) with 3 minute of continuously swept or stationary focused pulsed ultrasound, delivered at three different energy levels within allowable safety exposure limits.
• Then the potential anti-inflammatory effects of sFUS were assessed by measuring sFUS-stimulated changes in endotoxin-induced tumour necrosis factor (TNF) production in whole blood samples from insonified subjects (n=10).
• Zanos and colleagues observed that the stimulation with either continuously swept or focused pulsed ultrasound has an anti-inflammatory effect. The sFUS lowers TNF production for more than 2 hours, with TNF returning to baseline by 24 hours following sFUS.
• They noticed that this change in TNF is independent of anatomical target (i.e., spleen hilum or parenchyma) or ultrasound energy level.
• They also observed that there was no adverse impact on any clinical, biochemical, or haematological parameters.
• By this study Zanos and colleagues demonstrated that sFUS suppresses the normal inflammatory response in humans and this technique has potential implications for noninvasive bioelectronic therapy of inflammatory disorders.

Even though this finding is interesting a detailed study is warranted. Still there are lot of unanswered questions. Lot of practical questions need to be answered including How about the inflammation in the body after FUS? How frequently such treatments are needed to reduce the inflammation? How about the delivery of FUS to patients? If proved by detailed studies, such non-invasive technique may have a great potential in treating chronic inflammatory diseases.

Neutrophil extracellular trap interfering therapy

Neutrophils, are the most abundant type of leukocytes (white blood cells), which play an important role in innate immune response by providing defence against a number of bacterial and other microbial infections

• A novel mechanism of neutrophil mediated host response called NETosis was reported in 2004.
• Neutrophils form Neutrophil Extracellular Trap (NET) that protect the host from an array of infectious diseases has been reported to play a role in malignancy as well.
• This NET-mediated trapping mechanism of circulating tumour cells has been detected in a number of diverse type of cancers.
• The tumour infiltrating neutrophils produce NETs and also leads to tumour progression and subsequently promotes metastasis.
• NETosis can be considered as a double-edged sword. . Circulating levels of NET components, such as cfDNA, NE–DNA, MPO–DNA, and CitH3 can serve as beneficial biomarkers for several kind of cancers.
• Blocking the formation of NETs via small-molecule drugs against DNase I, NE inhibitors, MPO inhibitors, and PAD4 inhibitors might also have great potential, and studies have revealed that targeting NETs has resulted in significant reduction of tumour proliferation and metastasis as well as decreased resistance to radiotherapy, chemotherapy, and immunotherapy.
• Only limited studies are currently available, and the ongoing clinical trials also have not yet provided any clarification or clear inferences to target NETs.

Further studies may reveal detailed information about the connections between NETosis, cancers, and other diseases and help in identifying appropriate strategies to effectively modulate the dysregulated NETosis and associated mechanisms.

Memory of smell is linked to sound sleep

What is the purpose of sleep and how is it linked to memory? A question that ponders researchers for long time, came to an end. A cellular resolution to this question has been unravelled.

• Recent study observed that roundworms need a good night’s sleep to retain the memories linked with particular smells.
• Sleeping Caenorhabditis elegans (C. elegans) offers clues to the molecular changes underpinning the link between sleep and memory
• C. elegans is ideal for studying the changes in synapses that happen during sleep because they have only 302 neurons and researchers have already mapped its entire connectome — the web of all of the neurons and their connecting synapses.
• Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodelling.
• Chandra and co-workers showed that although C. elegans nervous system has a limited number of neurons, sleep is necessary for both memory consolidation and synaptic remodeling.
• In their study, when trained to avoid a sweet scent, C. elegans nematodes could remember to do so after 16 hours, as long as their post-training nap is uninterrupted. But disturbing their sleep prevents crucial changes to their nervous system that are involved in forming long-lasting memories.

This study demonstrate in a living organism that sleep is required for events immediately after training that drive memory consolidation and alter synaptic structures.

Engineered virus to deliver antigen for cancer vaccination

A major hindrance in the development of cancer neoantigen vaccines that prime the anti-tumour immune responses is the delivery of neoantigens to the tumour.

• By using the model antigen ovalbumin (OVA), Ji and co-workers, in a melanoma model, demonstrated a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung.
• They conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumour.
• OVA was then covalently displayed on IAV-CPG using click chemistry.
• Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumour-infiltrating lymphocytes compared to peptides alone.
• Finally they also engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge.
• Engineered IAVs may be equipped with any tumour neoantigen of interest to generate lung cancer vaccines.

This strategy of delivering antigen is a major step in cancer vaccination. Detailed in-depth studies are needed to translate this findings to the bed side.

A step closer towards artificial skin

A skin that can protect and detect things the same way human skin does is what we call as ‘artificial skin’.

Artificial skin or electronic skin (e-skin) is the future answer for people who are no longer able to feel because of skin damage or for those who have large wounds on their skin.

Artificial skin that simultaneously mimics sensory feedback and mechanical properties of natural skin holds substantial promise for next-generation robotic and medical devices.

• An electronic skin that can imitate the same activity that leads to the movement of body parts such as fingers, toes or limbs when prodded or injured has been developed.
• This technology may revolutionize the prosthetic devices, by providing the users with even a sense of touch.
• Wang and co-workers developed a prosthetic ‘e-skin’ that incorporates organic semiconductor transistors that are soft and flexible mimicking the mechanical aspects of a real skin. This device can transmit electrical signals to the brain to allow the wearer to ‘sense’ pressure, strain or variation in temperature.
• Wang and co-workers in this recent work describes a thin, flexible sensor that can transmit a signal to part of the motor cortex in a rat’s brain that causes the toe twitching of the animal, when the e-skin is pressed or squeezed.

The development of such a ‘proof of concept’ is a good leap in the development of e-skin. Research should focus in developing a less invasive ‘e-skin’ that could be used in people who have suffered major injuries, or have sensory disorders.

First Mitochondrial Donation Treatment in UK

There are reports recently regarding the birth of first UK baby with DNA from three people born after a ground-breaking IVF procedure.

This procedure aims to prevent children from inheriting incurable diseases from their mothers.

• Mitochondrial Donation Treatment (MDT), uses tissue from the eggs of healthy female donors to create IVF embryos that are free from harmful mutations their mothers carry and are likely to pass on to their children.
• Embryos combine sperm and egg from the biological parents with mitochondria from the donor’s egg, the resulting baby has DNA from the mother and father (more than 99.8%), plus a small amount of genetic material (approx. 37 genes) from the donor.
• This technique helps a women with mutated mitochondria to have babies without the risk of passing on such genetic disorders.
• Progress in MDT led the UK parliament to change laws in 2015 and permitted the procedure. Newcastle clinic was the first centre licenced to perform this procedure and first case got approved in 2018 by UK’s Human Fertilisation and Embryology Authority (HFEA).
• It is reported that HFEA has approved 30 cases. Due to patient confidentiality, no news came out. Recently ‘Guardian’ reported that HFEA confirmed a small number of babies have now born in UK after MDT.

At a practical level, how this MDT works is still an unrequited question. Theoretically the technique is good, but whether those babies born are for sure, free of such mitochondrial diseases? Whether there is any risk for those babies born with MDT, at later time points in their lives? Is there any risk of reversion of disease, if any defective mitochondria passed on during the technique? Lots of questions still need to be answered!!

Hope for treatment-resistant Glioblastoma

A new study shows promise for people with treatment resistant brain cancer - Glioblastoma.

• Blood Brain barrier protects the brain from any invaders including drugs to enter the brain.
• This barrier is a hindrance for the drugs to effectively reach brain.
• Now researchers have come up with an effective way to temporarily open up the barrier to allow the drug to reach the brain.
• A recent study by Sonabend and co-workers published in The Lancet Oncology found out a way to transiently open up the blood-brain barrier for allowing safe penetration of cytotoxic drugs into the brain.
• They found out that low-intensity pulsed ultrasound with simultaneous administration of intravenous microbubbles (LIPU-MB) can open the blood–brain barrier.
• Sonabend and team assessed the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma.
• 17 patients (nine men and eight women) were enrolled for this study.
• 17 people had their regrown tumour removed and an ultrasound device implanted in their skull, adjacent to the remaining cavity. Patients then received between two and six rounds of treatment spaced three weeks apart.
• During each session, participants were injected with microbubbles for 30 seconds and simultaneously received pulses of ultrasound waves for nearly five minutes.
• The waves reached a specific area of the brain encircling the tumour cavity, penetrating nearly 8 centimetres deep. That was followed by a 30-minute intravenous infusion of paclitaxel,
• Results of this study showed nearly four times as much paclitaxel compared with tissue outside of range.

This finding is interesting and looks like an early step in the right direction to treat recurring Glioblastoma. Definitely there need to be a continued study/testing to confirm this potential treatment strategy. If successful, this strategy could help improve the life span of patients with Glioblastoma, post diagnosis and surgery.

Finally a vaccine for RSV

A powerful new therapy against Respiratory syncytial virus (RSV), the first-ever RSV vaccine is out now.

US FDA approved this new drug developed by GSK for older adults.

• RSV, a respiratory virus that causes cold-like symptoms for many people, but can cause serious illness, hospitalization and death for infants and older people.
• In US, according to U.S. Centres for Disease Control and Prevention, 60,000 to 160,000 older adults are hospitalized each year with lung infections. About 6,000 to 10,000 of them die from RSV infections each year.
• Arexvy (respiratory syncytial virus vaccine, adjuvanted), a newly developed drug, reduced the risk of developing lung infections by 82.6 per cent compared to placebo.
• This vaccine is a recombinant subunit prefusion RSV F glycoprotein antigen (RSVPreF3) combined with company’s proprietary AS01E adjuvant.
• The approval of this new drug is based on data from the positive pivotal AReSVi-006 phase III trial that showed exceptional efficacy in older adults, including those with underlying medical conditions, and in those with severe RSV disease
• In this study, approximately 12,500 participants have received Arexvy and 12,500 participants have received a placebo. Among the participants who have received Arexvy and the participants who have received a placebo, the vaccine significantly reduced the risk of developing RSV-associated lower respiratory tract disease (LRTD) by 82.6% and reduced the risk of developing severe RSV-associated LRTD by 94.1%.

Will CAR T-cell therapy cure HIV?

A novel study to identify a potential cure for HIV by using immunotherapy is ongoing.

• Patient's own T-cells will be modified so that they can identify and target HIV cells to control the virus without medication.
• Modified T-cells, known as CAR T cells, are an FDA-approved treatment for different forms of cancer including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma.
• These chimeric antigen receptors ( CARs) can adhere to tumours to destroy them.
• Inspiration to use CART for HIV patients came from 3 cases cured of HIV due to bone marrow transplantation.
• All these three patients had leukemia and received bone marrow transplants from donors who carried the same mutation that blocks HIV infection, called CCR delta 32.
• From this inspiration, UC Davis Health researchers have already dosed two participants in their clinical trial looking to identify a potential cure for HIV utilizing CAR T-cell therapy.

So far, there have been no adverse events observed that were related to the treatment and the two participants are doing fine. We will wait and see how these patients are improving post CART transfusion.

Leach as a potential biocontrol agent

Snail-borne parasitic diseases (SPBDs) pose risk to human health and cause major socioeconomic problems in many tropical and sub-tropical countries.

• Millions of people in approximately 90 countries have suffered from SBPDs, in which snails serve as the transmitting vectors and intermediate hosts.
• Snails spread diseases including schistosomiasis and fascioliasis to humans and livestock. Both of those conditions are caused by flukes, that spend part of their life cycle in snails.
• Recent data (2021) suggests that, more than 250 million people, mostly children, needed preventive treatment against the blood fluke that causes schistosomiasis.
• Getting rid of snails that host the parasite may be a better prevention measure.
• Recent study by Saglam and co-workers observed that glossiphoniid leeches, Helobdella austinensis and congener species, consume freshwater snails indiscriminately, while other common leeches do not.
• A single adult H. austenensis, for example, can consume up to its weight in snails, e.g. Physella acuta, per day.
• Our predator-prey models suggest that snail populations could be eliminated in relatively short time periods (approximately six months) using a leech biocontrol approach.

More research and field trials are needed before leeches can become a snail biocontrol agent.

Battery can starve cancer cells to death

An implantable self-charging battery that can regulate tumour microenvironment persistently by the well-designed electrode redox reaction has been designed and tested in animals.

• Recent study in mice showed that self-charging battery draped around tumour eliminates oxygen from the cancer cells’ environment and this helped to boost the cancer therapies.
• Studies have showed that hypoxia-activated prodrugs (HAPs) didn’t show much benefit in clinical trials, mostly due to the fact that solid tumours are not evenly hypoxic enough for the drug to act.
• Huang and co-workers comes out with a self-charging battery with an oxygen scavenging property
• The battery consists of biocompatible polyimide electrode and zinc electrode, which can consume oxygen sustainably during battery discharge/self-charge cycle, thus modulating hypoxia level in tumour microenvironment.
• The oxygen reduction in battery lead to the formation of reactive oxygen species and showed 100% prevention of tumour formation.
• Sustainable consumption of oxygen causes adequate intra-tumoral hypoxic conditions over the course of 14 days
• Mice with such batteries wrapped around their breast cancer tumours, combined with cancer therapy (HAPs), showed a 90 percent decrease in tumour volume in two weeks’ time.
• This synergistic effect of the battery/HAPs reduced 90% of the tumour size. Use of such redox reactions in electrochemical battery provides a potential approach in tumour inhibition and regulation of tumour microenvironment.

More research is warranted to see the effect in humans as well. Also it is needed to see how to wipe of 100% of tumours as 90% reduction in tumour size is really dangerous, because if 10% of tumour is left out, those cell may cause the disease to come back and those cells may be resistant to HAPs and hypoxic conditions as well.

A potential Alzheimer's and schizophrenia medication

A recent study reveals a driver of brain cell damage in neurodegeneration

• Complement cascade protects us against infections. It has been reported that this pathway can become dysregulated in the adult brain, leading to cell damage and cell death observed in Alzheimer’s disease and schizophrenia.
• Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer’s disease and frontotemporal dementia. But how this happens remains indefinable till recently.
• A recent study by Zhou and co-workers identified pentraxin protein Nptx2a, as a regulator of the complement system in the adult brain.
• They observed that the loss of Nptx2 leaves the cascade unchecked, aggravating synapse destruction. They found out that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain.
• In mice models of neurodegeneration (Nptx2-deficient) they show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses
• Researchers overcame these effects by boosting Nptx2 levels or blocking complement protein in cells, suggesting that therapeutic strategies targeting the complement system could prevent or even reverse damage to brain cells in neurodegenerative disease.
• In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)–mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss.

These results opens up a more clear picture about the complement cascade and its role in neurodegenerative diseases. Even though there are lots of things not clear at the moment as what factors and sequence of events precisely drive the neurodegenerative disorders, still there is a ray of hope in Nptx2 as a therapeutic target for complement-associated neurodegenerative diseases.

Treatment possibility for alcohol poisoning

Consumption of alcohol can cause intoxication and will lead to impaired mobility and judgment. The only cure to being drunk is to wait it out.

• A recent study throws light in to naturally occurring hormone made by liver that helped drunk mice to sober up more quickly than they otherwise would have.
• Those drunk mice after receiving a shot of a hormone made by the liver, woke up from the drunken inertness twice as fast as those that didn’t received the shot.
• Recently Choi et al., observed that FGF21, a hormone made by the liver, counteracts alcohol-induced loss of consciousness and coordination. FGF21 stimulates arousal from intoxication without changing ethanol catabolism.
• Mice lacking FGF21 take longer than wild-type mice to recover their righting reflex and balance following ethanol exposure.
• Conversely, by administering a pharmacologic FGF21 in drunk mice, Choi and co-workers observed a reduction in the time needed for mice to recover from ethanol-induced unconsciousness and ataxia.
• This study also confirmed that FGF21 is having specificity to ethanol as this hormone did not counteract sedation caused by ketamine, diazepam or pentobarbital.

As there is no drug for treating alcohol poisoning, a drug that would help people to sober up would bring remarkable improvement in treating people rushed to the emergency room. FGF21 serves as an endogenous hormonal signal from liver to noradrenergic neurons in the brain to defend against ethanol-induced intoxication. Thus in coming days FGF21 might be targeted pharmaceutically for treating acute alcohol poisoning.

ANXA1 depletion drives Esophageal squamous-cell carcinoma

How Esophageal Squamous cell carcinoma progresses remains elusive till recently.

• Esophageal cancer is cancer that occurs in the esophagus, a long, hollow tube that runs from your throat to your stomach.
• Esophageal Squamous cell carcinoma (ESCC) is the most prevalent esophageal cancer worldwide.
• ESCC develops through multistage epithelial cancer formation. i.e., ESCC develops from normal epithelium, low and high-grade intraepithelial neoplasia to invasive carcinoma.
• But how this progression happens remains vague.
• A recent study by Chen and co-workers reported that there is a gradual and significant loss of ANXA1 (annexin A1) expression in epithelial cells due to its transcription factor KLF4 suppression along the lesion progression.
• This observation is done by carrying out single-cell RNA sequencing and spatial transcriptomics study of multistage esophageal lesions (79 lesions, n=29) of ESCC patients.
• They demonstrated that ANXA1 is a ligand to formyl peptide receptor type 2 (FPR2) on fibroblasts that maintain fibroblast homeostasis.
• Loss of ANXA1 leads to uncontrolled transformation of normal fibroblasts into cancer-associated fibroblasts (CAFs), which can be enhanced by secreted TGF-β from malignant epithelial cells.

This study highlighted the ANXA1/FPR2 signalling as an important crosstalk mechanism between epithelial cells and fibroblasts in promoting ESCC.

Disease modifying drug for Endometriosis

Researchers recently reported that monthly injections of antibody reversed revealing signs of endometriosis in monkeys

• Endometriosis is an often painful disorder in which tissue similar to the tissue that normally lines the inside of uterus, the endometrium, grows outside the uterus. It commonly involves the ovaries, fallopian tubes and the tissue that lines the pelvis. Endometriosis can also lead to fertility problems.
• Current treatments for this disease condition are limited to hormonal agents that can relieve pain but cannot cure the disease.
• Nishimoto-kakiuch and colleagues while studying human endometriotic samples found that the progression of this disease is associated with the development of inflammation and fibrosis.
• They also observed that there was an upregulation of IL-8 in the endometriotic tissue and that expression correlated with disease progression.
• They created a long-acting recycling antibody against IL-8 (AMY109) and evaluated its clinical potency in cynomolgus monkey model- both in spontaneously developed as well as surgically induced endometriosis.
• Both animal models confirmed pathophysiology that was highly comparable to that of human endometriosis.
• Monthly once subcutaneous injection of AMY109 to monkeys (n=11) for six months with surgically developed endometriosis reduced the volume of lesions, improved fibrosis and adhesions.
• They also observed that the cells derived from human endometriosis revealed AMY109 inhibited the recruitment of neutrophils to endometriotic lesions and the production of monocyte chemoattractant protein-1 from neutrophils, thus showing a potential of disease modifying therapy for patients.

Currently they started a Phase I clinical trial to test the safety of therapy in humans and hopefully, AMY109 may represent a disease-modifying therapy for patients with endometriosis.

Stem cell therapy for perianal fistulas

Researchers come up with autologous adipose-derived mesenchymal stem cell based treatment for refractory fistulizing perianal Crohn’s Disease

• Researchers at Mayo clinic developed a dissolvable plug delivered stem cell therapy in patients with single tract perianal fistulas.
• Perianal fistulas are painful tunnels between the intestine and the skin that often do not go away with standard medical or surgical care. People with Crohn's disease or other inflammatory bowel conditions are most at risk for this condition.
• In a prospective, phase 1 clinical trial, researchers loaded autologous adipose-derived mesenchymal stem cell onto a bioabsorbable plug that was then surgically implanted to close the anal fistula tract.
• Recently Eric and co-workers reported the results of their early research. They observed healing of single-tract fistulas
• In this study, 20 patients with perianal fistulas who had not responded to standard medical or surgical treatment were included.
• After in vitro expansion of stem cells researchers combined the cells with a plug created from a dissolvable material. They surgically implanted the plug to close the anal fistula tract then monitored the patients seven times within one year. They confirmed clinical healing through deep tissue imaging.
• Out of 20 patients, complete healing of 14/18 patients at six months and 13/17 patients at one year was observed. Three patients withdrew from the study during the course of the clinical trial.

Even though the initial study is promising, the main limitations of this current study was small sample size and restrictive inclusion criteria. So a study with larger sample sizes is warranted with more types of fistulas. In my opinion in another couple of years’ time, this procedure could likely become a routine clinical practice.

Kidney Stone Formation

A recent study found out that when rats were fed with lemon derived extracellular vesicle-like nanoparticles (LEVNs) isolated from lemon can block kidney stone formation.

• Kidney stones (also called renal calculi, nephrolithiasis or urolithiasis) are hard deposits made of minerals and salts that form inside kidneys. Kidney stones, represented by the calcium oxalate (CaOx) type, are highly prevalent and can bounce back.
• Lemon juice is a well-known home remedy for kidney stones. Cumulative evidence shows regular consumption of lemonade intervenes with stone development. However, the mechanism behind this is not clear until now.
• Zhang and colleagues observed that LEVNs isolated from lemonade can traffic from the gut to the kidney, primarily enriched in tubule cells and oral administration of LEVNs significantly lessens the progression of kidney stones in rats.
• Mechanistically, in addition to changing the crystallization of CaOx toward a less stable subtype, LEVNs suppress the CaOx-induced endoplasmic reticulum stress response of tubule cells, as indicated by homeostasis of specific signalling molecules and restoration of subcellular function, thus indirectly inhibiting stone formation.
• To exercise this regulation, endocytosed LEVNs traffic along the microtubules throughout the cytoplasm and are eventually recruited into lysosomes.
• Thus a LEVNs-mediated mechanism against renal calculi is established in vivo and the preliminary results provides positive evidence for consumption of lemonade in preventing stone formation.

Lemon juice helps in combating kidney stone is our conventional wisdom. I feel we should definitely go ahead and drink natural lemon juice to fend off kidney stones rather than going for an artificial nanoparticle!! Anyway, using lemon nanoparticles to treat kidney stone patients is a long way off!!

Cellular mechanisms behind psychedelics

A recent study suggests that Psychedelics can improve mental health by going inside the nerve cells and not from outside the cells. i.e. The location bias in 5-HT2AR signalling resolved!!

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and/or an apparent expansion of consciousness.

• Psychedelics are showing promise in clinical trials as treatments for mental health disorders.
• Psychedelics go underneath the cell surface to release their possible therapeutic effects.
• Several mental health conditions, including depression and post-traumatic stress disorder, are linked to chronic stress, which degrades neurons in the cortex over time. But repairing these cells could provide therapeutic benefits, like lowered anxiety and improved mood.
• It has been reported that Psychedelics- including psilocin, derived from mushrooms, and Lysergic acid diethylamide (LSD) do that repairing by promoting the growth of nerve cell dendrites .
• It is also known that psychedelic compounds promote cortical structural and functional neuroplasticity through the activation of serotonin 2A receptors (5-HT2ARs). But it was a mystery till now that why some 5-HT2AR agonists promote neuroplasticity, whereas others do not.
• A recent study by Vargas and co-workers found that activation of intracellular serotonin 2A receptors is responsible for the plasticity-promoting and antidepressant-like properties of psychedelic compounds, but serotonin may not be the natural ligand for those intracellular receptors
• They used molecular and genetic tools and demonstrated that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics. This results explain why serotonin does not engage similar plasticity mechanisms.

This study throw light in to the role of location bias in 5-HT2AR signalling and identified intracellular 5-HT2ARs as the therapeutic target. As an important note, this study also raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex. Research should focus on understanding the cellular mechanisms behind psychedelic’s potential therapeutic effects, which will ultimately pave the way to develop safer and more effective treatments for mental health disorders.

Finger print pattern development mystery cracked

Finger print pattern development and difference, an evolutionary enigma has been cracked now.

• Fingerprints are impressions left on surfaces by the friction ridges on the finger of a human. They are complex and individually unique patterns in the skin.
• The volar skin of the palms and soles is covered with fine parallel ridges called dermatoglyphs. On the proximal 2/3rds of the digits, dermatoglyphs are arranged as approximately transverse ridges, but form more complex “fingerprint” patterns at the distal tips.
• This pattern is established before birth and maintained throughout life and most common pattern includes arch, loop, and whorl.
• Dermatoglyphs are unique to the volar skin in human. The rest of the body carries hair follicles (HFs), which initiate during embryonic development as circular epithelial placodes upon intensification of expression of EDAR and WNT pathway genes. Each placode then recruits a dermal condensate by emitting an FGF20 signal and undergoes extended tubular downgrowth, driven by SHH signaling.
• The human fingerprint pattern (arrangement of epithelial primary ridges), form at approximately week 13 of gestation on the raised volar pads at the tips of the digits and by week 16, sweat glands also emerge. Arch, loop, or whorl pattern will be defined by week 15 of gestation. Primary ridge formation is completed by week 17.
• However, the mechanism that governs the pattern and morphogenesis of the primary ridges is not known.
• Glover and co-workers found out that fingerprint ridges are epithelial structures that undergo a truncated hair follicle developmental program and fail to recruit a mesenchymal condensate.
• Their spatial pattern is established by a Turing reaction-diffusion system, based on signaling between EDAR, WNT, and antagonistic BMP pathways.
• These signals resolve epithelial growth into bands of focalized proliferation under a precociously differentiated suprabasal layer.
• Ridge formation occurs as a set of waves spreading from variable initiation sites defined by the local signaling environments and anatomical intricacies of the digit, with the propagation and meeting of these waves determining the type of pattern that forms.
• Thus relying on a dynamic patterning system triggered at spatially distinct sites generates the characteristic types and unending variation of human fingerprint patterns!!

Aging and Atherosclerosis

Bone marrow age commands the clonality of smooth muscle-derived cells in atherosclerotic plaques.

• Atherosclerosis is the hardening and narrowing of arteries caused by cholesterol plaques lining the artery over time. It can put blood flow at risk as arteries become blocked.
• Aging is the predominant risk factor for atherosclerosis—the leading cause of death.
• Rare smooth muscle cell progenitors clonally expand, giving rise to up to approximately70% of atherosclerotic plaque cells;
• However, the effect of age on smooth muscle cell clonality is not known.
• Recent study by Kabir and co-workers published in Nature Aging observed that aged bone marrow derived cells noncell autonomously induce smooth muscle cell polyclonality and worsen atherosclerosis.
• Indeed, in myeloid cells from aged mice and humans, TET2 levels are decreased, which epigenetically silences integrin β3, resulting in increased tumor necrosis factor-α (TNFα) signaling.
• TNFα signals through TNF receptor 1 on smooth muscle cells to promote proliferation, and induces the recruitment and expansion of multiple smooth muscle cell progenitors into the atherosclerotic plaque.
• Notably, integrin β3 overexpression in aged BM preserves the dominance of the lineage of a single smooth muscle cell progenitor and attenuates the plaque burden.

This study demonstrates a molecular mechanism of aged macrophage-induced smooth muscle cell polyclonality and atherogenesis. This study may lead to novel therapeutic strategies.

Off-the-Shelf CART for Multiple Myeloma

Off-the-Shelf CART cell therapy is going to be a reality and showed promise in Multiple Myeloma

• Autologous CART Therapy: Cells drawn from a patient and then genetically modified and multiplied into large quantities and finally reintroduced back to the same patient in sufficient quantity to fight the cancer cells. Autologous CART therapy has been done so far and will take a month or more to produce.
• Off-the-shelf or Allogenic CAR T Therapy: Cells drawn from healthy donors and then genetically modified and stored in large batches which can be ready to be used. When a patient needs the CAR T cells, after tissue typing we can find the best match among the donor cells. This process will take few days only compared to allogenic CART which will take a month or more.
• Recent Phase I clinical trial at Memorial Sloan Kettering Cancer Centre, New York and other medical centres, where patients were given allogeneic CAR T cells instead of usual autologous cells. The results demonstrate that allogenic CAR T cell donation can be safe and effective.
• ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection.
• Mailankody and coworkers evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647) containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of first-in-human phase 1 UNIVERSAL trial.
• Primary objectives were determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response.
• The observation among the patients were: (a) Grade ≥3 adverse events were reported in 38 (88.0%) patients (b) Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. (c) infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response.
• Among patients treated with 320 × 106 CAR+ T cells and a fludarabine, cyclophosphamide and ALLO-647-based lymphodepletion regimen (n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months.

These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma.

Cancer Immunotherapy Resistance

An unexpected driver of cancer immunotherapy resistance identified

• Harmful effect of chronic Type I Interferon signalling on tumour-killing CD8+ T cells identified.
• Identifying signals that govern the differentiation of tumour-infiltrating CD8+ T cells toward exhaustion can improve current therapeutic approaches for cancer.
• Recent study showed that type I interferons act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumours.
• Chen and co-workers found enrichment of IFN-I-stimulated genes within exhausted CD8+ T cells in patients across various cancer types, with heightened type I interferon stimulated genes level correlating with poor response to immune checkpoint blockade therapy.
• In preclinical models, tumour-infiltrating CD8+ T cells devoid of IFN-I signalling develop less exhaustion features, provide better tumour control, and show greater response to immune checkpoint blockade mediated rejuvenation.
• Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in CD8+ T cells, leading to aberrant lipid accumulation and elevated oxidative stress.
• Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of CD8+ T cells.
• Blocking IFN-I signalling in CD8+ T cells improves anti-PD-1 therapy response.

Thus, cell-intrinsic IFN-I signalling regulates the extent of CD8+ tumour-infiltrating cells exhaustion and has important implications for immunotherapy.

Animal drug testing no longer a requirement before human trials

Will animal studies always say an answer about the efficacy of a newly developed drugs? Will those results always holds true in human trials?

As a person who worked in developing various "animal models" during the post-doctoral time and also have seen the effect of newly developed compounds and it’s efficacy in small animals, I always have an apprehension in unnecessarily sacrificing small animals

As a person who has seen many research works going on around me where especially "material scientists", "nanotechnologists" and also the so called "Cancer Biologists" are unnecessarily using animals for the sake of "Research" and also for the sake of "publications". It’s really pathetic!! Majority of them normally do not get translated to bed side.

• According to the new legislation signed recently by US President, there is no mandatory requirement to test new drugs in animals for receiving U.S FDA approval - A long sought after change by the animal welfare organizations.
• This new law amends the U.S. Federal Food, Drug, and Cosmetic Act, which was originally passed in 1938 i.e. a major shift away from animal use after more than 80 years of drug safety regulation!! Animal rights advocates have long been pushing for such a move.
• This new law allows FDA to promote a drug or biologic, a larger molecule such as an antibody, to human trials after either animal or nonanimal tests.
• Non animal tests including computer modeling, organ chips, organoid cultures etc. that have been developed over the past few years may be employed.
• From an animal ethics point of view, the needless suffering and death of animal test subjects can be avoided.

By eliminating the need of animal drug study for approval of a drug by U.S FDA, more effective drugs can be brought to the market more rapidly by cutting formalities that is not supported by current science. Even though the new legislation is signed and this law allows the agency to clear a drug for human trial without animal testing, we still don’t know how much the new law will change things at FDA. I hope that this law at least will open up discussions or thoughts among the "Real Scientists" on how to reduce animals and use alternative methods of drug testing before moving to human trial.

Human Brain Aging

Neurological sequelae often accompanies after COVID19

Severe COVID-19 has been associated with cognitive impairment and changes in the frontal cortex.

• Recently Mavrikaki et al., reported that COVID-19 is associated with molecular signatures of brain aging.
• In this study, they performed RNA sequencing on frontal cortex samples from patients (n=21) with severe COVID-19, uninfected controls (age and sex matched, n=22) , and uninfected people (n=9) who had received intensive care or ventilator treatment.
• They observed almost 7,000 differentially expressed genes in the patient samples compared to controls.
• Upregulated differentially expressed genes were enriched for genes involved in immune-related pathways, and downregulated differentially expressed genes were enriched for genes involved in synaptic activity, cognition and memory — a profile of transcriptional changes that resembles those previously observed in aging brains.
• Direct comparisons between frontal cortex samples from young and old individuals confirmed this overlap.
• Cultured human primary neurons when treated with tumour necrosis factor, interferon-β or interferon-γ induced transcriptional changes similar to those seen in severe COVID-19 patients, suggesting that acute clinical management of severe COVID-19-induced inflammation may be neuroprotective.
• The study concluded that the transcriptomic changes in frontal cortex of patients with severe COVID-19 were due to neuroinflammatory processes rather than a direct effect of the virus, as no SARS-CoV-2 RNA was detected in the patient samples.

This study signify the role of COVID-19 and brain aging. Even though there are limitations in this study including the variability in illness duration, imperfect quality of several samples etc., this study emphasize the value of neurological follow-up in those patients recovered from severe COVID-19.

Leukocyte Telomere Length vs. Assisted Reproductive Technology

Initial Leukocyte Telomere Length (LTL) is affected for those children born out of Assisted Reproductive Technology (ART)

LTL is a proposed marker of biological age.

ART is used to treat infertility. This works by removing eggs from the ovaries and then mixing them with sperms to make embryos. The embryos are then put back in the patient’s body. In vitro fertilization (IVF) is the most common and effective type of ART

• Codd and co-workers reported early last year that the elderly and male sex associate with shorter LTL, with women on average approximately 7 years younger in ‘biological age’ than men. In this study they observed that when compared to white Europeans, LTL is markedly longer in African and Chinese ancestries.
• Perinatal and childhood adverse outcomes associated with ART has been reported. But it was unknown whether the initial LTL, which is an indicator of age-related phenotypes in later life, is affected for those children born out of ART.
• Recent study by Wang et al., reported that one-year-old children conceived by ART had shorter LTLs than those conceived spontaneously.
• They observed that the blastocyst-stage embryo transfer was associated with shorter LTL in children conceived by ART.
• The association was validated in 586 children conceived by ART from five centres using different LTL quantification methods (that is, whole-genome sequencing (WGS) or qPCR).
• They also did animal study and found out that blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 and mice at 6 months (P = 0.042).
• From the in vitro study culturing of mice embryos they also observed that there was no telomere shortening in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage.

These finding warrants a detailed study to evaluate the long term consequences of ART especially for aging related phenotypes in those children conceived by ART.