tbuckley/cabot-search huggingface dataset:
PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression
Authors: Fengxian Zhai, Guozheng Pan, Lei Xue, Can Cheng, Jiabei Wang, Yao Liu, Lianxin Liu
Journal: Cancer Research (2024)

Abstract Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in FLT3-ITD+ AML patients, suggesting it might play a role in leukemogenesis. Here, we revealed that genetic and pharmacological suppression of PRDM16 greatly slowed the progression of FLT3-ITD-driven leukemia, sensitized leukemic cells to tyrosine kinase inhibitors (TKIs), and extended the survival of leukemic mice. PRDM16 enhanced activation of oncogenic FLT3-ITD and ligand-dependent activation of wild-type FLT3 in leukemic cells. Mechanistically, PRDM16 mediated monomethylation of FLT3-ITD at lysine 614 and promoted its ER localization, resulting in enhanced FLT3 signaling in leukemia cells. Moreover, pharmacological suppression of FLT3-ITD methylation in combination with TKIs increased the elimination of FLT3-ITD+ AML cells. Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.
Artificial Intelligence in Cardiovascular Clinical Trials
Authors: Jonathan W Cunningham, William T Abraham, Ankeet S Bhatt, Jessilyn Dunn, G Michael Felker, Sneha S Jain, Christopher J Lindsell, Matthew Mace, Trejeeve Martyn, Rashmee U Shah, Geoffrey H Tison, Tala Fakhouri, Mitchell A Psotka, Harlan Krumholz, Mona Fiuzat, Christopher M O'Connor, Scott D Solomon
Journal: Journal of the American College of Cardiology (2024)

Randomized clinical trials are the gold standard for establishing the efficacy and safety of cardiovascular therapies. However, current pivotal trials are expensive, lengthy, and insufficiently diverse. Emerging artificial intelligence (AI) technologies can potentially automate and streamline clinical trial operations. This review describes opportunities to integrate AI throughout a trial's life cycle, including designing the trial, identifying eligible patients, obtaining informed consent, ascertaining physiological and clinical event outcomes, interpreting imaging, and analyzing or disseminating the results. Nevertheless, AI poses risks, including generating inaccurate results, amplifying biases against underrepresented groups, and violating patient privacy. Medical journals and regulators are developing new frameworks to evaluate AI research tools and the data they generate. Given the high-stakes role of randomized trials in medical decision making, AI must be integrated carefully and transparently to protect the validity of trial results.
A Guide to Implementation Science for Phase 3 Clinical Trialists
Authors: Harriette G.C. Van Spall, Laura Desveaux, Tracy Finch, Cara C. Lewis, George A. Mensah, Yves Rosenberg, Kavita Singh, Francois Venter, Bryan J. Weiner, Faiez Zannad
Journal: Journal of the American College of Cardiology (2024)
Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia
Authors: Yihong Sun, Qiang Lv, Yuhan Guo, Zhifang Wang, Rongjie Huang, Xiaohong Gao, Yajun Han, Zhuhua Yao, Mingqi Zheng, Suxin Luo, Yue Li, Xiang Gu, Yumin Zhang, Junkui Wang, Lang Hong, Xueping Ma, Guohai Su, Jianlong Sheng, Chunlin Lai, Aidong Shen, Mian Wang, WeiHua Zhang, Shaorong Wu, Zeqi Zheng, Juxiang Li, Tingyan Zhong, Ying Wang, Liu He, Xin Du, Chang-Sheng Ma
Journal: Journal of the American College of Cardiology (2024)
ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis
Authors: Peiyi Xie, Lei Guo, Qiang Yu, Yufei Zhao, Mincheng Yu, Hui Wang, Mengyuan Wu, Wenxin Xu, Min xu, Xiao-Dong Zhu, Yongfeng Xu, Yong-Sheng Xiao, Cheng Huang, Jian Zhou, Jia Fan, Mien-Chie Hung, Huichuan Sun, Qing-Hai Ye, Bo Zhang, Hui Li
Journal: Cancer Research (2024)

Abstract Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
The Power of a Good Word: Enhancing the Efficacy of Analgesics in Clinical Settings
Authors: Roi Treister, Vered Cohen, Limor Issa, Karine Beiruti Wiegler, Alexander Izakson, Mariana Agostinho
Journal: Psychotherapy and Psychosomatics (2024)

Introduction: Communication between medical staff and patients about treatment efficacy elicits expectations of benefit and improves treatment outcomes. While demonstrated in multiple studies via different research methodologies, uniform communication protocols have not been adopted in clinical practice. Here, we summarize the results of two sister studies aimed at bridging this gap. Methods: Women undergoing C-section (study 1, randomized controlled trial) and patients undergoing general or otolaryngologic surgeries (study 2, control group design) were recruited and assigned to the “regular communication” (RC) or “enhanced communication” (EC) arms. The EC arm received positive information about treatment, while the RC arm received no such information. In both studies, the primary outcome was change in pain intensity; in study 2, an additional outcome was morphine consumption. Results: Eighty women successfully completed study 1, and 102 patients successfully completed study 2. In both studies, significant time*group interactions were observed (p &lt; 0.001). The analgesic effect was virtually twice as large in the EC arm compared to the RC arm. In study 2, in the last two timepoints of assessment, participants in the EC arm also consumed fewer doses of opioids than participants in the RC arm (p &lt; 0.001). No significant differences were found in vital signs. Conclusions: We provide ecological evidence that positive information about treatment significantly decreases pain and opioid consumption during routine clinical care. This study and others could encourage healthcare providers to harness the powerful effects of patients’ expectations of benefit to improve analgesics outcomes and, potentially, the outcomes of other symptoms.
A blood-based biomarker panel for non-invasive diagnosis of metabolic dysfunction-associated steatohepatitis
Authors: Xiang Zhang, Ming-Hua Zheng, Dehua Liu, Yufeng Lin, Sherlot Juan Song, Eagle Siu-Hong Chu, Dabin Liu, Seema Singh, Michael Berman, Harry Cheuk-Hay Lau, Hongyan Gou, Grace Lai-Hung Wong, Ni Zhang, Hai-Yang Yuan, Rohit Loomba, Vincent Wai-Sun Wong, Jun Yu
Journal: Cell Metabolism (2024)

The current diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form, metabolic dysfunction-associated steatohepatitis (MASH), is suboptimal. Here, we recruited 700 individuals, including 184 from Hong Kong as a discovery cohort and 516 from San Diego, Wenzhou, and Hong Kong as three validation cohorts. A panel of 3 parameters (C-X-C motif chemokine ligand 10 [CXCL10], cytokeratin 18 fragments M30 [CK-18], and adjusted body mass index [BMI]) was formulated (termed N3-MASH), which discriminated patients with MASLD from healthy controls with an area under the receiver operating characteristic (AUROC) of 0.954. Among patients with MASLD, N3-MASH could identify patients with MASH with an AUROC of 0.823, achieving 90.0% specificity, 62.9% sensitivity, and 88.6% positive predictive value. The diagnostic performance of N3-MASH was confirmed in three validation cohorts with AUROC of 0.802, 0.805, and 0.823, respectively. Additionally, N3-MASH identifies patients with MASH improvement with an AUROC of 0.857. In summary, we developed a robust blood-based panel for the non-invasive diagnosis of MASH, which might help clinicians reduce unnecessary liver biopsies.
Non-invasive lipid panel of MASLD fibrosis transition underscores the role of lipoprotein sulfatides in hepatic immunomodulation
Authors: Sin Man Lam, Zehua Wang, Jin-Wen Song, Yue Shi, Wen-Yue Liu, Lin-Yu Wan, Kaibo Duan, Gek Huey Chua, Yingjuan Zhou, Guibin Wang, Xiahe Huang, Yingchun Wang, Fu-Sheng Wang, Ming-Hua Zheng, Guanghou Shui
Journal: Cell Metabolism (2024)
FOXR2 targets LHX6+/DLX+ neural lineages to drive CNS neuroblastoma
Authors: Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael McNicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W. Tsai, Andrey Korshunov, Timothy N. Phoenix, Benjamin Ellezam, David T W. Jones, Michael D. Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, Claudia L. Kleinman
Journal: Cancer Research (2024)

Abstract Central nervous system neuroblastoma with FOXR2 activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2 specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 originate from LHX6+/DLX+ interneuron lineages, a lineage-of-origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics.
Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial
Authors: Lei Wang, Mengting Sun, Jinyang Li, Linghong Wan, Yuting Tan, Shuoran Tian, Yongying Hou, Linyu Wu, Ziyi Peng, Xiao Hu, Qihua Zhang, Zening Huang, Mengyi Han, Shiyin Peng, Yuwei Pan, Yuanfeng Ren, Mengsi Zhang, Dongfeng Chen, Qin Liu, Xianfeng Li, Zhong-yi Qin, Junyv Xiang, Mengxia Li, Jianwu Zhu, Qiyue Chen, Huiyan Luo, Shunan Wang, Tao Wang, Fan Li, Xiu-wu Bian, Bin Wang
Journal: Clinical Cancer Research (2024)

Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma. However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC.
YAP regulates HER3 signaling-driven adaptive resistance to RET inhibitors in RET-aberrant cancer
Authors: Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Hayato Kawachi, Masaki Ishida, Yohei Matsui, Soichi Hirai, Ryota Nakamura, Kenji Morimoto, Naoki Furuya, Sachiko Arai, Yasuhiro Goto, Yoshihiko Sakata, Kazumi Nishino, Michiko Tsuchiya, Akihiro Tamiya, Go Saito, Satoshi Muto, Takayuki Takeda, Koji Date, Yasuhito Fujisaka, Satoshi Watanabe, Daichi Fujimoto, Hisanori Uehara, Mano Horinaka, Toshiyuki Sakai, Seiji Yano, Shinsaku Tokuda, Koichi Takayama
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells. Experimental Design: Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho–receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion–positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes. Results: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion–positive lung cancer was associated with poor RET-TKI treatment outcomes. Conclusions: The YAP–HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.
Unearthing a prostate cancer cfDNA signature that “stems” from AR alterations
Authors: Rashad Nawfal, Razane El Hajj Chehade, Jacob E. Berchuck
Journal: Clinical Cancer Research (2024)

Androgen receptor alterations portend a poor prognosis in patients with advanced prostate cancer. A recent study identified a stemness signature enriched in cell-free DNA from androgen receptor-altered patients, associated with worse outcomes. These findings highlight the potential of epigenomic liquid biopsy tools to discover novel clinically relevant tumor molecular subtypes. See related article by Chauhan et al., p. 151.
Enzymes Repertoires and Genomic Insights into Lycium Barbarum Pectin Polysaccharides Biosynthesis
Authors: Haiyan Yue, Yiheng Tang, Aixuan Li, Lili Zhang, Yiwei Niu, Yiming Zhang, Hao Wang, Jianjun Luo, Yi Zhao, Shunmin He, Chang Chen, Runsheng Chen
Journal: Genomics Proteomics & Bioinformatics (2024)

Abstract Lycium barbarum, a member of the Solanaceae family, represents an important eudicot lineage with homology of food and medicine. Lycium barbarum pectin polysaccharides (LBPPs) are key bioactive ingredients of Lycium barbarum, and are among the few polysaccharides with both biocompatibility and biomedical activity. While previous studies have primarily focused on the functional properties of LBPPs, the mechanisms of biosynthesis and transport by key enzymes remain poorly understood. Here, we reported the completion of a 2.18-gigabase reference genome of Lycium barbarum, reconstructed the first entire biosynthesis of pectin polysaccharides and sugar transport, and characterized the important genes responsible for backbone extending, sidechain synthesis, and modification of pectin polysaccharides. Additionally, we characterized long non-coding RNAs (lncRNAs) associated with polysaccharide metabolism and identified a specific rhamnogalacturonan I (RG-I) rhamnosyltransferase, RRT3020, which enhances RG-I biosynthesis in LBPPs. These newly identified enzymes and pivotal genes endow L. barbarum with specific pectin biosynthesis capabilities, distinguishing it from other Solanaceae species. Our findings provide a foundation for evolutionary studies and molecular breeding to enhance the diverse applications of L. barbarum.
Dopaminergic Axon Tracts Within a Hyaluronic Acid Hydrogel Encasement to Restore the Nigrostriatal Pathway
Authors: Wisberty J. Gordián‐Vélez, Kevin D. Browne, Jonathan H. Galarraga, Dimple Chouhan, John E. Duda, Rodrigo A. España, H. Isaac Chen, Jason A. Burdick, D. Kacy Cullen
Journal: Advanced Healthcare Materials (2024)

Abstract Parkinson's disease is characterized by motor deficits emerging from insufficient dopamine in the striatum after degeneration of dopaminergic neurons and their long‐projecting axons comprising the nigrostriatal pathway. To address this, a tissue‐engineered nigrostriatal pathway (TE‐NSP) featuring a tubular hydrogel with a collagen/laminin core that encases aggregated dopaminergic neurons and their axonal tracts is developed. This engineered microtissue can be implanted to replace neurons and axons with fidelity to the lost pathway and thus may provide dopamine according to feedback from host circuitry. While TE‐NSPs have traditionally been fabricated with agarose, here a hyaluronic acid (HA) hydrogel is utilized to have a more bioactive encasement while expanding control over physical and biochemical properties. Using rat ventral midbrain neurons, it is found that TE‐NSPs exhibited improved neurite growth with HA relative to agarose, with no differences in electrically‐evoked dopamine release. When transplanted, HA hydrogels reduced average host neuron loss and inflammation around the implant compared to agarose, and TE‐NSP neurons and axonal tracts survived for at least 2 weeks to structurally emulate the lost pathway. This study represents an innovative use of HA hydrogels for neuroregenerative medicine and enables future studies expanding the control and functionality of TE‐NSPs.
PHGDH Induction by MAPK is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability
Authors: Neel Jasani, Xiaonan Xu, Benjamin Posorske, Yumi Kim, Kaizhen Wang, Olga Vera, Kenneth Y. Tsai, Gina M. DeNicola, Florian A. Karreth
Journal: Cancer Research (2024)

Abstract Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. While PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic BRAFV600E also promoted PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, depletion of PHGDH in genetic mouse melanoma models blocked tumor formation. In addition to BRAFV600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction. Consequently, melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction, which promoted cell death in vitro and attenuated melanoma growth in vivo. In summary, this study identified that PHGDH is essential for melanomagenesis and regulated by BRAFV600E, revealing a targetable vulnerability in BRAFV600E-mutant melanoma.
Looking back at the TEDDY study: lessons and future directions
Authors: Åke Lernmark, Daniel Agardh, Beena Akolkar, Patricia Gesualdo, William A. Hagopian, Michael J. Haller, Heikki Hyöty, Suzanne Bennett Johnson, Helena Elding Larsson, Edwin Liu, Kristian F. Lynch, Eoin F. McKinney, Richard McIndoe, Jessica Melin, Jill M. Norris, Marian Rewers, Stephen S. Rich, Jorma Toppari, Eric Triplett, Kendra Vehik, Suvi M. Virtanen, Anette-G. Ziegler, Desmond A. Schatz, Jeffrey Krischer
Journal: Nature Reviews Endocrinology (2024)
Periodontal diseases in Africa
Authors: Mojisola Olujitan, Patricia O. Ayanbadejo, Kehinde Umeizudike, Afolabi Oyapero, Christopher Okunseri, Azeez Butali
Journal: Periodontology 2000 (2024)

Abstract Periodontal diseases, a group of complex conditions marked by an excessive immune response and periodontal tissue destruction, are a global health concern. Since 1990, the incidence of these diseases has doubled, with Western sub‐Saharan Africa experiencing the highest burden. Accurate diagnosis and case identification are crucial for understanding the etiology, features of disease, research, treatment and prevention. Modern perspectives on periodontal disease classification are based on commonality among those affected. However, current literature is often plagued by methodological inconsistencies and focused on disease mechanisms in European populations. Health inequalities in low‐ and middle‐income countries (LMICs) are exacerbated by these challenges, with sub‐Saharan Africa, and Nigeria specifically, facing unique difficulties such as clinical personnel shortages and limited research infrastructure. This review explored disparities in periodontal disease research, care and outcomes in African populations. We highlighted these disparities and identified the factors contributing to inequities in periodontal health outcomes. We further demonstrated the critical need for inclusive and equitable healthcare and research practices tailored to the unique challenges faced by diverse populations and regions with limited resources. Addressing these disparities is essential for ensuring that advancements in healthcare are accessible to all, thereby improving global oral health and general health.