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Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc–dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction‐induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene‐induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans. This study offers a novel view on the role of telomere attrition in human tumours, providing evidence for tumour suppressor activity resulting from telomere dysfunction‐induced DNA damage responses.

It has been observed that osmotic stress induces various changes in different cell types. Mammalian kidney cells are normally exposed to high osmotic concentrations as a consequence of their participation in the urinary concentration mechanism (Natalia et al., 2005). Cell structure and volume dependent remodeling of cytoskeleton is known to be influenced as an adaptive response to withstand high osmotic stress (Di Ciano et al., 2002). We investigated the role and induction of p38MAPK and Heat Shock Proteins (HSPs) in both human hematopoietic and mouse kidney cells (cortical and medullary) in response to sodium chloride induced hyperosmotic stress. Inhibitors of p38 MAPK and HSPs were used to define their contributions to hyperosmotic stress. Acute stress led to increased p38 MAPK and HSP27 mRNA levels in the human hematopoietic cell line whereas an upregulation of p38MAPK mRNA in the cortical cells of kidney and an increase in HSP70.1 mRNA levels in the medullary cells of kidney was observed. Using RT-PCR and Western immunoblotting both mRNA and protein levels of heat shock proteins, HSP27 and HSP70 were quantified. The p38MAPK inhibitor, SB203580 inhibited the induction of HSP70 in the medullary cells. In addition, HSP inhibitor, KNK-437 also inhibited the p38MAPK levels thereby suggesting that both HSP70 and p38MAPK are required for each other's induction and activation in the hyperosmotically stressed medullary cells of the kidney. Since the p38MAPK levels were inhibited in the cortical cells in presence of KNK-437, it suggests that HSP70 plays a role in induction of p38MAPK in these cells. Studies with mIMCD-3 cells, the inner medullary collecting duct cell line and M-1, the cortical cell line from mouse, indicate that cells from different parts of the kidney respond differently to high osmotic stress.

Entomopathogenic fungi Metarhizium species are generally employed to manage the soil-dwelling stage of insect pests, and are known for their rhizocompetency property. Since this fungus is typically recommended for use in soil, it could potentially be investigated as a bioinoculant to reduce abiotic stress, such as salinity, along with improved plant growth promotion. Salt stress tolerance potential of native Metarhizium isolates was evaluated based on mycelial fresh weight, dry weight, and spore yield. All the isolates were found to tolerate NaCl concentrations (50 mM, 100 mM, 150 mM, 200 mM, 250 mM, and 300 mM) supplemented in the culture medium. Metarhizium anisopliae (AAUBC-M15) and Metarhizium pinghaense (AAUBC-M26) were found to be effective at tolerating NaCl stress up to 200 mM NaCl. These two isolates were analyzed in vitro for plant growth-promoting traits at elevated salt concentrations (100 and 200 mM NaCl). No significant effect on IAA production was reported with the isolate M. pinghaense (AAUBC-M26) (39.16 µg/mL) or in combination with isolate M. anisopliae (AAUBC-M15) (40.17 µg/mL) at 100 mM NaCl (38.55 µg/mL). The salinity stress of 100 mM and 200 mM NaCl had a significant influence on the phosphate solubilization activity, except in the co-inoculation treatment at 100 mM NaCl. The isolates were positive for ACC deaminase enzyme activity. An increase in salt concentration was accompanied by a steady and significant increase in chitinase enzyme activity. Total phenolics (149.3 µg/mL) and flavonoids (79.20 µg/mL) were significantly higher in the culture filtrate of Metarhizium isolates at 100 mM NaCl, and gradual decline was documented at 200 mM NaCl. M. pinghaense (AAUBC-M26) proved to be promising in reducing the salt stress in tomato seedlings during the nursery stage. In the pot culture experiment, the treatment comprising soil application + seedling root dip + foliar spray resulted in improved growth parameters of the tomato plant under salt stress. This study shows that Metarhizium, a fungus well known for controlling biotic stress brought on by insect pests, can also help plants cope with abiotic stress, such as salinity.

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management.

Genome-wide methylome sequencing of serial samples obtained from patients with acute myeloid leukemia reveals that epigenetic alleles and genetic alleles follow independent courses during disease evolution. Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.

Somatic cell nuclear transfer (SCNT) allows the multiplication of elite livestock and conservation of endangered species. However, restrictions on cow slaughter limit the access to oocytes for SCNT applications in Indian cattle breeds. To overcome this limitation, we utilized transvaginal ovum pick-up (OPU) method to collect oocytes, which were then used for the production of cloned embryos via the handmade cloning (HMC) technique. A total of 98 Sahiwal oocytes were collected, leading to the successful reconstruction of 24 SCNT Gir embryos. Out of these, five developed into blastocysts, which were transferred into five recipient cows. Two pregnancies were confirmed, but one was lost due to hydro-allantois condition. The other pregnancy continued to term, and a healthy Gir female calf weighing 32 kg was born. Microsatellite DNA analysis confirmed the genetic identity of the cloned calf to its donor. Postnatally, the calf was monitored for serum cytokine parameters, telomere length, and reproductive potentials. Cytokine profiling revealed variations between the cloned calf and naturally conceived counterparts; however, the born cloned calf did not exhibit any pathological conditions and has high telomere length compared to age-matched counterparts, and surviving well. Furthermore, to assess cloned cow utility in reproductive biotechnologies, we produced blastocyst stage embryos (35%) through OPU-IVF method and established one pregnancy from five transfers (20%). In conclusion, this study reports the first successful SCNT of Indian cattle breed and demonstrates the feasibility of the cloned cow for the production of OPU-IVF embryos.

This study evaluated the effects of the Breath–Body–Mind Workshop (BBMW) (breathing, movement, and meditation) on psychological and physical symptoms and inflammatory biomarkers in inflammatory bowel disease (IBD).MethodsTwenty-nine IBD patients from the Jill Roberts IBD Center were randomized to BBMW or an educational seminar. Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory 18, IBD Questionnaire, Perceived Disability Scale, Perceived Stress Questionnaire, Digestive Disease Acceptance Questionnaire, Brief Illness Perception Questionnaire, fecal calprotectin, C-reactive protein, and physiological measures were obtained at baseline and weeks 6 and 26.ResultsThe BBMW group significantly improved between baseline and week 6 on Brief Symptom Inventory 18 (P = 0.02), Beck Anxiety Inventory (P = 0.02), and IBD Questionnaire (P = 0.01) and between baseline and week 26 on Brief Symptom Inventory 18 (P = 0.04), Beck Anxiety Inventory (P = 0.03), Beck Depression Inventory (P = 0.01), IBD Questionnaire (P = 0.01), Perceived Disability Scale (P = 0.001), and Perceived Stress Questionnaire (P = 0.01) by paired t tests. No significant changes occurred in the educational seminar group at week 6 or 26. By week 26, median C-reactive protein values decreased significantly in the BBMW group (P = 0.01 by Wilcoxon signed-rank test) versus no significant change in the educational seminar group.ConclusionsIn patients with IBD, participation in the BBMW was associated with significant improvements in psychological and physical symptoms, quality of life, and C-reactive protein. Mind–body interventions, such as BBMW, which emphasize Voluntarily Regulated Breathing Practices, may have significant long-lasting benefits for IBD symptoms, anxiety, depression, quality of life, and inflammation. BBMW, a promising adjunctive treatment for IBD, warrants further study.

Background Globally, most children seek emergency care at general rather than specialized pediatric emergency departments. There remains significant variation in the provision of pediatric emergency care, particularly in resource-constrained settings. The objective of this study is to pilot a self-assessment tool to evaluate pediatric emergency care capabilities in low- and middle-income country (LMIC) hospitals on the African Continent. Methods This was a prospective cross-sectional descriptive study using a convenience sample of sub-Saharan African hospitals. The assessment tool was developed by operationalizing the technical contents of existing standards and guidelines from international bodies including the World Health Organization and International Federation of Emergency Medicine. The pilot was conducted at emergency departments located across different regions on the African continent. Descriptive statistics were used to evaluate different domains of pediatric emergency care capabilities including pediatric triage, protocols, staffing, training, equipment, consumables, and medicines. Results Sixteen hospitals with emergency departments completed the assessment tool (participation rate of 76%). The hospitals were in nine different countries across four regions of sub-Saharan Africa. National/academic hospitals comprised 56.3% of the participating hospitals. The majority, 44%, of these hospitals saw pediatric patient volumes of 2,000–4,999 patients per year. Dedicated pediatric triage spaces and resuscitation spaces were available at 37.5% and 56.3%, respectively. Formal pediatric resuscitation guidelines were used at 62.5%. Doctors on the self-assessment teams came from primarily pediatrics and general practitioner training backgrounds (both 68.8%). Basic respiratory and airway support equipment (e.g. oxygen, bag-valve mask devices) were available in all participating hospitals, whereas advanced airway equipment (e.g. pediatric intubation equipment) was available in 37.5% of hospitals. Most medicines from the World Health Organization Essential Medicines list were available at participating hospitals. Conclusions To date, this is the first assessment tool dedicated to the comprehensive evaluation of pediatric emergency care in LMICs. This pilot provides a first approach to evaluate pediatric emergency healthcare capabilities in the hospital setting with future directions to improve the tool based on qualitative feedback.