tbuckley/cabot-search huggingface dataset:
Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease
Authors: Tao Zhang, Byeong Mo Kim, Tae Ho Lee
Journal: Translational Neurodegeneration (2024)

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson's disease (PD). We have established an upstream effect of DAPK1 on Aβ and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aβ deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders.
Multifaceted roles for BCL3 in cancer: a proto-oncogene comes of age
Authors: Gillian Seaton, Hannah Smith, Andrea Brancale, Andrew D. Westwell, Richard Clarkson
Journal: Molecular Cancer (2024)

Abstract In the early 1990’s a group of unrelated genes were identified from the sites of recurring translocations in B-cell lymphomas. Despite sharing the nomenclature ‘Bcl’, and an association with blood-borne cancer, these genes have unrelated functions. Of these genes, BCL2 is best known as a key cancer target involved in the regulation of caspases and other cell viability mechanisms. BCL3 on the other hand was originally identified as a non-canonical regulator of NF-kB transcription factor pathways – a signaling mechanism associated with important cell outcomes including many of the hallmarks of cancer. Most of the early investigations into BCL3 function have since focused on its role in NF-kB mediated cell proliferation, inflammation/immunity and cancer. However, recent evidence is coming to light that this protein directly interacts with and modulates a number of other signaling pathways including DNA damage repair, WNT/β-catenin, AKT, TGFβ/SMAD3 and STAT3 – all of which have key roles in cancer development, metastatic progression and treatment of solid tumours. Here we review the direct evidence demonstrating BCL3’s central role in a transcriptional network of signaling pathways that modulate cancer biology and treatment response in a range of solid tumour types and propose common mechanisms of action of BCL3 which may be exploited in the future to target its oncogenic effects for patient benefit.
Geriatric Medicine as a Profession
Authors: Terry Fulmer
Journal: JAMA (2024)

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Abstract A028: Alcohol induces DNA damage and genomic instability in MCF-7 breast cancer cells and primary mammary tissues
Authors: Xiaohe Yang
Journal: Cancer Research (2024)

Abstract Alcohol consumption has been associated with increased breast cancer risk. Previous studies indicated that alcohol-induced DNA damage plays a central role in carcinogenesis. However, the underlying molecular mechanisms remain unclear. This study aimed to examine the effect of alcohol exposure on key DNA damage/repair pathways in both in vitro and in vivo settings. When MCF-7 breast cancer cells were exposed to 0.1 ~ 0.8% alcohol, the treatment induced concentration-dependent DNA damage, as indicated by the increased 8-OHdG (8-hydroxy 2 deoxyguanosine) production and p-H2AX foci formation. Signal transduction analysis showed that alcohol induced DNA damage signals, including p53, p21, E2F-1 and CHK1, and the markers in DNA repair pathways, including XLF, Rad50 and DNA-PK. p53 knockdown in MCF-7 cells resulted in enhanced DNA damage and DNA repair responses, which underscores the role of p53 in alcohol-induced cellular regulation. We also demonstrated that alcohol induces sister chromatid exchanges (SCEs) in MCF-7 cells, and ALDH2 knockout enhanced alcohol induced SCEs, which suggests that alcohol-induced acetaldehyde (AA) is a key mediator in this process. Moreover, we examined the DNA damage markers in mammary tissues of FVB/N mice exposed to alcohol and showed that alcohol exposure in vivo induced similar patterns of DNA damage and repair responses. Taken together, our data highlights the contribution of alcohol-induced DNA damage in cellular injury and the consequent tumorigenesis, which provide fundamental support for further studies on alcohol-induced DNA damage and carcinogenesis. Citation Format: Xiaohe Yang. Alcohol induces DNA damage and genomic instability in MCF-7 breast cancer cells and primary mammary tissues [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A028.
Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma
Authors: Rawan G. Faramand, Sae Bom Lee, Michael D. Jain, Biwei Cao, Xuefeng Wang, Kai Rejeski, Marion Subklewe, Johannes F. Fahrmann, Neeraj Y. Saini, Samir M. Hanash, Yun Pyo Kang, Darwin Chang, Paolo C. Rodriguez, Erin A. Dean, Taiga Nishihori, Bijal D. Shah, Aleksandr Lazaryan, Julio Chavez, Farhad Khimani, Javier A. Pinilla-Ibarz, Marian Dam, Kayla M. Reid, Salvatore A. Corallo, Meghan Menges, Melanie Hidalgo Vargas, Jay K. Mandula, Brian A. Holliday, Christina A. Bachmeier, Kelly Speth, Qinghua Song, Mike Mattie, Frederick L. Locke, Marco L. Davila
Journal: Blood Cancer Discovery (2024)

A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy.
Abstract A013: Selective HDAC6 inhibition by SP-2-225 enhances the innate anti-tumor immune response after radiation exposure
Authors: Scott Grindrod, Satish Noonepalle, Xingtang Li, David Quiceno, Mira Jung, Anatoly Dritschilo, Alejandro Villagra
Journal: Cancer Research (2024)

Abstract Circulating tumor DNA fragments and other antigens resulting from radiation therapy cause activation of the STING pathway and initiate an inflammatory anti-tumor immune response. However, when pro-inflammatory immune cells interact with the tumor microenvironment, they are rapidly converted to their anti-inflammatory, pro-tumor state associated with wound healing. HDAC6 presents an important target due to its role in immune regulatory processes involved in antitumor immune responses. We have shown that SP-2-225, a selective inhibitor of HDAC6, regulates macrophages to recognize, phagocyte, and present antigens to the adaptive immune system. Treatment with SP-2-225 enhances the production of cancer-associated antigens and macrophage antigen cross-presentation to T cells. Through a non-cytotoxic mechanism, SP-2-225 significantly reduced the tumor volume in syngeneic SM1 melanoma and 4T1 breast models. Tumor analysis from treated animals showed a shift in the M1/M2 ratio of the infiltrating macrophages as compared to controls, demonstrating that SP-2-225 caused a pro-inflammatory, antitumor shift in the macrophage equilibrium present in the tumor microenvironment. The putative mechanism was identified through adoptive cell therapy where macrophages from naive animals were harvested and treated ex-vivo with SP-2-225. Reimplantation of these SP-2-225 ex-vivo treated macrophages resulted in reduced tumor volumes when compared to both vehicle and untreated macrophage animal cohorts. We propose that this selective inhibitor of HDAC6 offers potential in combination with radiation therapy for cancer. Citation Format: Scott Grindrod, Satish Noonepalle, Xingtang Li, David Quiceno, Mira Jung, Anatoly Dritschilo, Alejandro Villagra. Selective HDAC6 inhibition by SP-2-225 enhances the innate anti-tumor immune response after radiation exposure [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A013.
Tented elevation with numerous tractions (TENT) technique to aid endoscopic submucosal dissection of a large cecal lesion
Authors: Sujata May Hernaez Mansukhani, Yohei Minato, Tony He, Rosula Esther Castillo Sanchez, Ioannis Marakis, Shunya Takayanagi, Ken Ohata
Journal: Endoscopy (2024)

Colorectal endoscopic submucosal dissection (ESD) remains a challenging procedure and various traction methods to help decrease the risk of complications have been studied [1] [2] [3]. We present the tented elevation with numerous tractions (TENT) technique, an individually placed, multidirectional, multipoint, internal traction method for ESD of a large cecal lesion.
DVsc: An Automated Framework for Efficiently Detecting Viral Infection from Single-Cell Transcriptomics Data
Authors: Fei Leng, Song Mei, Xiaolin Zhou, Xuanshi Liu, Yefeng Yuan, Wenjian Xu, Chongyi Hao, Ruolan Guo, Chanjuan Hao, Wei Li, Peng Zhang
Journal: Genomics Proteomics & Bioinformatics (2023)

Single-cell RNA sequencing (scRNA-seq) has emerged as a valuable tool for studying cellular heterogeneity in various fields, particularly in virological research. By studying the viral and cellular transcriptomes, the dynamics of viral infection can be investigated at a single-cell resolution. However, limited studies have been conducted to investigate whether RNA transcripts from clinical samples contain substantial amounts of viral RNAs, and a specific computational framework for efficiently detecting viral reads based on scRNA-seq data has not been developed. Hence, we introduce DVsc, an open-source framework for precise quantitative analysis of viral infection from single-cell transcriptomics data. When applied to approximately 200 diverse clinical samples that were infected by more than 10 different viruses, DVsc demonstrated high accuracy in systematically detecting viral infection across a wide array of cell types. This innovative bioinformatics pipeline could be crucial for addressing the potential effects of surreptitiously invading viruses on certain illnesses, as well as for designing novel medicines to target viruses in specific host cell subsets and evaluating the efficacy of treatment. DVsc supports the FASTQ format as an input and is compatible with multiple single-cell sequencing platforms. Moreover, it could also be applied to sequences from bulk RNA sequencing data. DVsc is available at http://62.234.32.33:5000/DVsc.
Usefulness of a novel narrow-diameter endoscope for endoscopic balloon dilation of esophageal strictures
Authors: Koichi Soga, Toshikuni Suda, Ikuhiro Kobori, Yasumi Katayama, Masaya Tamano
Journal: Endoscopy (2024)

Esophageal stricture is a narrowing of the esophageal lumen, often causing esophageal obstruction [1] [2]. Dilation of strictures by endoscopy using balloon dilation is indicated to restore the patency of the esophageal lumen [3]. We present the case of a 55-year-old Japanese man who presented with chest discomfort. Upper gastrointestinal endoscopy (UGE) revealed a full-circumferential ulcer in the mid-portion of the esophagus, without obvious dysmorphic epithelium ([Fig. 1]). In the absence of obvious malignancy on biopsy, proton pump inhibitors (PPI) were prescribed for severe reflex esophagitis. On day 36 of PPI treatment, the patient reported aggravation of esophageal stasis with solid food. On UGE, an esophageal stricture was observed and was treated by endoscopic esophageal dilatation (EED) using a 12-mm-diameter balloon (CRE PRO GI Wireguided Balloon; Boston Scientific, USA). EED needed to be repeated 2 weeks later. On this second occasion, the stricture was assessed using an ordinary 9.8-mm-diameter upper gastrointestinal endoscope (EG-840T; Fujifilm, Japan), as used on the previous occasion. The endoscope could not be passed through the region of stricture due to scarring in the area of the ulcer ([Fig. 2]). Therefore, we selected to use a narrow-diameter, 7.9-mm upper gastrointestinal endoscope (EG-840TP; Fujifilm). Although the narrow-diameter endoscope could not be passed through the region of stenosis, it could be safely inserted into the esophageal inlet, providing a more detailed assessment of the stricture compared to the 9.8-mm diameter endoscope. The narrow-diameter endoscope includes a 3.2-mm hole for endoscopic forceps, which allowed us to perform EED using a 13.5-mm-diameter balloon (CRE PRO GI Wireguided Balloon) without difficulty ([Fig. 3]; [Video 1]). After EED, the endoscope could be passed through the region of stenosis without resistance. Based on our experience, we propose that the novel narrow-diameter endoscope is a potential first-choice endoscope for safe and reliable EED.
Abstract PR011: Novel role of glycogen synthase kinase-3β in determining cancer cell response to PARPi through regulation of 53BP1 function
Authors: Fen Xia, Heba Allam, Scarlett Acklin, Mousumi Patra, Kirk West, Justin Leung
Journal: Cancer Research (2024)

Abstract Glycogen synthase kinase-3β (GSK3β) is a multifunctional serine/threonine kinase involved in various cellular processes and signaling pathways. Accumulating evidence suggests GSK3β plays a role in cancer treatment with effects on tumorigenesis and treatment response. We have previously shown that inhibition of GSK3β protects neurons from ionizing radiation-induced apoptosis through regulation of the repair of double strand breaks (DSBs). Here, we investigate the molecular mechanism underlying GSK3β regulation of DSB repair. We illustrate that GSK3β directly interacts with 53BP1 and phosphorylates 53BP1 at threonine 334 amino acid (T334) within a region heavily phosphorylated by several stress kinases. Phosphorylation at T334 inhibits 53BP1’s function in recruitment to and retention at DSB sites as well as canonical NHEJ. In contrast, phosphorylation at Thr334 of 53BP1 enhances single strand DNA resection and promotes homologous recombination (HR) repair. Most importantly, genetic and pharmacologic inhibition of GSK3β-53BP1 signaling axis dramatically enhances the PARPi cytotoxic response of BRCA1 proficient cancer cells. The assessment of the effect of GSK3β-53BP1 axis on tumor cell response to radiation treatment is underway. In conclusion, this study establishes the connection between GSK3β kinase and DSB repair through its phosphorylation and regulation of 53BP1 property. Moreover, it demonstrates that GSK3β kinase activity uniquely results in inhibition of 53BP1 as opposed to other kinases that enhance 53BP1 function. Importantly, this novel signaling axis provides a strategy for targeting BRCA1-proficinet cancer cell resistance to PARPi. Citation Format: Fen Xia, Heba Allam, Scarlett Acklin, Mousumi Patra, Kirk West, Justin Leung. Novel role of glycogen synthase kinase-3β in determining cancer cell response to PARPi through regulation of 53BP1 function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR011.
Microbiome in Female Reproductive Health: Implications for Fertility and Assisted Reproductive Technologies
Authors: Liwen Xiao, Zhenqiang Zuo, Fangqing Zhao
Journal: Genomics Proteomics & Bioinformatics (2023)

Abstract The microbiome plays a critical role in the process of conception and the outcomes of pregnancy. Disruptions in microbiome homeostasis in women of reproductive age can lead to various pregnancy complications, which significantly impact maternal and fetal health. Recent studies have associated the microbiome in the female reproductive tract (FRT) with assisted reproductive technology (ART) outcomes, and restoring microbiome balance has been shown to improve fertility in infertile couples. This review provides an overview of the role of the microbiome in female reproductive health, including its implications for pregnancy outcomes and ARTs. Additionally, recent advances in the use of microbial biomarkers as indicators of pregnancy disorders are summarized. A comprehensive understanding of the characteristics of the microbiome before and during pregnancy and its impact on reproductive health will greatly promote maternal and fetal health. Such knowledge can also contribute to the development of ARTs and microbiome-based interventions.
Abstract A024: Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability
Authors: Tae-Hee Lee, Xuan C. Qiao, Tongyu Wu, Vladislav Kuzin, Xianzhen Zhou, Vijayalalitha Ramanarayanan, Laura Baranello, Philipp Oberdoerffer
Journal: Cancer Research (2024)

Abstract Genome integrity is inherently at risk due to the torsional constraints imposed by DNA transactions. Topoisomerase 1 (TOP1) is essential for genomic stability by removing DNA supercoils generated during replication and transcription. Aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs), however, result in DNA lesions that drive transcription-associated mutation burden and are a cytotoxic consequence of many clinically used chemotherapeutic agents. What protects genomic regions prone to elevated torsional stress from the cytotoxic potential of TOP1 enzymes remains unknown. Here, we identify macroH2A1.1, the only nucleosome component with an inherent ability to bind the TOP1cc repair-essential poly(ADP-ribose) (PAR) protein modification, as an essential means to establish a TOP1-permissive chromatin environment. MacroH2A1.1 is one of two alternatively spliced isoforms of the macro-histone variant macroH2A1, and comparative proteomics between the two isoforms uncovered a macroH2A1.1-specific and PARP activity-dependent interaction with the TOP1cc repair effector TDP1 as well as downstream base excision repair (BER) factors XRCC1 and LIG3. Consequently, macroH2A1.1 loss or inactivation of its PAR-binding domain resulted in impaired XRCC1 recruitment to damaged DNA and defective TOP1cc turnover, while the macroH2A1.2 splice isoform is unable to bind PAR or protect from TOP1ccs. Genome-wide mapping of macroH2A1.1, TOP1 and TOP1-DNA adducts identified macroH2A1.1 as a regulatory hub for TOP1 activity that ensures transcriptional integrity by preventing excessive TOP1cc accumulation at transcription start sites. Impaired macroH2A1.1 splicing, a frequent cancer feature, correlated with sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Finally, we find that aberrant macroH2A1 alternative splicing in cancer correlates with BER-related mutation signatures. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability. Citation Format: Tae-Hee Lee, Xuan C. Qiao, Tongyu Wu, Vladislav Kuzin, Xianzhen Zhou, Vijayalalitha Ramanarayanan, Laura Baranello, Philipp Oberdoerffer. Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A024.
Strategies that regulate LSD1 for novel therapeutics
Authors: Meng Li, Mengge Dai, Bing Cheng, Shaotong Li, Enhui Guo, Junwei Fu, Ting Ma, Bin Yu
Journal: Acta Pharmaceutica Sinica B (2024)

Histone methylation plays a crucial role in regulating chromatin structure and gene transcription, which is essential for epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases, making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage. LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9 (H3K4/H3K9), resulting in either transcription repression or activation. While the roles of LSD1 in transcriptional regulation are well-established, studies have revealed that LSD1 can also be dynamically regulated by other factors. For example, the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1. Moreover, some post-transcriptional modifications and cellular metabolites can also regulate LSD1 expression and its demethylase activity. Therefore, in this review, we summarize how proteins involved in the transcriptional corepressor complex formation, post-translational modification, and metabolites act as regulatory factors for LSD1 activity through direct interaction or other mechanisms.