Circadian clock and body's response to oxygen deficiency

A key component of the circadian clock that regulates the body's response to oxygen deficiency has been discovered.

• How each cell reacts to the lack of oxygen is determined by the Hypoxia-inducible factor 1-alpha (HIF-1α). If there is plenty of oxygen, HIF-1α will be unstable and breaks down quickly. Whereas if there is scarcity of oxygen, HIF-1α stabilizes, accumulates and enters the nuclei and triggers the transcriptional regulation.
• In a recent study by Dandavate and co-workers found out the key component that undergoes changes over the progression of the day and night that could affect occurrence of diseases, mainly influenced by the oxygen cycle of the body.
• Dandavate and her team found out that BMAL1 (brain and muscle Arnt-like 1) protein is also a key player of the circadian clock and this protein is necessary for stabilizing and activating the HIF-1α.
• BMAL1 play an independent role in activating the body's plan for dealing with oxygen shortage.
• They developed genetically engineered mice (three groups) that could not produce either one or both of the HIF-1α/BMAL1 proteins in their liver tissue and examined what is happening in each group of mice.
• They observed that in the absence of BMAL1, the HIF-1α protein failed to accumulate.
• They also observed that of BMAL1and/or HIF-1α are responsible for the activation of the genetic response needed to deal with oxygen scarcity.
• Thus, the transcriptional response of liver to hypoxia is mainly dependent on BMAL1 or HIF-1α and the hepatic BMAL1/HIF-1α deficient mice exhibit daytime dependent mortality upon hypoxia.

This study found out that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response. These findings will give a possible explanation (i.e. molecular insights and pathophysiology) of why asthma, cardiac arrest and other disease conditions strike in the early hours of morning.

Ovarian cancer cripple T cells

Ovarian cancer cells cripple T cells and hinder their attack by blocking their energy supply.

Recent study discovered the mechanism of how ovarian cancer cells use to maim immune cells (T cells) and hamper their attack by blocking the energy supply to them.

• A major hurdle in treating ovarian cancer is its tumour niche. In this tumour microenvironment, T cells lose their capacity to fight as a result of its inability to take up lipid molecules.
• T cells use lipid molecules and burn it in their mitochondria and generate energy to power their fight against pathogens and cancer cells.
• Fatty-acid-binding protein 5 (FABP5) play an important role in organizing the effective import and transferring of lipids that fuel mitochondrial respiration to withstand the bioenergetic requirements of cytotoxic T cells. Till recently the molecular mechanism behind this immune-metabolic axis is not known.
• A recent study by Hwang and co-workers discovered the mechanism behind the T cell lipid metabolism and how the T cells do the antitumour function in an ovarian cancer.
• In patient derived tumour specimens and in vivo models of ovarian cancer, they found out that FABP5 is trapped inside the cytosol of T cells and not moving to its cell surface to help them take up the lipids from the niche.
• They also discovered a protein (cytoskeletal organizer) called Transgelin 2 (TAGLN2) which interacts with FABP5 and facilitates FABP5’s cell surface localization and function in activated cytotoxic T cells.
• Further studies by Hwang and colleagues revealed that endoplasmic reticulum (ER) stress responses induced by the ovarian tumour microenvironment repress TAGLN2 in infiltrating cytotoxic T cells, thereby imposing their dysfunctional state.
• Restoration of TAGLN2 expression in ER stressed cytotoxic T cells lead to an increased lipid uptake, mitochondrial respiration and cytotoxic capacity.
• Then they used CAR-T cells overexpressing TAGLN2 and observed that it bypassed the harmful effects of tumour induced ER stress and confirmed therapeutic efficacy in mice with metastatic ovarian cancer.
• Hwang and colleagues thus established the role of TAGLN2 in T cell lipid metabolism.

This study reveals the key mechanism behind the immunosuppression in ovarian cancer. This finding will pave the way for new opportunities to improve the efficacy of adoptive T cell immunotherapies in solid tumours by preserving the TAGLN2–FABP5 axis.

Oral Bacteria & Cancer

Presence of certain oral bacteria could determine the risk for head and neck squamous cell cancer development

• A recent study by Kwak and co-workers identified novel oral bacterial species including both commensals and periodontal pathogenic bacterial complexes that together presents a 50% increased risk of head and neck squamous cell cancer.
• They analysed bacterial and fungal DNA from the saliva samples of 159,840 individuals. The samples were collected and tracked those individuals for a mean of 5.1 years.
• Among the samples analysed, oral microbe DNA in 236 patients were diagnosed with head and neck squamous cell cancer. They compared this with 458 randomly selected study members who had remained cancer free.
• Kwak and colleagues found out that 13 oral bacterial species were associated with the development of head and neck squamous cell cancer, whereas there were no significant associations between oral fungi and cancer.
• Species included Prevotella salivae, Streptococcus sanguinis, and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria.
• They also observed that the combination of the red periodontal bacterial pathogen complex and the orange complex were linked with a moderately raised head and neck squamous cell cancer risk.

This study holds great potential in the prognosis and prevention of head and neck squamous cell cancer. The identified bacteria and bacterial complexes hold promise as possible biomarkers in identifying those individuals with high risk in developing cancer and thereby may help in a personalized approach for preventing head and neck squamous cell cancer.

Cure for Type 1 Diabetes

Patient-derived islet cells generated from iPS cells when transplanted back to a patient cured type 1 diabetes.

• In a recent study by Wang and co-workers, autologous transplantation of chemically induced pluripotent stem cell (CiPSC) derived islet cells into a patient with Type 1 diabetes resulted in continued insulin independence and re-established glycemic control.
• Autologous CiPSCs were generated from adipose-derived mesenchymal stromal cells (ADSCs) isolated from the patient’s adipose tissue by chemical reprogramming.
• Then they differentiated iPSCs in vitro into insulin-producing islet-like cells and transplanted beneath the abdominal anterior rectus sheath of a type 1 diabetes patient.
• Within two weeks and 18th day post transplantation, the patient’s daily exogenous insulin dose requirement began to reduce from baseline of 54 ± 0.9 units/day and 43 units/day respectively.
• 75 days post-transplantation, the patient achieved sustained insulin independence.
• Time-in-target glycemic range of the transplanted patient increased from a baseline value of 43.18% to 96.21% by month 4 after transplantation, followed by a decrease in glycated hemoglobin.
• The transplanted patient showed a stable glycemic control, with time-in-target glycemic range at more than 98% and glycated hemoglobin at around 5%.
• The patient was monitored for a year and the clinical data met all study endpoints with no indication of transplant related abnormalities.

This research outcome is really promising. The results from this islet cells transplanted patient is opening up new avenues for diabetic therapy and ultimately cure. Large cohort study in this direction and assessing the safety and efficacy of CiPSC islet transplantation in type 1 diabetes are warranted.

Metabolic Fitness of T cell

Intercellular mitochondrial transfer augments T cell metabolic fitness and antitumor efficacy

• There are reports on the limited efficacy and exhaustion of T cells during adoptive T cell therapies, especially against solid tumours.
• One of the major reasons for the T cell exhaustion is the harsh tumour microenvironment disrupting the normal mitochondrial activity of the transferred T cells.
• Thus impaired mitochondrial ability coordinates transcriptional and epigenetic programs related to terminal exhaustion, leading to faulty antitumor T cell responses and cancer immune avoidance.
• Research groups are trying various ways to enhance mitochondrial function in infused T cells.
• Baldwin and colleagues reported a ground breaking platform to provide exogenous mitochondria to T cells to overcome such limitation.
• They found out that bone marrow stromal cells launch nanotubular connections with T cells and influence these intercellular thoroughfares to transplant stromal cell mitochondria into CD8+ T cells.
• Baldwin and team also observed that the optimal mitochondrial transfer required Talin 2 on both donor and recipient cells and the CD8+ T cells with donated mitochondria showed improved mitochondrial respiration and spare respiratory capacity.
• Mitochondrial transferred T cells when injected into tumour-bearing animals, expanded more vigorously, infiltrated the tumour more efficiently, and showed fewer signs of exhaustion compared to those T cells that did not take up mitochondria.
• The enhanced antitumor responses were seen across a variety of different T cell platforms (TCR, CAR, and TILs) in diverse in vitro and in vivo settings against both liquid and solid tumours.
• This study clearly shows that the mitochondria-boosted CD8+ T cells facilitated excellent antitumor response, leading to prolonged animal survival.

These results from the study determine intercellular mitochondrial transfer as an example of organelle medicine, opening opportunities to next-generation cell therapies.

HIV Immunization

New study suggests a multidose immunization regimen has got protective effect against HIV.

• A recent study recommends that childhood immunization against HIV may provide protection one day against the infection in adolescence, thereby providing a lifelong protection against the virus.
• Early childhood may be the best time for employing an HIV immunization regimen as this period i.e. from weaning and sexual introduction presents a low-risk window for viral acquisition.
• Nelson and co-workers confirmed that sequential six vaccinations containing modified protein from the HIV envelope confirmed stimulated initial response in young nonhuman primates.
• They developed a broadly neutralizing antibody (bnAb) against HIV virus before the individual get exposed to the virus.
• Nelson and colleagues assessed the ability of bnAb B cell lineage–designed HIV envelope SOSIP (protein stabilized by a disulfide bond between gp120-gp41- named “SOS”- and an isoleucine-to-proline point mutation-named “IP”- at residue 559) to induce precursor CD4 binding site (CD4bs)- targeting bnAbs in early life..
• They did this study using five infant rhesus macaques in three priming doses, starting from less than a week after birth. They followed these with three doses of the vaccine similar to the original HIV envelope protein, with the last dose when the animal was 78 weeks old (roughly equivalent to 4 or 5 years old for a human). As a control, five animals received all six doses of the original envelope protein vaccine.
• 3 out of 5 animals that received the altered version of the priming vaccine developed antibodies that appeared to be precursors to the broadly neutralizing response.
• Further tests confirmed that the developed antibodies attack the protein on the surface of the virus that binds to CD4 T cells, thereby preventing the viral entry to the cell

This study shows that a multidose immunization schedule with bnAb lineage-designed SOSIPs has the potential for stimulating early B cell responses with the capacity to mature into protective HIV bnAbs before sexual debut. More studies need to done to confirm how reliably the neutralising response happens in larger cohorts.

Reversal of Aging

A new treatment can reverse multiple hallmarks of aging. TERT activating compound can reverse aging.

• Aging is a time dependent process that leads to the loss of physiological integrity and fitness in living organisms.
• The process of the loss of physiological integrity and fitness in living organisms is steered by multiple mechanisms that ultimately lead to the collection of cellular damage and subsequent decline in organ function and tissue homeostasis.
• Researchers have identified a small molecule that promoted tissue rejuvenation, including new neuron development, and lessened multiple aging hallmarks in aged mice
• Shim and colleagues have shown that therapeutically reinstating a certain level of specific subunit of the telomerase enzyme can significantly reduce the signs and symptoms of aging in preclinical models.
• They identified a small molecule that reinstates the physiological level of telomerase reverse transcriptase (TERT), which is normally suppressed with the process of aging.
• Upkeeping TERT levels in aged lab animal models results in the reduction of cellular senescence and tissue inflammation, stimulated new neuron formation with enhanced memory and improved neuromuscular function leading to augmented strength and coordination.
• By high-throughput screen of over 650,000 compounds, Shim and colleagues identified a small molecule - TERT activating compound (TAC), that epigenetically de-represses the TERT gene and restores physiological expression present in young cells.
• In preclinical models equivalent to adults over 75 years , TAC treatment for six months led to new neuron formation in the hippocampus (memory centre), improved performance in cognitive tests, as well as there was an increase in genes involved in learning, memory, and synaptic biology.
• From pre-clinical models, it was also observed that the TAC treatment leads to reduction in inflammaging, eliminated senescent cells, enhanced neuromuscular function, coordination, grip strength, and speed.

Findings from this study provide a preclinical proof of concept for physiological TERT activation as an approach to alleviate hallmarks of aging and related pathologies. A large cohort clinical study is warranted to validate these findings. This study opens up avenues for the therapeutic interventions especially for age-related diseases such as Alzheimer’s, Parkinson’s, heart disease, and cancer.

Early Menopause

Uncommon genetic variant is linked to early menopause

Woman with homozygous stop-gain variant rs117316434(A) attains menopause early.

• In woman, the exhaustion of the primordial follicle pool results in menopause.
• Usually on an average, natural fertility of a woman ends ten years before the menopause.
• Nearly 1 - 4 percentage of woman experience primary ovarian insufficiency (POI) and cessation of menses before 40 years. Thus early menopause and POI are renowned cause of infertility.
• A recent study by Oddsson and co-workers discovered a single nucleotide variant rs117316434(A), results in condensed protein being translated from a gene, CCDC201, which is greatly expressed in oocytes.
• According to their study, they discovered that women homozygous for the stop-gain variant rs117316434(A), attain menopause nine years earlier than other women.
• This genotype was seen at a ratio of 1:10,000 women in northern Europe and more than half of those women experience POI.

This study suggests the homozygosity for CCDC201 gene’s loss of function will have considerable impact on the female reproductive health. Thus testing women for such genetic variant may be done, so as to plan when to have children or to plan their reproductive life as well as to treat those with such genetic variant for early menopause.

METRNL and T Cells

METRNL Protein and Tumour-Infiltrating T Cells

A protein Meteorin-like (METRNL) exhausts energy from T cells and rigorously controls their ability to fight cancer.

• Protein METRNL is known to generates heat in cold or exercising animals by affecting the mitochondria in fat cells. Its role in cancer or T cells is not reported till now.
• It was believed that the metabolic dysfunction is one of the limiting factor for T cells capability to fight cancers.
• Recent study by Jackson and co-workers found out that CD8+T cells secrete METRNL, when stimulated repeatedly to eradicate tumour cells.
• This protein acts via the autocrine and paracrine signalling and disrupts the electron transport chain while interacting with mitochondria. This results in mitochondrial depolarization and decreased oxidative phosphorylation, which triggers a compensatory bioenergetic shift to glycolysis.
• This ultimately results in the hypo-function of T cells as T cells will be unable to meet the energy demands to kill the tumour cells.
• The bioenergetic insufficiency of CD8+ T cells created by the protein METRNL leads to the tumour growth and spreading.

This study demonstrates a possible translation of METRNL ablation for increased CD8+ T cell function in killing tumour cells. Thus targeting the METRNL pathway is useful in supporting the bioenergetic fitness of CD8+ Tumour infiltrating lymphocytes.

Novel Combinatorial Therapy for Colorectal Cancer

A novel two drug method for colorectal cancer has shown promise

• Nonconventional way of treating colorectal has been proposed by researchers from the Netherlands Cancer Institute
• Instead of inhibiting cell division, this approach uses one hyperactive oncogenic signalling drug to stress out the cells and another drug will kill the stressed out cells. According to the research group, this approach may be beneficial for microsatellite stable colon cancer, which is otherwise hard to treat.
• Dias and co-workers suggests that induction of hyperactivation by protein phosphatase 2A (PP2A) inhibitor engages stress response in colon cancer cells and these cells thus will be vulnerable to WEE1 inhibition
• Genetic and compound screens recognize the combined inhibition of PP2A and WEE1 as synergistic. They work by collapsing DNA replication and activates early mitosis followed by cell death.

This study was conducted in vitro as well as in vivo. Dias and colleagues are planning to carry forward this findings to a clinical trial.

Intermittent Fasting and Anti-Aging

A recent study divulges intermittent fasting can control aging through autophagy

Dietary interventions, such as caloric restriction and intermittent fasting, can slow down aging and promote longevity.

• Recent study conducted at the Institute of Molecular Biology and Biotechnology at the Paris Cité University, and at the University of Graz, Austria showed the mechanism by which spermidine regulates autophagy to promote the anti-aging effects of intermittent fasting.
• Hofer and colleagues showed that intermittent fasting increases the spermidine levels in individuals that boosts the pliability and survival of cells and organisms through the activation of autophagy.
• The research team used various experimental models including nematode, yeast, fruit fly, mouse and human cell lines to conclude this finding. Hofer and team asked the question of whether the cellular and physiological outcomes of caloric check and fasting depend on polyamine metabolism. They found out that spermidine levels were increased upon definite regimens of fasting or caloric restriction in all these organisms and prolonged the life span.
• Conversely, the use of appropriate spermidine inhibitors neutralizes the benefits of autophagy on the lifespan through intermittent fasting

This study throws light into the processes through which dietary habits can affect the aging of human beings. By these findings, new approaches will evolve for addressing age-related diseases aiming to enhance life expectancy and quality of life for elderly individuals.

Thermal Facial Image

Facial temperature patterns may be used to diagnose metabolic diseases and diseases of aging

• Body temperature is an important feature in aging and longevity as well as an important homeostatic factor that affects cellular function and survival of an organism.
• Body temperature is closely related to protein denaturation, metabolism and enzyme activities of an organism.
• In humans, the core body temperature is likely to decrease with age. It is also reported that high body temperature suggests an elevated metabolic rate, and this can even be stimulated by psychological and metabolic stress.
• It has been reported that the facial vascular and fat dissemination is augmented and closely linked with body surface temperature.
• Recently Yu and co-workers identified delicate temperature differences using a specific Artificial Intelligence (AI) derived spatial temperature patterns and a thermal camera.
• They collected thermal facial images of 2,811 individuals between 20 to 90 years of age and developed the ThermoFace method to automatically process and analyse images, and then created thermal age and disease prediction models.
• The ThermoFace deep learning model for thermal facial age has a mean absolute deviation of nearly 5 years in cross validation and 5.18 years in an independent cohort.
• The difference between predicted and chronological age is extremely related with metabolic parameters, sleep time, and gene expression pathways like DNA repair, lipolysis, and ATPase in the blood transcriptome, and it is modifiable by exercise.
• Constantly, ThermoFace disease predictors predict metabolic diseases like fatty liver with high accuracy (AUC > 0.80), with predicted disease probability associated with metabolic parameters.
• This study observed that those people with metabolic disorders (fatty liver disease and diabetes) showed faster thermal aging and they are likely to have elevated temperatures in the eye area than those without these conditions. People with raised blood pressure had higher cheek temperatures.
• They also showed that simple exercise of rope jumps (800jumps/day) for two weeks reduced the thermal facial aging by five years.

Cholesterol lowering drug and Diabetic Retinopathy

A recent study suggest fenofibrate therapy may reduce diabetic retinopathy progression.

• For more than 30 years, Fenofibrate is a drug that has been used to lower cholesterol.
• Preiss and co-workers recently reported that Fenofibrate reduces the risk of progression of diabetic retinopathy by 27%.
• A trial on Lowering Events in Non-proliferative retinopathy in Scotland (LENS) coordinated by the Oxford population health, compared the fenofibrate therapy with a placebo on the progression of retinopathy.
• In this study, 1,151 patients with type 1 or type 2 diabetes and also had early to moderate diabetic retinopathy, who participated in a routine diabetic eye screening program were included.
• Trial participants received 145-mg fenofibrate tablets or placebo.
• The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy.
• The results from the four year study showed that those patients who received fenofibrate had a 27% lower risk of requiring to be referred for specialized treatment for diabetic retinopathy compared to those patients who received placebo.

Sildenafil and Dementia

A recent study suggest sildenafil could help in preventing Dementia

• Sildenafil, a phosphodiesterase-5 inhibitor, generally known as Viagra is a well-known medication to treat erectile dysfunction and pulmonary arterial hypertension.
• Recently OxHARP trial by Webb and co-workers from the University of Oxford found out that sildenafil can enhance the blood flow to the brain and helps improve the function of brain blood vessels in patients at increased risk of vascular dementia.
• Vascular dementia is a condition caused by the brain damage or chronic damage to the small blood vessels in the brain due to impaired blood flow to brain. The patients with this condition have problems including reasoning, judgement, planning and memory. This chronic damage not only lead to vascular dementia but also to strokes and brain bleeds. This disease condition currently lacks specific therapies.
• The OxHARP trial was a double-blind, placebo-controlled study (n=75). The participants included in this trial were those who had a minor stroke and presented signs of mild to moderate small vessel disease.
• Each participant received sildenafil, a placebo, and cilostazol (a similar drug) over three-week periods in a randomized order. The study employed cardiovascular physiology tests, ultrasound, and functional MRI scans to evaluate the drugs' effects.
• The key findings from this trial were: (a) Sildenafil improved blood flow in both large and small brain vessels (b) Sildenafil showed improved blood flow response to carbon dioxide, indicating improved cerebrovascular function (c) Both sildenafil and cilostazol lowered blood vessel resistance in the brain but sildenafil caused very few side effects compared to the other drug.

The findings from the OxHARP trial looks promising. However, to confirm these findings and to explore the potential of sildenafil in treating vascular dementia, a large clinical trial is warranted.

AI to predict patient outcomes

Predictive model for immunotherapy response has been developed by research teams from MSKCC and NIH, USA

• Immune checkpoint blockade in cancer treatment is really promising, as this therapy eliminate the inhibitory pathways that obstruct the effectiveness of CD8+ T cells (Cytotoxic T cells). However the impact of such therapy in cancer treatment or predicting the response of such therapy is challenging.
• A study by the research teams at Memorial Sloan Kettering Cancer Centre (MSKCC) and the National Institutes of Health (NIH), USA (Chang and co-workers) have developed an artificial intelligence (AI) tool to predict whether the immunotherapy is going to be effective in patients.
• This research team used two predictive markers: tumour mutational burden and programmed cell death 1 ligand 1 (PD-L1) to predict the therapy response outcome.
• By using six feature logistic regression model, they developed a clinical score called LORIS (logistic regression-based immunotherapy-response score), which can predict the response of immunotherapy and can identify those patients who will respond to such therapy even with lower mutational burden or PD-L1 expression.
• LORIS helps in predicting patient objective response and short-term and long-term survival.

Development of this new AI tool may help all those patients undergoing immunotherapy. With few of the readily measurable features, LORIS may help in improving the clinical decisions as well as in improving the precision medicine approach by the clinicians. However, a larger prospective study is warranted to further evaluate this AI model in clinical settings.

Birdflu in Cows

Spillover of the avian influenza virus (H5N1) to cows had been reported in US and it is suggested that the milking process can be a possible route of viral spread between cows and also from cows to humans.

• Avian virus that has killed hundreds of millions of birds has now infected cattles in US.
• On 25th March, 2024 the US Health officials reported that H5N1 virus had been detected in dairy cows for the first time. Currently, the infections have been confirmed in nine states of US and in few dairy workers. All had mild symptoms only.
• Recent study by Sage et al., and Caserta et al., showed that milk from those cows infected with H5N1 comprises enormous numbers of viral particles and these particles can survive for hours in splattered milk. Thus virus can spread from cow to cow as well as from cow to humans as well.
• It was believed that cattles could not get infected with avian flu due to the lack of receptor that allows virus to enter their cells.
• But recent study by Kristensen and co-workers suggested that the virus can infect the cells in the mammary glands.
• Influenza A virus receptors on host cells are sialic acids that are bound to galactose in either an α2,3 or α2,6 linkage. Human Influenza A virus preferentially bind to human receptor (SA-α2,6), whereas avian virus have a preference for avian receptor (α2,3). These two receptors are apparently expressed in the bovine mammary gland.

Kidney Transplant Failure

A new therapeutic approach is safe and efficacious against rejection post kidney transplantation.

• In kidney transplantation, a prominent cause of transplant failure is antibody mediated rejection. So far there are no treatments available to effectively combat this hurdle in the long term.
• A recent clinical study by Katharina and co-workers from Vienna come up with a new therapeutic principle and has been found to be both safe and highly effective in transplant medicine.
• The clinical study involved 22 patients diagnosed with antibody-mediated rejection at least 180 days after kidney transplantation.
• A randomized double-blind and placebo-controlled clinical study was conducted and the patients were given either felzartamab, a humanized monoclonal antibody directed against CD38 or placebo.
• Patients received nine infusions of felzartamab (at a dose of 16 mg/kg body weight n=11) or placebo (n=11) for six months, followed by a six month observation period.
• The primary outcome of the study was safety and side-effect profile of felzartamab and the secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels.
• After 24 weeks, morphologic antibody mediated rejection was resolved with felzartamab (in 9 of 11 patients, 82%) than with placebo (2 of 10 patients, 20%).
• In the felzartamab group, microvascular inflammation score was lower and also a lower molecular score reflecting the probability of antibody-mediated rejection and the level of donor-derived cell-free DNA, than in the placebo.
• At 52 weeks, the relapse of rejection was registered in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels.

This study demonstrated that felzartamab had an acceptable safety profile as well as an effective therapy for late antibody-mediated rejection.

Gut, Bone Marrow, Tumor Axis

Gut microbiota linked to fatty diet drives cancer progression

• High fat diet is considered as a risk factor for the progression of cancers through the disturbance of intestinal microbiota. But how such a diet leads to the progression of cancer remains ambiguous.
• A recent study by Chen et al., discovered that obesity and obesity-related gut microbiome were linked to poor prognosis and advanced disease condition in breast cancer patients.
• Chen and co-workers took tissues and fecal samples from 61 breast cancer patients before the treatment. They observed that the obese patients (with BMI  24) had higher concentration of bacteria Desulfovibrio than the control (BMI 24).
• In mice model experiments also they observed that a high fat diet elevated the concentration of Desulfovibrio bacteria in the guts of mice, there by suppressing their immune system and facilitate the tumour progression.
• High fat diet associated gut microbiota creates leucine to encourage cancer progression by the generation and activation of polymorphonuclear MDSCs (myeloid-derived suppressor cells) in breast cancer and melanoma mice models.
• Leucine created by the high fat diet associated gut microbiota activates the mTORC1 signalling pathway in myeloid progenitors for polymorphonuclear MDSC differentiation.
• In clinic, the raised leucine level in the peripheral blood stimulated by the high fat diet microbiota was correlated with abundant tumoral polymorphonuclear MDSC infiltration and poor clinical outcomes in female patients with breast cancer.
• These findings exposed a new axis the “Gut- Bone Marrow-Tumor” axis, which is involved in high fat diet mediated cancer development.

This findings may open up an opportunity for anticancer therapeutic strategies by targeting the abnormal metabolism of the gut microbiota. As this study being done in China, we need to consider the gut microbiome composition of people over there. Gut microbiome can differ from place to place and also it will differ based on the diet people used to consume. So the caveat of this study is that, this study may not translate to other populations!!. A large multicentre study across the world may provide an answer.

Prognostic Biomarker for Breast Cancer

Researchers from Hunan Normal University, China have identified a new prognostic marker for invasive breast cancer.

• The research team found out a protein called retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L), and its expression levels may serve as a potential prognostic marker for invasive breast cancer.
• Yi and co-workers found out that RPGRIP1L expression was substantially raised in invasive breast cancer tissues compared to normal breast tissues.
• They also observed a prominent decline in the survival rates in those patients with elevated RPGRIP1L gene expression.
• Elevated RPGRIP1L gene expression is also associated with a range of adverse clinicopathological features including HER2 positivity, ER positivity, old age (patients over 60), and specific tumor stages such as T2, N0 and N3, suggesting more aggressive cancer as well as larger tumours.
• They also recognized 50 genes and 15 proteins whose expression levels were positively correlated with RPGRIP1L. Most of these genes and proteins are implicated in significant biological processes including proliferation of T cells, immune response, cytokine activity and metabolic regulation.
• This study also explored the therapeutic potential in light of these findings and identified four compounds (viz. abrine, epigallocatechin gallate, gentamicin, and tretinoin) that could downregulate the RPGRIP1L expression in laboratory.

Altogether, this study strongly showed that RPGRIP1L could be a new prognostic biomarker for invasive breast cancer and the compounds they identified could form the basis of new treatment strategies aimed at modifying RPGRIP1L levels to affect disease development and improve survival rates for breast cancer patients

Diverticulitis & Gut Microbiome

Gut microbiome composition and the metabolic activity may be associated with lots of diseases.

• Infection or inflammation that occurs in the pouches (diverticula) that forms in the intestine is called diverticulitis.
• Diverticulitis then terminate in other problems, including obstruction, fistula or abscess development or peritonitis. This condition is among the top 10 gastrointestinal disorders.
• Still the etiopathogenesis of diverticulitis remains a mystery.
• Recently Ma and co-workers, with the help of stool collected from diverticulitis patients (n=121) and age and race matched controls (n=121) performed shotgun metagenomic sequencing and untargeted metabolomics profiling.
• They observed that the microbial community structure and metabolomic reports were different in patients compared to the controls.
• The difference include augmentation of Ruminococcus gnavus, a proinflammatory gram-positive anaerobic bacterium, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides.
• This study also observed covariable microbial and metabolic features specific to the disease, diverticulitis (Bilophila wadsworthia and bile acids).
• This study also discovered the microbial composition modified the defensive association between a judicious fibre rich diet and diverticulitis.

This study highlights and provides an alarm to the inflammation related microbial and metabolomic signature related with this disease. This study thus supports the possibility of microbial-based diagnostics and therapeutic targets for diverticulitis.

Tumour origin

Prediction of tumour origin in cancers of unknown primary origin with cytology-based deep learning has been reported.

• Due to indefinable nature of the cancer of unknown primary (CUP) site, the diagnosis of such cancers remains a big question.
• CUP display as pleural and peritoneal serous outpourings or effusions.
• A recent study by Tian and co-workers pulled out 57,220 cytological images from 43,688 patients and developed a deep learning method that can recognize malignancy and forecast tumour origin in both hydrothorax and ascites.
• They call it as “tumour origin differentiation using cytological histology” (TORCH).
• Tian and team examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets.
• In both internal and external testing sets, TORCH attained area under the receiver operating curve values ranging from 0.953 to 0.991 for diagnosis of cancer and 0.953 to 0.979 for tumour origin localization.
• TORCH precisely forecasted primary tumour origins, with a top -1 accuracy of 82.6% and top-3 accuracy of 98.9%.
• Compared to pathologist’s results, TORCH showed better prediction efficacy (than junior pathologist’s)

This preliminary study highlights the potential of TORCH as a valuable supplementary tool in clinical practice. Even though the study is promising, a large cohort study and further validation in randomized trials is warranted. To me it looks like, deep learning methods and Artificial Intelligence may take over pathologists in diagnosing and prognosing diseases in the near future.

Nanoplastic Menace

Will nanoplastics and microplastics really harm human beings? An unanswered question even though there were concerns about its potential health risks.

• A recent study by Marfella and co-workers identified that diminutive bits of plastic inside the arteries may escalate the risks of cardiovascular disease.
• They conducted a prospective, multi-center, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease.
• The primary end point of the study was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of nano and microplastic particles in plaque as compared with patients with plaque that showed no evidence of such nano and microplastic particles.
• Marfella and co-workers excised carotid plaque specimens and analysed for the presence of nano and microplastics using pyrolysis gas chromatography mass spectrometry, stable isotope analysis, and electron microscopy.
• 304 patients were enrolled in this study. Out of which, 257 patients completed a follow-up of 33.7 ± 6.9 months.
• From the carotid artery plaque, polyethylene (n=150, 58.4%) and polyvinyl chloride (n=31, 12.1%) was detected.
• They observed that patients in whom nano and micro plastic particles were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected.

This study concluded that the patients with carotid artery plaque in which nano and micro-plastic particles were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom nano and microplastic particles were not detected. Observations from this study is certainly a cause for concern to the mankind!!

Breast Milk and Obesity

Thirty nine million children under the age of 5 were overweight/obese, according to WHO. A recent study pointed out that high-intensity exercise increases breast milk adiponectin concentrations and that may affect the infants

• WHO recommends breastfeeding for the first 6 months of life.
• It was observed that breastfed children have lower likelihood of becoming overweight/obese compared with bottle-fed children.
• Recent evidence suggests that breast milk composition may play a role in the mother-to-child transmission of obesity through lactational programming.
• Recently Holmen and co-workers observed that high-intensity exercise increases breast milk adiponectin concentrations.
• Adiponectin is an adipokine that plays a role in glucose and fat metabolism, which can cross the intestinal barrier and may modify infant metabolism.
• In the study participants who were exclusively breastfeeding a 6–12 week-old term infant (n = 20) were selected with (a) moderate-intensity continuous training (MICT), (b) High-intensity interval training (HIIT), and (c) No activity (REST).
• At each condition, Holmen and co-workers collected breast milk at 07:00 h (before exercise/rest), 11:00 h (immediately after exercise/rest), 12:00 h (1 h after exercise/rest), and 15:00 h (4 h after exercise/rest) and determined adiponectin concentrations using ELISA.
• They observed that Adiponectin concentrations increased 1 h after HIIT, from 4.6 (± 2.2) μg/L in the 07:00 h sample to 5.6 (± 2.6) μg/L.
• This change was 0.9 μg/L greater than the change between these two timepoints in the REST condition (p = 0.025).

Mothers who did high-intensity interval training had higher levels of adiponectin in their breast milk after their exercise session. It is probable that this hormone is absorbed through the intestines of breastfeeding babies, thus changing how their metabolism functions. Having low levels of this hormone is associated with insulin resistance and type 2 diabetes. Further studies should determine the impact of exercise-induced elevations in breast milk adiponectin concentrations on growth and metabolism in infancy.

CAR-T and Glioma

Targeting of two brain tumor-associated proteins with bivalent CAR-T cells shows promising results in Glioblastoma patients from an ongoing phase I clinical trial at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center, USA.

• In a phase 1 clinical trial Bagley and co-workers intrathecally delivered bivalent chimeric antigen receptor CAR-T cells targeting two receptors.
• Epidermal growth factor receptor (EGFR) is estimated to be present in 60 percent of all glioblastomas (GBMs) and interleukin-13 receptor alpha 2 (IL13Rα2) is expressed in over 75 percent of GBMs.
• As these two proteins are commonly found in brain tumors, they targeted EGFR and IL13Rα2 to recurrent glioblastoma (rGBM) patients.
• A total of six patients with rGBM were treated in a phase 1 trial and all six patients had progressive, multifocal disease at the time of treatment.
• The primary endpoints were safety and determination of the maximum tolerated dose whereas the secondary end point include the frequency of manufacturing failures and objective radiographic response (ORR).
• MRI scans 24 to 48 hours after CAR T cell administration revealed reduced tumor sizes in all six patients, and these reductions have been sustained out to several months later in a subset of patients.
• One of the major concerns was the early onset of neurotoxicity associated with CAR-T is such cases.
• At both dose levels (1 ×107 cells; n = 3 as well as 2.5 × 107 cells; n = 3) the researchers reported that all patients (n=6) had substantial but manageable neurotoxicity.

This first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. This encouraging results requires confirmation with additional patients and longer follow-up time. A real hope for GBM patients.

RNAi and Hypertension

According to new Phase II trial results, an RNA interference therapeutic agent, Zilebesiran, helps control blood pressure for several months in patients who are on standard of care.

• Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension.
• Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen (AGT) synthesis.
• AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System, a cascade that has a key role in blood pressure regulation .
• AGT’s inhibition has well-established antihypertensive effects.
• Zilebesiran is given as a single injection and its long-lasting effects could be a boon, especially in patients whose blood pressure is poorly controlled by standard treatments
• In the KARDIA-2 Phase II trial results released so far, the treatment significantly lowered blood pressure for at least three months.
• The KARDIA-2 results build on the Phase II KARDIA-1 data, presented at the congress of the American Heart Association Scientific Sessions in November 2023, and published by Bakris and co-workers recently.
• They found out that in a phase 2 trial, subcutaneous zilebesiran doses of 150, 300, or 600 mg every 6 months or 300 mg every 3 months significantly decreased systolic blood pressure at 3 and 6 months vs placebo.

All these recent reports suggests that, with at least twice-yearly dosing in combination with standard of care medication, zilebesiran has strong potential to sustain lower blood pressure and reduce the risk of stroke, heart attack and death that can result from inadequate treatment. Results from the trial looks like Zilebesiran has the potential to be used as an effective antihypertensive drug with quarterly or biannual dosing.

Universal Antivenom

A synthetic antibody that broadly neutralizes snake venom long chain α-neurotoxins developed.

• According to WHO, 5.4 million people worldwide are bitten by snakes each year and out of which, 1.8 to 2.7 million cases of envenomings happens every year.
• Around 81,410 to 137,880 people die each year because of snake bites.
• Current treatment strategy for snakebites envenoming rely on polyclonal antivenom derived from animals such as horses.
• Although these treatments can be life-saving, they can also result in serum sickness and anaphylaxis, and they require identification of the species of snake behind the bite.
• To address the current limitations, Khalek and co-workers recently used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins produced by numerous medically relevant snakes (cobras, kraits, and mambas), thereby addressing the limitations of the current
• This antibody bound diverse toxin variants with high affinity, blocked toxin binding to the nicotinic acetylcholine receptor in vitro, and protected mice from lethal venom challenge.

This research finding offers a promising framework for the creation of a monoclonal antibody-based universal antivenom to treat snakebite envenoming.

Memory B cells

A new type of Type 2 Memory B cells has been identified

• Food allergy is caused by allergen-specific IgE antibodies. But little is known about the B cell memory of persistent IgE responses.
• A recent study identified a type 2–polarized memory B cells that hold the memory of proteins that cause allergies (peanut).
• This Type 2 marked memory B cells was identified in single-cell RNA sequencing experiments by Ota and co-workers
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• These cells differentially expressed IL-4 and IL-13 regulated genes, such as FCER2/CD23+, IL4R, and germline IGHE, and carried highly mutated B cell receptors.
• CD23+IgG1+ memory B cells transcribing germline IGHE are a unique memory population containing precursors of high-affinity pathogenic IgE-producing cells that are likely to be involved in the long-term persistence of peanut allergy.

This study suggest that this Type 2 Memory B cells expressing IgG, CD23, and IL-4Rα as the source of pathogenic, allergen-specific IgE-producing cells.

Transmission of Alzheimer’s Disease

Recently iatrogenic Alzheimer’s disease has been reported for the first time.

• Alzheimer’s disease is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels and by neurofibrillary tangles of hyperphosphorylated Tau.
• Normally, Alzheimer’s disease arise spontaneously in older people. In USA for instance, about 1 in 9 people aged 65 and older have the disease.
• Alzheimer’s disease is not contagious and is not transmitted between individuals in everyday life, including caretaking and most medical settings.
• But there is a recent report of unintentionally induced Alzheimer’s disease in patients who received cadaveric pituitary-derived growth hormone.
• In 5 patients unusual symptoms of Alzheimer’s started early between 38 and 55 years of age.
• By looking at their previous history, Banerjee and co-workers noticed that all 5 patients received treatment with cadaver-derived pituitary growth hormone injections, a source of growth hormone used then, as children or teenagers to treat growth disorders.
• The study found out that the factors were contaminated with prions, that caused the disease called Creutzfeldt-Jakob disease (CJD). Globally, more than 200 people were affected.
• It was also observed that a higher-than-expected levels of Aβ in the brains of four people who had died with CJD.
• After analysing the results from those patients underwent growth hormone treatment, the researchers come to the conclusion that the growth hormones were contaminated with both CJD prions and Aβ seeds.
• This study points out that that Alzheimer’s disease like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms.

This study throw light to the iatrogenic Alzheimer’s disease transmission. The results of this research emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures.

Cannabis and adolescent brain

Delta-9-tetrahydrocannabinol (THC) changes teens’ brains

• According to the National Survey on Drug Use and Health, USA, only 35 percent of 12 to 17year olds perceive a “great risk of harm” from smoking marijuana once or twice a week.
• Compared to the past, the cannabis products available now are more potent. (i.e. the products available now can increase the risks for addiction and psychosis).
• Marijuana plants have been bred to contain more delta-9-tetrahydrocannabinol (THC), the main psychoactive chemical.
• In 1995, the total percent of THC by weight of marijuana plant material was around 4 percent whereas now marijuana with a THC potency of 20 percent or more is available.
• THC binds to one of the main receptors, called CB1, of the endocannabinoid system. This complex system influences many functions in the body.
• Studies in animals have found that exposure to THC in adolescence can reduce CB1 receptors in the brain and lead to long-lasting problems with memory and learning.
• THC alters the prefrontal cortex, which matures during adolescence and is integral to problem-solving and emotional regulation. Thus THC changes teens’ brains.

Morning Sickness

Fetally-derived protein GDF15 is the reason behind morning sickness

• Up to 80 percent of pregnant women get nauseous in the early pregnancy period. In that cohort, about half of the women vomit as well. Thus a combination of these two symptoms are often called as morning sickness.
• Up to 3 percentage of pregnant women will develop a condition called Hyperemesis Gravidarum (HG).
• In such women, vomiting will be so severe and frequent that it can lead to weight loss, dehydration and even hospitalization and death of the foetus or mother.
• So far researchers speculated morning sickness is caused by oestrogen or other hormones that are elevated early in pregnancy, elevated thyroid hormone, infections etc.
• Recently Fejzo and colleagues identified that this sickness is a disease.
• They observed that pregnant women with nausea and vomiting during pregnancy had higher levels of a protein called GDF15 in their blood than pregnant women without such symptoms.
• This protein which is made throughout the body and helps cells respond to stress, was previously found to act on a part of the brain involved in producing nausea and vomiting.
• Fejzo and colleagues observed that women with a genetic variant in the GDF15 gene have up to 10 times the risk of developing HG than people without the variant.
• Interestingly, those women with the genetic variant produce less GDF15 protein before pregnancy, but have elevated levels of GDF15 in their blood when they become pregnant.
• The striking finding here is that most of the GDF15 produced in pregnancy comes from the foetus and placenta.

This is an interesting finding and there is a possibility of developing drugs to block GDF15, thereby stopping or reversing this sickness. But before developing drugs few questions need to be answered including (a) what is the status of GDF15 in other ethnic groups, as this study focussed on people with European descent only (b) More in vivo safety data is needed to confirm that blocking GDF15 is not going to affect the growing foetus.