Many chemotherapeutic agents target cellular components or processes that are present in all cancers, yet clinical responses to these agents vary greatly between cancer types and even patient age - the basis for these broad-scale differences are unclear. The vast majority of targeted and cytotoxic cancer therapies including ionizing radiation produce pro-apoptotic signaling in exposed cells, suggesting that the mitochondrial apoptosis sensitivity of cancer cells could act as a central signaling “node” to broadly impact therapy outcomes. To test this, we used BH3 profiling and complementary chemosensitivity assays to analyze hundreds of primary cancer specimens across twelve major cancer types. We find that cancers with typically favorable outcomes including certain hematologic malignancies, testicular cancer, and some pediatric cancers contain mitochondria that are highly primed for apoptosis, which renders them hypersensitive to cytotoxic as well as targeted agents and radiation therapy. Priming levels in many epithelial cancers including ovarian cancer and non-small cell lung cancer are highly heterogeneous, mirroring their variability in clinical outcomes. Finally, many tumor types that are typically chemoresistant including adult soft tissue sarcomas, hepatocellular carcinoma and pancreatic cancer are almost completely resistant to pro-apoptotic signaling. By analyzing in vitro and in vivo pancreatic, ovarian, hepatocellular and sarcoma tumorigenesis models, we find that apoptotic priming generally increases during neoplastic transformation, in part due to consistent upregulation of pro-apoptotic proteins BAX and BAK. However, the level of apoptotic priming in cancer cells is constrained by the baseline apoptosis sensitivity of normal cells prior to transformation. Remarkably, we find that apoptotic priming is dynamically regulated by cell lineage and differentiation state but can also be modulated by oncogenes. For instance, Myc activation typically increases apoptotic priming while activation of mutant Ras signaling decreases it - these changes in priming alter the chemosensitivity of cancer cells. Finally, we use inducible mouse tumor models to demonstrate that neoplastic transformation of cells from developmentally immature tissues yields pediatric tumors that are more primed for apoptosis than equivalent tumors arising in adults. This difference in priming causes pediatric tumors to be more sensitive to front-line therapies and BH3 mimetics targeting pro-survival BCL-2 family proteins in vitro and in vivo. Thus, lineage-determined regulation of apoptosis prior to and during neoplastic transformation leads to broad-scale differences in cancer cell chemosensitivity and can be exploited therapeutically by targeting BCL-2 family proteins. Citation Format: Cameron Fraser, Xingping Qin, Kenichi Shimada, Johan Spetz, Mary Heather Florido, Rumani Singh, Stacey Yu, Adam Presser, Zintis Inde, Gaurav Joshi, Jennifer Guerriero, Francisco Sanchez-Rivera, Alison Karst, Omar Lopez, Chendi Li, Peter Winter, Ying Yue, Peter Sorger, Jingwei Cheng, Izidore Lossos, Aaron Hata, Ronny Drapkin, Adam Palmer, James Decaprio, Manisha Thakuria, Charles Yoon, Ursula Matulonis, Matthew Meyerson, Elizabeth Stover, Diana Cardona, Kris Wood, Shayna Sarosiek, David Kirsch, Joseph Mancias, Andrew Cherniack, Anthony Letai, Kristopher Sarosiek. Cancer sensitivity to therapy is constrained by apoptosis regulation in cells of origin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6130.

Abstract Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor. Significance: Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.

In the present experiment a total of 213 and 60 demonstrations were conducted on pigeon pea and chickpea crops respectively during three consecutive years from 2017–18, 2018–19, 2019–20 for productivity enhancement and sustainability of farmers income. The findings in respect to pigeon pea and chickpea, overall yield trend of demonstrations ranged from 12.43–17.38 q/ha and 14.62–18.97 q/ha and yield increase ranged from 36.70–43.14% and 42.67–57.91% over the local practices yield, respectively. The average percent reduction in affected plant/m2 and percent reduction in affected pod/plant were recorded 45.92 and 40.42 in pigeon pea and 45.48 and 44.56 in chickpea, respectively. The overall disease reduction was recorded 43.74% in pulse crops. The yield parameter reflected significantly more over district, state and national level productivity in pigeon pea and chickpea crop. Wide yield gap of both pulse crops also indicated that farmers should adopt latest production technologies with high yielding varieties and integrated plant protection components will subsequently change this alarming trend of galloping yield gap. Average gross returns and net returns of demonstration in pigeon pea and chickpea crops were 39.49 and 56.21% and 53.99 and 91.83% higher than the farmers’ practices respectively. Average benefit cost ratio was found higher throughout the study in pigeon pea and chickpea i.e. 3.34 and 3.01 respectively. The productivity was better over existing practices under demonstrations. Hence, pulses production and protection technology have a broad scope for increasing the area and production of pulse crops.

Flood is one of the major disasters occurring worldwide, which occurs frequently and affects many lives and property. In the present study, an automatic flood inundation mapping approach based on Sentinel-1 SAR datasets was used for the assessment of monsoonal flood events of the Brahmaputra River from 2015 to 2020. Google Earth Engine was used to prepare potential flood inundation maps using a change detection technique by processing SAR images. In total, around 144 SAR images were analysed for the study period, and it was found that the flood inundation extent was more in 2015 and 2016 at about 6 lakh hectares; thereby, it decreased in 2017 and 2018 near to 3.5 lakh hectares. Again, an increase in inundation extent was observed of about 6 lakh hectares in 2019 and 2020, respectively. The results were evaluated by applying binarisation thresholding, removing permanent water bodies and shadows from SAR images to delineate the actual flooded areas. It shows an encouraging overall validation accuracy of 93.6

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Although major organ toxicities frequently arise in patients treated with cytotoxic or targeted cancer therapies, the mechanisms that drive them are poorly understood. Here, we report that vascular endothelial cells (ECs) are more highly primed for apoptosis than parenchymal cells across many adult tissues. Consequently, ECs readily undergo apoptosis in response to many commonly used anticancer agents including cytotoxic and targeted drugs and are more sensitive to ionizing radiation and BH3 mimetics than parenchymal cells in vivo. Further, using differentiated isogenic human induced pluripotent stem cell models of ECs and vascular smooth muscle cells (VSMCs), we find that these vascular cells exhibit distinct drug toxicity patterns, which are linked to divergent therapy-induced vascular toxicities in patients. Collectively, our results demonstrate that vascular cells are highly sensitive to apoptosis-inducing stress across life span and may represent a "weakest link" vulnerability in multiple tissues for development of toxicities.

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A site-specific evaluation of pigeon pea (Cajanus cajan (L.) Millsp.) variety IPA 203 was carried out through farmers participatory approach during two consecutive years, i.e. 2018-19 to 2019-20. The results revealed that the average yield 15.40 q/ha was recorded from pigeon pea variety IPA 203 as compared to farmers practice 9.79 q/ha and an average yield advantage registered up to 57.30% higher over the farmers’ practice. It was also observed that the higher number of primary branches/plant (6), number of pods/plant (385), seed index (14.80 g/100 seed), net returns (₹ 55147.5/ha) and BCR (3.52) from high yielding pigeon pea variety IPA 203 as compared to the farmers’ practice, i.e., 3, 313, 11.50, 9.79, ₹ 29490/- and 2.51, respectively. The growth and yield attributes were considerably lower under farmer’s practices because of considerable variation in the extent of adoption of recommended variety and technology depending upon the amount of risk involved in terms of cost, convenience, skill and knowledge about the concerned practice. Average extension gap, technology gap and technology index of pigeon pea were found 5.61, 4.60 q/ha and 23.00% respectively. Variations in the technology gap and index percentage were observed due to variation in agro-climatic parameters, soil fertility, biotic stresses, and socio-economic status and management practices. This variation can be narrowed down by encourage the farmers to adopt economical viable technologies of pulse crops. From evaluation of the technology, it can be concluded that replacement of local/old varieties with new varieties would increase the production and net income of the farmers.

The changes that veterinary services have undergone in India over the last decades are expected to continue and result in the further involvement of paravets and Animal Health workers (AHWs) for Minor Veterinary Services delivery. Gopalamitras (Animal Health Workers (AHWs) of Andhra Pradesh) performance in Minor Veterinary Services delivery remains a major concern from stakeholders ’perspective. In the light of the above context, this paper focuses on the Strengths, Weaknesses, Opportunities and Threats (SWOT) of Gopalamitras. The major strengths are highly accessible for the farmers and proactive in AI service delivery. The major weaknesses are the services are target oriented and poor attention for preventive service delivery. The major opportunities are creating strong link with AHD and untapping the potential for extension and preventive services. The major threats are lack of assessment criteria evaluation procedures for their services in terms of quality and involvement in unauthorized service delivery. These findings can be reviewed by the policy makers to strengthen and explore the capacity of AHWs as a third tier of Animal Husbandry Department in Minor Veterinary service delivery.

An 8‐year‐old male child, born out of nonconsanguineous marriage, presented with dark‐colored skin lesion over the neck and abdomen. The parents of the child gave history of diminished vision and difficulty in speech and learning. The child was admitted at the age of 7 days for polycystic kidney diseasediagnosed by ultrasonographic findings. There was no history of skeletal deformity, neurological defects, or hearing impairment. There was no history of a similar dark‐colored lesion in the family.

The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.