tbuckley/cabot-search huggingface dataset:
Human skeletal muscle aging atlas
Authors: Veronika R. Kedlian, Yaning Wang, Tianliang Liu, Xiaoping Chen, Liam Bolt, Catherine Tudor, Zhuojian Shen, Eirini S. Fasouli, Elena Prigmore, Vitalii Kleshchevnikov, Jan Patrick Pett, Tong Li, John E. G. Lawrence, Shani Perera, Martin Prete, Ni Huang, Qin Guo, Xinrui Zeng, Lu Yang, Krzysztof Polański, Nana-Jane Chipampe, Monika Dabrowska, Xiaobo Li, Omer Ali Bayraktar, Minal Patel, Natsuhiko Kumasaka, Krishnaa T. Mahbubani, Andy Peng Xiang, Kerstin B. Meyer, Kourosh Saeb-Parsy, Sarah A. Teichmann, Hongbo Zhang
Journal: Nature Aging (2024)

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment. We found that distinct subsets of muscle stem cells exhibit decreased ribosome biogenesis genes and increased CCL2 expression, causing different aging phenotypes. Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction. Overall, we present a comprehensive human skeletal muscle aging resource ( https://www.muscleageingcellatlas.org/ ) together with an in-house mouse muscle atlas to study common features of muscle aging across species.
Environmental Exposures and Pediatric Cardiology: A Scientific Statement From the American Heart Association
Authors: Justin P. Zachariah, Pei-Ni Jone, Andrew O. Agbaje, Heather H. Ryan, Leonardo Trasande, Wei Perng, Shohreh F. Farzan
Journal: Circulation (2024)

Environmental toxicants and pollutants are causes of adverse health consequences, including well-established associations between environmental exposures and cardiovascular diseases. Environmental degradation is widely prevalent and has a long latency period between exposure and health outcome, potentially placing a large number of individuals at risk of these health consequences. Emerging evidence suggests that environmental exposures in early life may be key risk factors for cardiovascular conditions across the life span. Children are a particularly sensitive population for the detrimental effects of environmental toxicants and pollutants given the long-term cumulative effects of early-life exposures on health outcomes, including congenital heart disease, acquired cardiac diseases, and accumulation of cardiovascular disease risk factors. This scientific statement highlights representative examples for each of these cardiovascular disease subtypes and their determinants, focusing specifically on the associations between climate change and congenital heart disease, airborne particulate matter and Kawasaki disease, blood lead levels and blood pressure, and endocrine-disrupting chemicals with cardiometabolic risk factors. Because children are particularly dependent on their caregivers to address their health concerns, this scientific statement highlights the need for clinicians, research scientists, and policymakers to focus more on the linkages of environmental exposures with cardiovascular conditions in children and adolescents.
The role of the brain renin-angiotensin system in Parkinson´s disease
Authors: Jose Luis Labandeira-Garcia, Carmen M. Labandeira, Maria J. Guerra, Ana I. Rodriguez-Perez
Journal: Translational Neurodegeneration (2024)

Abstract The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca 2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood–brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
1,2,4,5‐Tetraoxane derivatives/hybrids as potent antimalarial endoperoxides: Chronological advancements, structure−activity relationship (SAR) studies and future perspectives
Authors: Abdul Rahaman T. A., Thakar Neha Rajendra, Kshirsagar Prasad Suhas, Sirish K. Ippagunta, Sandeep Chaudhary
Journal: Medicinal Research Reviews (2024)

Abstract Malaria is a life‐threatening disease that affects tropical and subtropical regions worldwide. Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5‐tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5‐tetraoxanes were fused with various aryl/heteroaryl/alicyclic/spiro moieties (steroid‐based 1,2,4,5‐tetraoxanes, triazine‐based 1,2,4,5‐tetraoxanes, aminoquinoline‐based 1,2,4,5‐tetraoxanes, dispiro‐based 1,2,4,5‐tetraoxanes, piperidine‐based 1,2,4,5‐tetraoxanes and diaryl‐based 1,2,4,5‐tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992–2022). We summarize the most significant in vitro, in vivo results and structure–activity relationship studies of 1,2,4,5‐tetraoxane‐based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5‐tetraoxane‐based hybrids to treat malaria.
Abstract P64: Adipose-enriched Peri-tumoral Stroma Prognosticates Poorer Survival in Breast Cancers
Authors: Hannah Si Hui Lau, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Yirong Sim, Jelmar Quist, Aye Aye Thike, Puay Hoon Tan, Shazib Pervaiz, Anita Grigoriadis, Kanaga Sabapathy
Journal: Cancer Research (2024)

Abstract Background: Breast cancers display a large degree of diversity between and within tumors. Intra-tumoral heterogeneity is contributed by variations in tumor cells and non-malignant stromal and immune cells of the tumor microenvironment (TME). So far, studies on the TME have focused on intra-tumoral stroma, whereas little attention has been given to the peri-tumoral microenvironment, extending beyond the tumor margins into the surrounding histologically normal-appearing tissues. Here, we hypothesized that intrinsic intra-tumoral heterogeneity impacts the more distal peri-tumoral stroma, which may in turn affect tumor growth and development. Methods: A systematic, multi-regional transcriptomic profiling analysis of the tumor and peri-tumoral regions from 8 ER+/PR+/HER2− invasive breast carcinomas was performed using the human Clariom™ S Assay. For each patient, 5 spatially distinct tumor samples were obtained, while peri-tumoral samples were collected from 4 different sides and at varying distances up to 7 cm from tumor margins. Pathway enrichment analyses and cellular deconvolution were performed to determine their molecular characteristics and cell type compositions. Gene expression signatures identified from peri-tumoral samples were applied to tumor-adjacent normal RNA-seq samples from 50 TCGA ER+/PR+/HER2− breast cancer patients to determine their prognostic value. Results: The 8 tumors displayed varying levels of spatial diversity in their biological properties, including 3 tumors with basal-classified regions. Four peri-tumoral clusters with distinct pathway activities and cell compositions were identified, but were independent of distance and location to the tumor. Two clusters reflect the major breast peri-tumoral states – a pro-inflammatory, adipose-enriched phenotype which was significantly associated with poorer overall survival (HR=4.28, p-value=0.02), and an adaptive immune cell- and myofibroblast-enriched phenotype. Conclusion: This suggests that the peri-tumoral stroma may be an important determinant in cancer progression. Moreover, independent of spatially-defined patterns, the peri-tumoral phenotype appears to be driven by inter-individual variations in the proportion of fibroglandular and fat tissue of the breast. Citation Format: Hannah Si Hui Lau, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Yirong Sim, Jelmar Quist, Aye Aye Thike, Puay Hoon Tan, Shazib Pervaiz, Anita Grigoriadis, Kanaga Sabapathy. Adipose-enriched Peri-tumoral Stroma Prognosticates Poorer Survival in Breast Cancers [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P64.
Abstract P50: <i>PAX9</i> Activates Cell Death via Autophagic Degradation of EGFR in Oral squamous Cell Carcinoma
Authors: Chandra Sekhar Bhol, Gautam Sethi, Sujit Kumar Bhutia
Journal: Cancer Research (2024)

Abstract PAired boX 9 (PAX9) gene belongs to the PAX family and is critically essential for physiology and development. It has a significant role in maintaining squamous cell differentiation, and its downregulation is associated with tumor initiation and malignant transformation. In this study, we have analyzed the tumor suppressive potential of PAX9 by activating autophagy-dependent apoptosis in oral squamous cell carcinoma (OSCC). PAX9 overexpression inhibited cell growth and triggered apoptosis in OSCC. Moreover, PAX9 restricted orosphere formation and epithelial-mesenchymal transition in OSCC. Similarly, overexpression of PAX9 in OSCC induced autophagy activation and displayed enhanced lysosomal function in the transcriptional-dependent mechanism. Interestingly, PAX9-activated autophagy caused EGFR degradation leading to OSCC inhibition, thus establishing that PAX9 could induce lethal autophagy. In addition, PAX9 involves chemosensitizing OSCC to anticancer drugs, which exhibited profound growth inhibitory potential in OSCC. To check the status of PAX9 expression in OSCC in patient tissue, we performed IHC, and surprisingly, the expression of PAX9 was found to decreased in a higher grade of cancer tissues compared to the normal tissues. Further, we established a DMBA-induced oral carcinoma in hamster model, and it was observed that the expression of PAX9 was decreased in the 12th and 16th weeks of DMBA-exposed tissue compared to the normal tissue. On a mechanistic view, PAX9 expression was reduced with enhanced expression of DNMT1 in exposure to carcinogen in OSCC in vitro, indicating a potential association of methylation in controlling the expression of PAX9 during carcinogenesis. Citation Format: Chandra Sekhar Bhol, Gautam Sethi, Sujit Kumar Bhutia. PAX9 Activates Cell Death via Autophagic Degradation of EGFR in Oral squamous Cell Carcinoma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P50.
Abstract P57: A Transcriptome-Wide Meta-Analysis Reveals Lack Of Cancer-Cell Intrinsic Determinants Of Response To Immune Checkpoint Blockade
Authors: Yu Amanda Guo, Tanmay Kulshrestha, Mei Mei Chang, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Aaron C. Tan, Daniel S.W. Tan, Iain Beehuat Tan, Anders Jacobsen Skanderup
Journal: Cancer Research (2024)

Abstract Immune-checkpoint blockade therapy (ICB) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Current FDA-approved biomarkers for ICB include PD-L1 expression, microsatellite instability (MSI), and high tumor mutation burden (TMB) of &amp;gt;10mutations/Mb. In addition, gene expression signatures of tumor immune phenotypes have been proposed to predict for ICB response. Despite these efforts, there is a lack of large-scale transcriptome-wide studies to identify and characterize potential biomarkers of ICB response conserved across cancer types in a cell type specific manner. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. We identified 59 stroma-specific differentially expressed genes associated with ICB-response, which were strongly enriched in immune-related pathways and processes. Stromal expression of CXCL9, CXCL13, IFNG, and CD274 were among the top positive determinants of ICB response, consistent with current knowledge. Interestingly, we also identified a group of potential immune-suppressive genes, including FCER1A, associated with poor response to ICB. Surprisingly, the unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic features of ICB response conserved across tumor types. Overall, our results suggest that cancer cells lack tissue-agnostic molecular determinants of ICB response, which has implications for the development of improved ICB diagnostics and treatments. Citation Format: Yu Amanda Guo, Tanmay Kulshrestha, Mei Mei Chang, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Aaron C. Tan, Daniel S.W. Tan, Iain Beehuat Tan, Anders Jacobsen Skanderup. A Transcriptome-Wide Meta-Analysis Reveals Lack Of Cancer-Cell Intrinsic Determinants Of Response To Immune Checkpoint Blockade [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P57.
Abstract P49: PROTAC A1874: A Potential Targeted Therapy for Breast Cancer
Authors: Charlie Marvalim, Arpita Datta, Serena Bee Kee Seah, Edward Kai-Hua Chow, Soo Chin Lee
Journal: Cancer Research (2024)

Abstract Background PROteolysis TArgeting Chimera (PROTAC) A1874 is a heterobifunctional structured compound consisting of a BRD4-recognizing ligand and an MDM2-recognizing ligand that functions to degrade BRD4 via the ubiquitin-proteasome system. A1874 also plays a dual role in downregulating downstream BRD4 regulator, MYC, and stabilizing p53 within nanomolar concentrations. This PROTAC thus presents itself as a potential therapy for both estrogen-receptor positive (ER+) and triple-negative breast cancer (TNBC) subtypes, which typically harbors wild-type p53 and are associated with MYC overexpression respectively. Thus, this study aims to 1) investigate the anti-oncogenic effects and mechanism of A1874 and 2) its effect in combination with existing therapies in several breast cancer (BC) cell lines. Methods A panel of BC cell lines harboring different p53 status were tested for their sensitivity to A1874. Several functional assays were conducted to determine the anti-oncogenic effects of A1874. Bliss scores were calculated using SynergyFinder to determine the interaction of drugs in combination with A1874. Results BC cell lines with p53 WT status showed significantly lower IC50 sensitivity to A1874 in the nanomolar range compared to those with p53 mutation, which exhibited sensitivity in the micromolar range regardless of subtypes. Moreover, it is effective in Tam-resistant ER+, p53 WT cells. A1874 exclusively degrades BRD4 in p53 WT cells and causes G1 arrest, inhibition of colony formation, proliferation, and migration. Knockdown of MDM2 or TP53, and lentiviral transduction of p53 mutant plasmid resulted in significant reduction in sensitivity to A1874 in p53 WT cell lines and abrogate its BRD4-degrading effect. Combination of A1874 with the mutant p53 reactivating drug, PRIMA-1, synergistically resensitize mutant p53 cells to the cytotoxic effect of A1874 across subtypes. Conclusions Our results highlight a promising potential of PROTAC A1874 as a therapeutic drug in breast cancer, specifically the ER+ subtype which typically retains its p53 WT status. Citation Format: Charlie Marvalim, Arpita Datta, Serena Bee Kee Seah, Edward Kai-Hua Chow, Soo Chin Lee. PROTAC A1874: A Potential Targeted Therapy for Breast Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P49.
Abstract P42: Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy
Authors: Divya Ram Jayaram, Sigal Frost, Chanan Argov, Vijayasteltar Belsamma Liju, Nikhil Ponnoor Anto, Amitha Muraleedharan, Assaf Ben-Ari, Rose Sinay, Ilan Smoly, Ofra Novoplansky, Noah Isakov, Debra Toiber, Chen Keasar, Moshe Elkabets, Esti Yeger-Lotem, Etta Livneh
Journal: Cancer Research (2024)

Abstract About 40% of human mRNAs contain upstream open reading frames (uORFs) in their 5’-untranslated regions. Some of these uORF sequences thought to attenuate scanning ribosomes or lead to mRNA degradation were recently shown to be translated, although the function of most encoded peptides remains unknown. Our recent study was the first to reveal a uORF-encoded peptide exhibiting kinase inhibitory activity (Jayaram DR, et al. PNAS (2021)). This uORF (uORF2), upstream of a protein kinase C (PKC) family member (PKCeta) main ORF, encodes for a peptide (uPEP2) containing the typical PKC pseudosubstrate (PS) motif present in all PKCs that auto-inhibits their kinase activity. We show direct binding and selective inhibition of the catalytic activity of novel PKCs by uPEP2 (but not of classical or atypical PKCs). Functionally, treatment of breast cancer cells with uPEP2 diminished cell survival and their migration and synergized with chemotherapy by interfering with the response to DNA damage. Furthermore, in a xenograft of MDA-MB-231 triple-negative breast cancer in mice models, uPEP2 suppressed tumor progression, invasion, and metastasis. The endogenous deletion of uORF2 by CRISPR/Cas9 in the non-tumorigenic MCF-7 cells showed that it impedes cell proliferation, acting as a growth suppressor. Its role in tumor formation and metastasis is presently studied in breast cancer models with metastasis to the lungs. Together, we point to a new layer of protein regulation by a uORF-encoded kinase inhibitor, which could present a forerunner for other uORFs, possessing kinase inhibitory function. Notably, we have recently identified an additional uORF with a PS motif upstream of another PKC. As kinase inhibitors, uORF-encoded peptides may play a role in signaling and stress, acting in cis and/or in trans, forming diverse regulatory networks, thereby opening new views into eukaryotic protein regulation and cancer biology. Citation Format: Divya Ram Jayaram, Sigal Frost, Chanan Argov, Vijayasteltar Belsamma Liju, Nikhil Ponnoor Anto, Amitha Muraleedharan, Assaf Ben-Ari, Rose Sinay, Ilan Smoly, Ofra Novoplansky, Noah Isakov, Debra Toiber, Chen Keasar, Moshe Elkabets, Esti Yeger-Lotem, Etta Livneh. Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P42.
Abstract P33: Novel Reporter Cell Models for Efficient Interrogation of Helicase Activity in Cancer-associated DDX3X Mutations
Authors: Zhi Sheng Poh, James Tan Chia Wei, Brandon Han Siang Wong, Kottaiswamy Amuthavalli, Suat Hoon Tan, Nicholas Francis Grigoropoulos, Navin Kumar Verma
Journal: Cancer Research (2024)

Abstract DDX3X is an ATP-dependent RNA helicase involved in diverse cellular processes. Somatic mutations in the DDX3X gene exhibit oncogenic or tumor suppressive activities depending on cancer types. However, helicase modulating roles of specific DDX3X mutations remain elusive mainly due to lack of an appropriate cell culture model system. Here, we report our development of novel transgenic cell lines capable of interrogating DDX3X helicase activity. To evaluate the helicase activity of the DDX3X mutations in question, we designed a reporter plasmid that measures the luciferase signal corresponding to the helicase activity. Using 8 different point mutations in the DDX3X that we identified earlier in relapsed/refractory patients with diffuse large B cell lymphoma (DLBCL), we show that these DDX3X mutants displayed defective helicase activity. DDX3X mutant knock-in DLBCL cells also displayed abolished helicase unwinding capabilities, validating our reporter cell models. We were able to extend the application of our reporter cells to interrogate Y chromosome-linked male paralog DDX3Y. In male lymphoma patients, ectopic DDX3Y expression can compensate for DDX3X loss to restore global protein synthesis. We narrowed down DDX3Y helicase and ATPase domains to be critical for cellular translation, ruling out DDX3Y involvement in ribosomal elongation. Unexpectedly, DDX3Y helicase is less efficient in RNA unwinding as compared to DDX3X revealing subtle differences despite having a high level of homology. The developed DDX3X reporter cells can be applied widely to evaluate the effects of DDX3X mutations in diseases as well as study the biology of DDX3X and DDX3Y. Citation Format: Zhi Sheng Poh, James Tan Chia Wei, Brandon Han Siang Wong, Kottaiswamy Amuthavalli, Suat Hoon Tan, Nicholas Francis Grigoropoulos, Navin Kumar Verma. Novel Reporter Cell Models for Efficient Interrogation of Helicase Activity in Cancer-associated DDX3X Mutations [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P33.
In multiple myeloma, monthly treatment with zoledronic acid beyond two years offers sustained protection against progressive bone disease
Authors: Thomas Lund, Michael Tveden Gundesen, Annette Juul Vangsted, Carsten Helleberg, Einar Haukås, Trine Silkjær, Jon Thor Asmussen, Elena Manuela Teodorescu, Bo Amdi Jensen, Tobias Schmidt Slørdahl, Hareth Nahi, Anders Waage, Niels Abildgaard, Fredrik Schjesvold
Journal: Blood Cancer Journal (2024)

In multiple myeloma, monthly treatment with zoledronic acid beyond two years offers sustained protection against progressive bone disease