tbuckley/cabot-search huggingface dataset:
A Small Molecule Agonist of Krüppel-Like Factor 15 in Proteinuric Kidney Disease
Authors: Yiqing Guo, Nehaben A. Gujarati, Andrew K. Chow, Brock T. Boysan, Robert Bronstein, John C. He, Monica P. Revelo, Navjot Pabla, Robert C. Rizzo, Bhaskar Das, Sandeep K. Mallipattu
Journal: Journal of the American Society of Nephrology (2024)

Key Points A human podocyte-based high-throughput screen identified a novel agonist of Krüppel-like factor 15 (BT503), independent of glucocorticoid signaling. BT503 demonstrated renoprotective effects in three independent proteinuric kidney murine models. BT503 directly binds to inhibitor of nuclear factor kappa-B kinase subunit beta to inhibit NF-κB activation, which, subsequently restores Krüppel-like factor 15 under cell stress. Background Podocyte loss is the major driver of primary glomerular diseases such as FSGS. While systemic glucocorticoids remain the initial and primary therapy for these diseases, high-dose and chronic use of glucocorticoids is riddled with systemic toxicities. Krüppel-like factor 15 (KLF15) is a glucocorticoid-responsive gene, which is essential for the restoration of mature podocyte differentiation markers and stabilization of actin cytoskeleton in the setting of cell stress. Induction of KLF15 attenuates podocyte injury and glomerulosclerosis in the setting of cell stress. Methods A cell-based high-throughput screen with a subsequent structure–activity relationship study was conducted to identify novel agonists of KLF15 in human podocytes. Next, the agonist was tested in cultured human podocytes under cell stress and in three independent proteinuric models (LPS, nephrotoxic serum nephritis, and HIV-1 transgenic mice). A combination of RNA sequencing and molecular modeling with experimental validation was conducted to demonstrate the direct target of the agonist. Results The high-throughput screen with structure–activity relationship study identified BT503, a urea-based compound, as a novel agonist of KLF15, independent of glucocorticoid signaling. BT503 demonstrated protective effects in cultured human podocytes and in three independent proteinuric murine models. Subsequent molecular modeling with experimental validation shows that BT503 targets the inhibitor of nuclear factor kappa-B kinase complex by directly binding to inhibitor of nuclear factor kappa-B kinase subunit beta to inhibit canonical NF-κB signaling, which, in turn, restores KLF15 under cell stress, thereby rescuing podocyte loss and ameliorating kidney injury. Conclusions By developing and validating a cell-based high-throughput screen in human podocytes, we identified a novel agonist for KLF15 with salutary effects in proteinuric murine models through direct inhibition of inhibitor of nuclear factor kappa-B kinase subunit beta kinase activity.
Epithelium/imcDC2 axis facilitates the resistance of neoadjuvant anti-PD-1 in human NSCLC
Authors: Yongyuan Chen, Zheyu Shao, Zhixing Hao, Zhongwei Xin, Xiaoke Chen, Lijian Huang, Di Chen, Mingjie Lin, Qinyuan Liu, Xia Xu, Jinfan Li, Dang Wu, Jun Yan, Ying Chai, Pin Wu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Therapeutic resistance is a main obstacle to achieve long-term benefits from immune checkpoint inhibitors. The underlying mechanism of neoadjuvant anti-PD-1 resistance remains unclear. Methods Multi-omics analysis, including mass cytometry, single-cell RNA-seq, bulk RNA-seq, and polychromatic flow cytometry, was conducted using the resected tumor samples in a cohort of non-small cell lung cancer (NSCLC) patients received neoadjuvant anti-PD-1 therapy. Tumor and paired lung samples acquired from treatment-naïve patients were used as a control. In vitro experiments were conducted using primary cells isolated from fresh tissues and lung cancer cell lines. A Lewis-bearing mouse model was used in the in vivo experiment. Results The quantity, differentiation status, and clonal expansion of tissue-resident memory CD8+ T cells (CD8+ TRMs) are positively correlated with therapeutic efficacy of neoadjuvant anti-PD-1 therapy in human NSCLC. In contrast, the quantity of immature CD1c+ classical type 2 dendritic cells (imcDC2) and galectin-9+ cancer cells is negatively correlated with therapeutic efficacy. An epithelium/imDC2 suppressive axis that restrains the antitumor response of CD8+ TRMs via galectin-9/TIM-3 was uncovered. The expression level of CD8+ TRMs and galectin-9+ cancer cell-related genes predict the clinical outcome of anti-PD-1 neoadjuvant therapy in human NSCLC patients. Finally, blockade of TIM-3 and PD-1 could improve the survival of tumor-bearing mouse by promoting the antigen presentation of imcDC2 and CD8+ TRMs-mediated tumor-killing. Conclusion Galectin-9 expressing tumor cells sustained the primary resistance of neoadjuvant anti-PD-1 therapy in NSCLC through galectin-9/TIM-3-mediated suppression of imcDC2 and CD8+ TRMs. Supplement of anti-TIM-3 could break the epithelium/imcDC2/CD8+ TRMs suppressive loop to overcome anti-PD-1 resistance. Trial registration number NCT03732664 .
The human cost of political inertia: barriers to effective humanitarian responses
Authors: Tasnime Osama
Journal: BMJ (2024)

The human cost of political inertia: barriers to effective humanitarian responses Tasnime Osama clinical editorMédecins Sans Frontières (MSF) Scientific Days provide a platform to showcase research conducted by MSF staff and global health researchers in humanitarian and low resource settings, drawing attention to the humanitarian-development nexus.This year there were four main themes-the need to translate research into tangible solutions, ensuring the right people receive the right drugs at the right dose, going beyond estimating mortality, and innovating to protect vulnerable populations.The conference offered insights into the ongoing advances and barriers in humanitarian health.This conference without borders-which was attended by people from 132 nationalities-delivered a compelling overview of the multifaceted efforts required to advance global health, charting a path forward for more effective, accessible, inclusive, and equitable interventions in humanitarian settings and beyond.
Emergency Severity Index Version 4 and Triage of Pediatric Emergency Department Patients
Authors: Dana R. Sax, E. Margaret Warton, Mamata V. Kene, Dustin W. Ballard, Tina J. Vitale, Jenna A. Timm, Eloa S. Adams, Katherine R. McGauhey, Jesse M. Pines, Mary E. Reed, Adina S Rauchwerger, Daniel D Di Lena
Journal: JAMA Pediatrics (2024)

Importance Most emergency departments (EDs) across the US use the Emergency Severity Index (ESI) to predict acuity and resource needs. A comprehensive assessment of ESI accuracy among pediatric patients is lacking. Objective To assess the frequency of mistriage using ESI (version 4) among pediatric ED visits using automated measures of mistriage and identify characteristics associated with mistriage. Design, Setting, and Participants This cohort study used operational measures for each ESI level to classify encounters as undertriaged, overtriaged, or correctly triaged to assess the accuracy of the ESI and identify characteristics of mistriage. Participants were pediatric patients at 21 EDs within Kaiser Permanente Northern California from January 1, 2016, to December 31, 2020. During that time, version 4 of the ESI was in use by these EDs. Visits with missing ESI, incomplete ED time variables, patients transferred from another ED, and those who left against medical advice or without being seen were excluded. Data were analyzed between January 2022 and June 2023. Exposures Assigned ESI level. Main Outcomes and Measures Rates of undertriage and overtriage by assigned ESI level based on mistriage algorithm, patient and visit characteristics associated with undertriage and overtriage. Results This study included 1 016 816 pediatric ED visits; the mean (SD) age of patients was 7.3 (5.6) years, 479 610 (47.2%) were female, and 537 206 (52.8%) were male. Correct triage occurred in 346 918 visits (34.1%; 95% CI, 34.0%-34.2%), while overtriage and undertriage occurred in 594 485 visits (58.5%; 95% CI, 58.4%-58.6%) and 75 413 visits (7.4%; 95% CI, 7.4%-7.5%), respectively. In adjusted analyses, undertriage was more common among children at least 6 years old compared with those younger 6 years; male patients compared with female patients; patients with Asian, Black, or Hispanic or other races or ethnicities compared with White patients; patients with comorbid illnesses compared with those without; and patients who arrived by ambulance compared with nonambulance patients. Conclusions and Relevance This multicenter retrospective study found that mistriage with ESI version 4 was common in pediatric ED visits. There is an opportunity to improve pediatric ED triage, both in early identification of critically ill patients (limit undertriage) and in more accurate identification of low-acuity patients with low resource needs (limit overtriage). Future research should include assessments based on version 5 of the ESI, which was released after this study was completed.
Interleukin-2 immunotherapy reveals human regulatory T cell subsets with distinct functional and tissue-homing characteristics
Authors: Miro E. Raeber, Dominic P. Caspar, Yves Zurbuchen, Nannan Guo, Jonas Schmid, Jan Michler, Alina C. Martin, Urs C. Steiner, Andreas E. Moor, Frits Koning, Onur Boyman
Journal: Immunity (2024)

Highlights•Low-dose IL-2 immunotherapy restores Treg cells in SLE patients•Treg cell expansion is paralleled by clinical and serological response•IL-2 drives distinct Treg cell subsets that can home to the gut, skin, or inflamed sites•Skin-homing Treg cells appear in the skin in close interaction with endothelial cellsSummaryDue to its stimulatory potential for immunomodulatory CD4+ regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has gained considerable attention for the treatment of autoimmune diseases. In this investigator-initiated single-arm non-placebo-controlled phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we generated a comprehensive atlas of in vivo human immune responses to low-dose IL-2. We performed an in-depth study of circulating and cutaneous immune cells by imaging mass cytometry, high-parameter flow cytometry, transcriptomics, and targeted serum proteomics. Low-dose IL-2 stimulated various circulating immune cells, including Treg cells with a skin-homing phenotype that appeared in the skin of SLE patients in close interaction with endothelial cells. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell activation programs, including gut-homing CD38+, skin-homing HLA-DR+, and highly proliferative inflammation-homing CD38+ HLA-DR+ Treg cells. Collectively, these data define the distinct human Treg cell subsets that are responsive to IL-2 immunotherapy.Graphical abstract
Endovascular Stroke Thrombectomy for Patients With Large Ischemic Core
Authors: Huanwen Chen, Jin Soo Lee, Patrik Michel, Bernard Yan, Seemant Chaturvedi
Journal: JAMA Neurology (2024)

Importance Recently, 6 randomized clinical trials—RESCUE-Japan-LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism—Japan Large Ischemic Core Trial), ANGEL-ASPECT (Trial of Endovascular Therapy for Acute Ischemic Stroke With Large Infarct), SELECT2 (Trial of Endovascular Thrombectomy for Large Ischemic Strokes), TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke), TENSION (Endovascular Thrombectomy for Acute Ischemic Stroke With Established Large Infarct), and LASTE (Large Stroke Therapy Evaluation)—have concluded their investigations on the efficacy and safety of endovascular thrombectomy (EVT) for the treatment of patients with ischemic stroke, anterior-circulation large vessel occlusions, and large areas of ischemic changes defined as an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 5 or less. Overall, the results appeared to be positive, with 5 of the 6 trials meeting their primary efficacy end point, and 1 trial that was a near miss. However, questions remain regarding how these trial results should be interpreted and incorporated into routine clinical practice. Observations In this narrative review and analysis of published trials, important nuances of the available clinical data were identified, and important areas of lingering uncertainty were highlighted, including the efficacy and safety of EVT for patients with a low ASPECTS score in late treatment windows and those with large core volumes. Also emphasized was the possibly important role of advanced neuroimaging modalities such as perfusion and magnetic resonance imaging when making EVT treatment decisions for select patients with low ASPECTS scores. Conclusions and Relevance Recent trial data provide strong evidence that EVT is safe and effective for patients with anterior, large vessel–occlusion stroke and low ASPECTS scores who present within 6 hours from stroke onset. However, patient outcomes often remain poor despite EVT treatment. The efficacy and safety of EVT for patients with low ASPECTS scores who present beyond 6 hours of stroke onset remain uncertain, and the current trial data seem too scarce to justify forgoing advanced stroke imaging during this extended time window. Furthermore, the efficacy and safety of EVT for patients with large core volumes (100 mL or greater) or M2 occlusions (ie, occlusions of the second segment of the middle cerebral artery) remain uncertain. Future research to better identify patients likely to meaningfully respond to EVT is needed to further optimize the stroke triage process and health care resource utilization.
Promoting Child Health by Protecting the Patient-Clinician Relationship From Politics
Authors: Aaron M. Milstone, Alison A. Galbraith, Susan L. Rosenthal, Jay Griffin Berry, Thomas F. Boat, John V. Campo, Ellen Wright Clayton, Jason S. Debley, Andrea F. Duncan, Leonard H. Epstein, Alexander G. Fiks, Elena Fuentes-Afflick, Jill S. Halterman, Renee M. Johnson, Amaris M. Keiser, Ron Keren, Tracy A. Lieu, Megan A. Moreno, Debra L. Palazzi, Shawn J. Rangel, Martha C. Sola-Visner, Lindsay A. Thompson, Maria Trent, John M. VanBuren, Julie T. Vo, Dimitri A. Christakis
Journal: JAMA Pediatrics (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Apixaban vs Aspirin in Patients With Cancer and Cryptogenic Stroke
Authors: Babak B. Navi, Cenai Zhang, Benjamin Miller, Mary Cushman, Scott E. Kasner, Mitchell S. V. Elkind, David L. Tirschwell, W. T. Longstreth, Richard A. Kronmal, Morin Beyeler, Jordan Elm, Richard M. Zweifler, Joseph Tarsia, Carlo W. Cereda, Giovanni Bianco, Gianluca Costamagna, Patrik Michel, Joseph P. Broderick, David J. Gladstone, Hooman Kamel, Christopher Streib
Journal: JAMA Neurology (2024)

Approximately 10% to 15% of ischemic strokes are associated with cancer; cancer-associated stroke, particularly when cryptogenic, is associated with high rates of recurrent stroke and major bleeding. Limited data exist on the safety and efficacy of different antithrombotic strategies in patients with cancer and cryptogenic stroke.
Ubiquitin‐specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1/PTEN/PI3K signaling
Authors: Huiyan Sun, Yu Meng, Lei Yao, Songtao Du, Yayun Li, Qian Zhou, Yihuang Liu, Yating Dian, Yuming Sun, Xiaomin Wang, Xiao‐wei Liang, Guangtong Deng, Xiang Chen, Furong Zeng
Journal: MedComm (2024)

Metastasis is a major contributing factor that affects the prognosis of melanoma patients. Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin-specific protease 22 (USP22) as a pro-oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin-specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial-mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1/PTEN/PI3K pathway. In addition, we conducted an United States Food and Drug Administration-approved drug library screening and identified topotecan as a clinically applicable USP22-targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3-induced ferroptosis through suppressing the PI3K/Akt/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22-targeting drug to limit melanoma metastasis.
Low‐dose ionizing radiation‐induced RET/PTC1 rearrangement via the non‐homologous end joining pathway to drive thyroid cancer
Authors: Yuhao Liu, Jiaojiao Zhu, Shenghui Zhou, Yifan Hou, Ziyan Yan, Xingkun Ao, Ping Wang, Lin Zhou, Huixi Chen, Xinxin Liang, Hua Guan, Shanshan Gao, Dafei Xie, Yongqing Gu, Ping‐Kun Zhou
Journal: MedComm (2024)

Thyroid cancer incidence increases worldwide annually, primarily due to factors such as ionizing radiation (IR), iodine intake, and genetics. Papillary carcinoma of the thyroid (PTC) accounts for about 80% of thyroid cancer cases. RET/PTC1 (coiled-coil domain containing 6 [CCDC6]-rearranged during transfection) rearrangement is a distinctive feature in over 70% of thyroid cancers who exposed to low doses of IR in Chernobyl and Hiroshima‒Nagasaki atomic bombings. This study aims to elucidate mechanism between RET/PTC1 rearrangement and IR in PTC. N-thy-ori-3-1 cells were subjected to varying doses of IR (2/1/0.5/0.2/0.1/0.05 Gy) of IR at different days, and result showed low-dose IR-induced RET/PTC1 rearrangement in a dose-dependent manner. RET/PTC1 has been observed to promote PTC both in vivo and in vitro. To delineate the role of different DNA repair pathways, SCR7, RI-1, and Olaparib were employed to inhibit non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ), respectively. Notably, inhibiting NHEJ enhanced HR repair efficiency and reduced IR-induced RET/PTC1 rearrangement. Conversely, inhibiting HR increased NHEJ repair efficiency and subsequent RET/PTC1 rearrangement. The MMEJ did not show a markable role in this progress. Additionally, inhibiting DNA-dependent protein kinase catalytic subunit (DNA-PKcs) decreased the efficiency of NHEJ and thus reduced IR-induced RET/PTC1 rearrangement. To conclude, the data suggest that NHEJ, rather than HR or MMEJ, is the critical cause of IR-induced RET/PTC1 rearrangement. Targeting DNA-PKcs to inhibit the NHEJ has emerged as a promising therapeutic strategy for addressing IR-induced RET/PTC1 rearrangement in PTC.
GLP-1RA vs DPP-4i Use and Rates of Hyperkalemia and RAS Blockade Discontinuation in Type 2 Diabetes
Authors: Tao Huang, Alessandro Bosi, Anne-Laure Faucon, Morgan E. Grams, Arvid Sjölander, Edouard L. Fu, Yang Xu, Juan Jesus Carrero
Journal: JAMA Internal Medicine (2024)

Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk.
Laser ablation of stage 4 buccal cancer: A paradigm shift in management.
Authors: Rusy Bhalla, Seemantini Bhalla
Journal: Journal of Clinical Oncology (2024)

164 Background: Laser ablation of soft tissue tumors is fast gaining ground in the field of Oncology. Conventional Oral cancer treatment is blamed most often for a radical dip in Quality of Life post-surgery and Radiotherapy. Mutilation, Mouth closure, inability to speak, eat or drink normally discourages patients to adopt surgery in early stages or even treatment as a whole. Laser technology uses controlled heat to burn the cancer affected tissues under sonography control. The new technique of Laser Ablation has removed the need for cutting of face and the need for radiotherapy. Methods: 54 patients were diagnosed with stage 4 inoperable cancer on clinical and radiological examination. Criteria for inoperability were size of tumor more than 3.5 cms and less than 5 cms, involvement of upper or lower Gingivo buccal sulcus with or without involvement of bone. Laser ablation was achieved by using 980mm diode laser. The margins of effective tumor ablation are assessed under sonography. The lymph nodes were laserised percutaneously under sonography control. Post operatively patients were administered chemotherapy by a standard cisplatin, paclitaxel and 5Fu 3 weekly for 6 cycles. Results: All patients showed a decrease in their swelling within 1 month of the procedure. There was an increase in appetite and well being within 2 weeks of the procedure. 47 (90%) patients had a total resolution of the tumor with laser and chemotherapy at 2 months. MRI scans done after 3 months showed a resolution of the original lesion with resolution of lymph nodes. 8 patients (9%) showed a recurrence in the operated area which did not settle on repeat laserisation. These patients underwent standard commando operation at other institutions. 41(75%) patients showed an MRI consistent with no active cancer at 8 months. All of these patients had a weight increase from 4 to 10 kgs compared from pre laser weight over this period. 13 (24%) patients showed a recurrence in neck lymph nodes after 8 months. Of these patients 8 (60%) patients showed a good response to laserisation of the affected node. Over all 80% of patients of stage 4 inoperable buccal cancer were in remission at 2 years with no sign of cancer on MRI scans. Conclusions: Laser ablation of oral cancer in late stage oral cancer should be offered as an alternative to patients not willing for a standard commando operation. Skill sets required for the same are different from conventional surgery. It involves a working knowledge of sonography and has a short learning curve.