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Abstract The Department of Biotechnology at Savitribai Phule Pune University organized an International Conference on Biology Beyond Boundaries: Mitochondrial Insights, Computational Breakthroughs, and Clinical Transformations. The symposium provided a highly interactive platform for sharing scientific ideas, cultural enrichment, and collaborations between scientists working across multidisciplinary areas including cell death and mitochondrial biology, computational approaches, and translational research to combat various human diseases. More than 250 delegates including international scientists, junior investigators, and students joined this exciting event. Several sessions were dedicated for junior investigators and graduate students to highlight scientific excellence as well as to gather scientific feedback in advancing their ongoing research. Although promising progress has been made in infectious diseases in India, noncommunicable diseases such as cancer, cardiac, and neurodegenerative diseases are increasing, leading to higher funding in these areas of research. The success of this meeting has provided a platform for future scientific conferences, which will foster collaborations between multidisciplinary areas of biological sciences to prevent and treat various human diseases in India, as well as further showcase the progress in Biomedical Sciences and Biotechnology throughout India.

Rituximab combined with systemic chemotherapy significantly improves the rate of complete response in B-cell lymphomas. However, acquired rituximab resistance develops in most patients leading to relapse. The mechanisms underlying rituximab resistance are not well-understood. MDM2 and MDM4 proteins are major negative regulators of p53, but they also have p53-independent activities in mouse models of lymphomagenesis. Whether MDM2 or MDM4 is involved in rituximab resistance has not been explored. Here we report that MDM2 and MDM4 are upregulated in p53-mutant rituximab-resistant cells by transcriptional and post-transcriptional mechanisms. Knockdown of MDM2 or MDM4 significantly hindered growth of rituximab-resistant cells. To explore whether targeting the RING-domain of MDM2-MDM4 heterodimers is a viable strategy for the treatment of rituximab-resistant lymphomas, we identified MMRi36 in a high throughput small-molecule screen. Here we show that MMRi36 binds and stabilizes MDM2-MDM4 RING heterodimers and acts as an activator of the MDM2-MDM4 E3 ligase complex in vitro and promotes proteasomal degradation of MDM2/MDM4 proteins in cells. MMRi36 potently induces p53-independent apoptosis in p53-mutant lymphoma cells and it exerts non-apoptotic anti-lymphoma effect in rituximab resistant cells. The pro-apoptotic mechanisms of MMRi36 involves activation of both caspase 3 and caspase 7 associated with increased polyubiquitination and degradation of XIAP. Therefore, MMRi36 is a novel prototype small-molecule for targeting MDM2/MDM4/XIAP for degradation and induction of apoptosis in p53-mutant lymphomas.

Software quality assurance has grown in importance in the fast-paced world of software development. One of trickiest parts of creating and maintaining software is predicting how well it will perform. The term "computer evaluation" refers to use of advanced AI techniques in software quality assurance, replacing human evaluations and paving the way for a new era in software evaluation. We proposed Hybrid Elephant herding optimized Conditional Long short-term memory (HEHO-CLSTM) to estimate Software Quality Prediction. Software quality prediction and assurance has grown in importance in ever-changing world of software development. Software quality prediction encompasses a wide range of activities aimed at improving the quality of software systems via the use of data-driven approaches for prediction, evaluation and enhancement. We have collected Software Defects data and we feature extracted the attributes using linear discriminant Analysis (LDA). The suggested system improves the accuracy, AUC and Buggy instance compared with the current methods.

Abstract The School of Life Sciences at the Jawaharlal Nehru University in New Delhi, India held an International Symposium on Mitochondria, Cell Death and Human Diseases on February 18–19, 2023. The meeting provided a highly interactive forum for scientific discussion, cultural exchange, and collaborations between international scientists working in diverse areas of mitochondrial biology, cell death, and cancer. The two-day symposium attracted more than 180 delegates that included leading international scientists, early career researchers in India, as well as postdoctoral fellows and students. Several of the students, postdoctoral fellows, and junior faculty presented platform talks and had a chance to showcase the depth and emerging progress in biomedical research in India. The meeting will be instrumental for planning future congresses and symposium throughout India, not only to focus on mitochondrial biology, cell death and cancer but to foster continued ferment and collaborations in the biological sciences throughout India.

Abstract Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPRmt inhibitor that blocked HSP60’s interaction with ClpP and abrogated survival signaling without altering HSP60’s chaperonin function. Disruption of HSP60-ClpP interaction with the UPRmt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPRmt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP–mediated UPRmt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.

Abstract The International Conference on Cell Death in Cancer and Toxicology 2018 (February 20–22, 2018) provided an international forum for scientific collaborations across multiple disciplines in cancer, cell death, and toxicology. During the three-day symposium, researchers and clinicians shared recent advances in basic, clinical, and translational research in cancer. Several student poster abstracts were selected for platform talks and many young investigators participated in the meeting. Together, this highly interactive meeting showcased the rapid expansion in biomedical research in India and paved the way for future meetings on cell death and cancer throughout India.

The human genetic code encrypted in thousands of genes holds the secret for synthesis of proteins that drive all biological processes necessary for normal life and death. Though the genetic ciphering remains unchanged through generations, some genes get disrupted, deleted and or mutated, manifesting diseases, and or disorders. Current treatment options—chemotherapy, protein therapy, radiotherapy, and surgery available for no more than 500 diseases—neither cure nor prevent genetic errors but often cause many side effects. However, gene therapy, colloquially called “living drug,” provides a one-time treatment option by rewriting or fixing errors in the natural genetic ciphering. Since gene therapy is predominantly a viral vector-based medicine, it has met with a fair bit of skepticism from both the science fraternity and patients. Now, thanks to advancements in gene editing and recombinant viral vector development, the interest of clinicians and pharmaceutical industries has been rekindled. With the advent of more than 12 different gene therapy drugs for curing cancer, blindness, immune, and neuronal disorders, this emerging experimental medicine has yet again come in the limelight. The present review article delves into the popular viral vectors used in gene therapy, advances, challenges, and perspectives.

Development of therapeutic resistance is responsible for most prostate cancer (PCa) related mortality. Resistance has been attributed to an acquired or selected cancer stem cell phenotype. Here we report the histone deacetylase inhibitor apicidin (APC) or ER stressor thapsigargin (TG) potentiate paclitaxel (TXL)‐induced apoptosis in PCa cells and limit accumulation of cancer stem cells. TXL‐induced responses were modulated in the presence of TG with increased accumulation of cells at G1‐phase, rearrangement of the cytoskeleton, and changes in cytokine release. Cytoskeletal rearrangement was associated with modulation of the cytoplasmic and mitochondrial unfolded protein response leading to mitochondrial dysfunction and release of proapoptotic proteins from mitochondria. TXL in combination with APC or TG enhanced caspase activation. Importantly, TXL in combination with TG induced caspase activation and apoptosis in X‐ray resistant LNCaP cells. Increased release of transforming growth factor‐beta (TGF‐β) was observed while phosphorylated β‐catenin level was suppressed with TXL combination treatments. This was accompanied by a decrease in the CD44+CD133+ cancer stem cell‐like population, suggesting treatment affects cancer stem cell properties. Taken together, combination treatment with TXL and either APC or TG induces efficient apoptosis in both proliferating and cancer stem cells, suggesting this therapeutic combination may overcome drug resistance and recurrence in PCa.

Human Nanog1 is a 305-amino acid (aa) homeodomain-containing transcription factor critical for the pluripotency of embryonic stem (ES) and embryonal carcinoma (EC) cells. Somatic cancer cells predominantly express a retrogene homolog of Nanog1 called NanogP8, which is ~99% similar to Nanog at the aa level. Although the predicted M.W of Nanog1/NanogP8 is ∼35 kD, both have been reported to migrate, on Western blotting (WB), at apparent molecular masses of 29-80 kD. Whether all these reported protein bands represent authentic Nanog proteins is unclear. Furthermore, detailed biochemical studies on Nanog1/NanogpP8 have been lacking. By combining WB using 8 anti-Nanog1 antibodies, immunoprecipitation, mass spectrometry, and studies using recombinant proteins, here we provide direct evidence that the Nanog1 protein in NTERA-2 EC cells exists as multiple M.W species from ~22 kD to 100 kD with a major 42 kD band detectable on WB. We then demonstrate that recombinant NanogP8 (rNanogP8) proteins made in bacteria using cDNAs from multiple cancer cells also migrate, on denaturing SDS-PAGE, at ~28 kD to 180 kD. Interestingly, different anti-Nanog1 antibodies exhibit differential reactivity towards rNanogP8 proteins, which can spontaneously form high M.W protein species. Finally, we show that most long-term cultured cancer cell lines seem to express very low levels of or different endogenous NanogP8 protein that cannot be readily detected by immunoprecipitation. Altogether, the current study reveals unique biochemical properties of Nanog1 in EC cells and NanogP8 in somatic cancer cells.

Reduction or depletion of mitochondrial DNA (mtDNA) has been associated with cancer progression. Although imbalanced mtDNA content is known to occur in prostate cancer, differences in mtDNA content between African American (AA) and Caucasian American (CA) men are not defined. We provide the first evidence that tumors in AA men possess reduced level of mtDNA compared to CA men. The median tumor mtDNA content was reduced in AA men. mtDNA content was also reduced in normal prostate tissues of AA men compared to CA men, suggesting a possible predisposition to cancer in AA men. mtDNA content was also reduced in benign prostatic hyperplasia (BPH) tissue from AA men. Tumor and BPH tissues from patients ≥ 60 years of age possess reduced mtDNA content compared to patients 7 compared to ≤ 7, whereas reduced mtDNA content was observed in tumors of Gleason grade >7 compared to ≤ 7. Together, our data suggest that AA men possess lower mtDNA levels in normal and tumor tissues compared to CA men, which could contribute to higher risk and more aggressive prostate cancer in AA men.

In the intrinsic death pathway, cytochrome C (CC) released from mitochondria to the cytosol triggers Apaf-1 apoptosome formation and subsequent caspase activation. This process can be recapitulated using recombinant Apaf-1 and CC in the presence of nucleotides ATP or dATP [(d)ATP] or using fresh cytosol and CC without the need of exogenous nucleotides. Surprisingly, we found that stored cytosols failed to support CC-initiated caspase activation. Storage of cytosols at different temperatures led to the loss of all (deoxy)nucleotides including (d)ATP. Addition of (d)ATP to such stored cytosols partially restored CC-initiated caspase activation. Nevertheless, CC could not induce complete caspase-9/3 activation in stored cytosols, even with the addition of (d)ATP, despite robust Apaf-1 oligomerization. The Apaf-1 apoptosome, which functions as a proteolytic-based molecular timer appeared to be defective as auto-processing of recruited procaspase-9 was inhibited. Far Western analysis revealed that procaspase-9 directly interacted with Apaf-1 and this interaction was reduced in the presence of physiological levels of ATP. Co-incubation of recombinant Apaf-1 and procaspase-9 prior to CC and ATP addition inhibited CC-induced caspase activity. These findings suggest that in the absence of nucleotide such as ATP, direct association of procaspase-9 with Apaf-1 leads to defective molecular timer, and thus, inhibits apoptosome-mediated caspase activation. Altogether, our results provide novel insight on nucleotide regulation of apoptosome.

Software quality assurance has grown in importance in the fast-paced world of software development. One of trickiest parts of creating and maintaining software is predicting how well it will perform. The term "computer evaluation" refers to use of advanced AI techniques in software quality assurance, replacing human evaluations and paving the way for a new era in software evaluation. We proposed Hybrid Elephant herding optimized Conditional Long short-term memory (HEHO-CLSTM) to estimate Software Quality Prediction. Software quality prediction and assurance has grown in importance in ever-changing world of software development. Software quality prediction encompasses a wide range of activities aimed at improving the quality of software systems via the use of data-driven approaches for prediction, evaluation and enhancement. We have collected Software Defects data and we feature extracted the attributes using linear discriminant Analysis (LDA). The suggested system improves the accuracy, AUC and Buggy instance compared with the current methods. [ABSTRACT FROM AUTHOR]