tbuckley/cabot-search huggingface dataset:
Immune Checkpoint Blockade Delays Cancer Development and Extends Survival in DNA Polymerase Mutator Syndromes
Authors: Akshada Sawant, Fuqian Shi, Eduardo Cararo Lopes, Zhixian Hu, Somer Abdelfattah, Jennele Baul, Jesse R. Powers, Christian S. Hinrichs, Joshua D. Rabinowitz, Chang S. Chan, Edmund C. Lattime, Shridar Ganesan, Eileen P. White
Journal: Cancer Research (2024)

Abstract Mutations in the exonuclease domains of the replicative nuclear DNA polymerases POLD1 and POLE are associated with increased cancer incidence, elevated tumor mutation burden (TMB), and enhanced response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond, highlighting the need for a better understanding of how TMB affects tumor biology and subsequently immunotherapy response. To address this, we generated mice with germline and conditional mutations in the exonuclease domains of Pold1 and Pole. Engineered mice with Pold1 and Pole mutator alleles presented with spontaneous cancers, primarily lymphomas, lung cancer, and intestinal tumors, while Pold1 mutant mice also developed tail skin carcinomas. These cancers had highly variable tissue-type dependent increased TMB with mutational signatures associated with POLD1 and POLE mutations found in human cancers. The Pold1 mutant tail tumors displayed increased TMB, however, only a subset of established tumors responded to ICB. Similarly, introducing the mutator alleles into mice with lung cancer driven by mutant Kras and Trp53 deletion did not improve survival, whereas passaging these tumor cells in vitro without immune editing and subsequently implanting them into immune-competent mice caused tumor rejection in vivo. These results demonstrated the efficiency by which cells with antigenic mutations are eliminated in vivo. Finally, ICB treatment of mutator mice earlier, before observable tumors had developed delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the potential of ICB in high-risk individuals for cancer prevention.
Evolutionary Dynamics of RuBisCO: Emergence of the Small Subunit and its Impact Through Time
Authors: Kaustubh Amritkar, Bruno Cuevas-Zuviría, Betül Kaçar
Journal: Molecular Biology and Evolution (2024)

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is an ancient protein critical for CO2-fixation and global biogeochemistry. Form-I RuBisCO complexes uniquely harbor small subunits that form a hexadecameric complex together with their large subunits. The small subunit protein is thought to have significantly contributed to RuBisCO's response to the atmospheric rise of O2 ∼2.5 billion years ago, marking a pivotal point in the enzyme's evolutionary history. Here, we performed a comprehensive evolutionary analysis of extant and ancestral RuBisCO sequences and structures to explore the impact of the small subunit's earliest integration on the molecular dynamics of the overall complex. Our simulations suggest that the small subunit restricted the conformational flexibility of the large subunit early in its history, impacting the evolutionary trajectory of the Form-I RuBisCO complex. Molecular dynamics investigations of CO2 and O2 gas distribution around predicted ancient RuBisCO complexes suggest that a proposed "CO2-reservoir" role for the small subunit is not conserved throughout the enzyme's evolutionary history. The evolutionary and biophysical response of RuBisCO to changing atmospheric conditions on ancient Earth showcase multi-level and trackable responses of enzymes to environmental shifts over long timescales.
Exploring evolution to uncover insights into protein mutational stability
Authors: Pauline Hermans, Matsvei Tsishyn, Martin Schwersensky, Marianne Rooman, Fabrizio Pucci
Journal: Molecular Biology and Evolution (2024)

Determining the impact of mutations on the thermodynamic stability of proteins is essential for a wide range of applications such as rational protein design and genetic variant interpretation.Since protein stability is a major driver of evolution, evolutionary data are often used to guide stability predictions. Many state-of-the-art stability predictors extract evolutionary information from multiple sequence alignments (MSA) of proteins homologous to a query protein, and leverage it to predict the effects of mutations on protein stability. To evaluate the power and the limitations of such methods, we used the massive amount of stability data recently obtained by deep mutational scanning to study how best to construct MSAs and optimally extract evolutionary information from them. We tested different evolutionary models and found that, unexpectedly, independent-site models achieve similar accuracy to more complex epistatic models. A detailed analysis of the latter models suggests that their inference often results in noisy couplings, which do not appear to add predictive power over the independent-site contribution, at least in the context of stability prediction. Interestingly, by combining any of the evolutionary features with a simple structural feature, the relative solvent accessibility of the mutated residue, we achieved similar prediction accuracy to supervised, machine learning-based, protein stability change predictors. Our results provide new insights into the relationship between protein evolution and stability, and show how evolutionary information can be exploited to improve the performance of mutational stability prediction.
Ex vivo imaging of subacute myocardial infarction with ultra-short echo time 3D quantitative T1- and T1ρ -mapping MRI in mice
Authors: Iida Räty, Antti Aarnio, Mikko J Nissi, Sanna Kettunen, Anna-Kaisa Ruotsalainen, Svetlana Laidinen, Seppo Ylä-Herttuala, Elias Ylä-Herttuala
Journal:  (2024)

Abstract Aims The aim of this study was to develop an ultra-short echo time 3D magnetic resonance imaging (MRI) method for imaging subacute myocardial infarction (MI) quantitatively and in an accelerated way. Here, we present novel 3D T1- and T1ρ-weighted Multi-Band SWeep Imaging with Fourier Transform and Compressed Sensing (MB-SWIFT-CS) imaging of subacute MI in mice hearts ex vivo. Methods and results Relaxation time–weighted and under-sampled 3D MB-SWIFT-CS MRI were tested with manganese chloride (MnCl2) phantom and mice MI model. MI was induced in C57BL mice, and the hearts were collected 7 days after MI and then fixated. The hearts were imaged with T1 and adiabatic T1ρ relaxation time–weighted 3D MB-SWIFT-CS MRI, and the contrast-weighted image series were estimated with a locally low-rank regularized subspace constrained reconstruction. The quantitative parameter maps, T1 and T1ρ, were then obtained by performing non-linear least squares signal fitting on the image estimates. For comparison, the hearts were also imaged using 2D fast spin echo-based T2 and T1ρ mapping methods. The relaxation rates varied linearly with the MnCl2 concentration, and the T1 and T1ρ relaxation time values were elevated in the damaged areas. The ischaemic areas could be observed visually in the 3D T1, 3D T1ρ, and 2D MRI maps. The scar tissue formation in the anterior wall of the left ventricle and inflammation in the septum were confirmed by histology, which is in line with the results of MRI. Conclusion MI with early fibrosis, increased inflammatory activity, and interstitial oedema were determined simultaneously with T1 and T1ρ relaxation time constants within the myocardium by using the 3D MB-SWIFT-CS method, allowing quantitative isotropic 3D assessment of the entire myocardium.
Distributions of plasmidic genes encoding extended-spectrum and AmpC β-lactamases, and susceptibilities of global non-carbapenemase-producing meropenem-resistant Enterobacterales to ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam-avibactam, 2017–2022
Authors: Shio-Shin Jean, Hou-Tai Chang, Chao-Lin Huang, I-Min Liu, Po-Chuen Hsieh, Po-Ren Hsueh
Journal: Journal of Infection (2024)
A synthetic peptide, derived from neurotoxin GsMTx4, acts as a non-opioid analgesic to alleviate mechanical and neuropathic pain through the TRPV4 channel
Authors: ShaoXi Ke, Ping Dong, Yi Mei, JiaQi Wang, Mingxi Tang, Wanxin Su, JingJing Wang, Chen Chen, Xiaohui Wang, JunWei Ji, XinRan Zhuang, ShuangShuang Yang, Yun Zhang, Linda M Boland, Meng Cui, Masahiro Sokabe, Zhe Zhang, QiongYao Tang
Journal: Acta Pharmaceutica Sinica B (2024)

Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.
18F-FDG PET/CT of Intrapulmonary Schwannoma Mimicking Lung Cancer in the Right Lower Lobe
Authors: Zhiying Liang, Wei Li
Journal: Clinical Nuclear Medicine (2024)

Abstract A 53-year-old woman was found to have a soft tissue mass in the right lower lung lobe on chest CT, raising suspicion of lung cancer. For staging, 18 F-FDG PET/CT was performed, which demonstrated intense tracer uptake in the mass (SUV max , 14.6). Subsequently, surgical excision was undertaken, and histopathological examination of the resected specimen confirmed the diagnosis of a schwannoma.
Macrophage membrane-biomimetic ROS-responsive platinum nanozyme clusters for acute kidney injury treatment
Authors: Hanzhi Deng, Ying Qu, Bingyang Chu, Tianying Luo, Meng Pan, Liping Yuan, Dong Mo, Zhongwu Bei, Tingyu Yang, Xicheng Li, Yi Lu, Zhiyong Qian
Journal: Biomaterials (2024)
Non-selective b adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants
Authors: Jinsuke Nishino, Wenhuo Hu, Ashwin Kishtagari, Bo Shen, Xiang Gao, Caroline M. Blackman, Adetola Kassim, Naimisha Marneni, Abhisar V. Cherukuri, Russell Vittrup, Fatma N. Kalkan, Rahul Shah, Chul Ahn, Ang Gao, Abeer Ahmedrabie, Robert H. Collins, Amer M. Zeidan, Aram Bidikian, Lohith Gowda, Brian C. Shaffer, Yazan F. Madanat, Zhiyu Zhao, Stephen S. Chung, Sean J. Morrison
Journal: Cancer Discovery (2024)

Abstract Peripheral nerves promote mouse bone marrow regeneration by activating b2 and b3 adrenergic receptor signaling, raising the possibility that non-selective b blockers could inhibit engraftment after hematopoietic cell transplants (HCTs). We observed no effect of b blockers on steady-state mouse hematopoiesis. However, mice treated with a non-selective b blocker (carvedilol), but not a b1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received non-selective, but not b1-selective, b blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, non-selective b blockers were associated with little or no delay in engraftment. The inhibitory effect of non-selective b blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells.
RAD51 testing in patients with early HER2-negative breast cancer and homologous recombination deficiency: post-hoc analysis of the GeparOla trial
Authors: Guillermo Villacampa, Alba Llop-Guevara, Natalie Filmann, Andrea Herencia, Peter A. Fasching, Thomas Karn, Frederik Marmé, Peter Klare, Volkmar Müller, Andrea Stefek, Christian Schem, Christoph Uleer, Tanja Fehm, Gabriele Doering, Elmar Stickeler, Marion van Mackelenbergh, Bärbel Felder, Valentina Nekljudova, Judith Balmaña, Carsten Denkert, Sibylle Loibl, Violeta Serra
Journal: Clinical Cancer Research (2024)

The randomized GeparOla trial reported comparable pathological complete response (pCR) rates with neoadjuvant containing olaparib vs. carboplatin treatment. Here, we evaluate the association between functional homologous repair deficiency (HRD) by RAD51 foci and pCR, and the potential of improving patient selection by combining RAD51 and stromal tumor infiltrating lymphocytes (sTILs). This is a post-hoc blinded, biomarker analysis from the randomized GeparOla trial. Patients with early-stage HER2-negative breast cancer and HRD assessed by Myriad myChoice or BRCA1/BRCA2 mutation were randomized 1:1 to receive i) paclitaxel plus olaparib or ii) paclitaxel plus carboplatin, both followed by epirubicin/cyclophosphamide. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Overall, 90/97 (92.8%) samples were evaluable for RAD51 testing and 72/90 (80.0%) were RAD51-low. The pCR rate in patients with RAD51-low tumors was 66.7% (48/72), while it decreased to 22.2% (4/18) in those with RAD51-high. In the multivariable model including clinicopathological factors and treatment, the RAD51 score remained significantly associated with pCR (OR=12.03, 95%CI 2.60-55.73, p=0.002). Patients with RAD51-low and high sTILs in their tumors achieved a pCR rate of 75.0% (27/36). Similar results were observed for olaparib or carboplatin. In the exploratory DFS analysis, no differences were observed between RAD51 groups (high vs. low: HR=0.85, 95% CI 0.25-2.97). In a pre-selected population with HRD according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARPi or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.
Genomic profiling reveals <i>SMARCA4</i> mutations are associated with shorter overall and intracranial progression free survival in melanoma brain metastasis patients
Authors: Grant M. Fischer, Nayan Lamba, Jayne Vogelzang, Ayal Aizer, Keith L. Ligon
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Melanoma brain metastases (MBMs) are a common, lethal complication of metastatic melanoma. Despite improvements in treatments, subsets of MBM patients experience rapid decline, and few prognostic biomarkers have been identified. An improved understanding of the molecular features specifically associated with MBM overall survival (OS) and intracranial progression free survival (PFS) could facilitate the development of more effective clinical management strategies. Experimental Design: We established an initial cohort of 102 MBMs, 970 unmatched melanoma extracranial metastases (ECMs), and 569 unmatched melanoma primaries with available targeted exome sequencing data covering 182 genes and a validation cohort of 50 MBMs with SMARCA4 genomically profiled. Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model were used to evaluate associations between pathogenic genomic alterations and OS and intracranial PFS. We evaluated 14 MBMs and 19 ECMs with paired RNA sequencing and whole exome sequencing data to identify genotype-transcriptome correlations. Results: Of 43 genes significantly mutated amongst MBMs, only pathogenic mutations in SMARCA4 significantly associated with shorter OS and intracranial PFS on univariable and multivariable analyses in MBM patients but not from first ECM or primary tumor diagnosis. SMARCA4 mutations significantly associated with enrichment of oxidative phosphorylation (OXPHOS) and depletion of immune signaling gene sets. Conclusions: Pathogenic SMARCA4 mutations independently predict an association with shorter OS and intracranial PFS in MBM patients and associate with expression of pathways known to mediate melanoma virulence. These findings add to our understanding of MBM pathogenesis and suggest their potential use as prognostic biomarkers and possible therapeutic opportunities.
Tularemia — United States, 2011–2022
Authors: Shannan N. Rich, Alison F. Hinckley, Austin Earley, Jeannine M. Petersen, Paul S. Mead, Kiersten J. Kugeler
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Tularemia is a rare nationally notifiable zoonosis, caused by the tier-1 select agent Francisella tularensis, that has been reported from all U.S. states except Hawaii. Clinical manifestations typically include fever and localized symptoms that vary by route of infection. The case fatality rate of tularemia is typically <2% but can be higher depending on clinical manifestation and infecting strain. Tularemia is treatable with antibiotics. During 2011-2022, a total of 47 states reported 2,462 tularemia cases, but four central states (Arkansas, Kansas, Missouri, and Oklahoma) accounted for 50% of all reported cases. Incidence was highest among children aged 5-9 years (0.083 per 100,000 population) and adult males aged 65-84 years (range = 0.133-0.161). Incidence among American Indian or Alaska Native persons (0.260) was approximately five times that among White persons (0.057). The average annual incidence of tularemia in the United States during 2011-2022 (0.064) was 56% higher than that reported during 2001-2010 (0.041), largely resulting from increased reporting of probable cases. These findings might reflect an actual increase in human infection or improved case detection amid changes in commercially available laboratory tests during this period. Reducing tularemia incidence will require tailored prevention education; mitigating morbidity and mortality will require health care provider education, particularly among providers serving tribal populations, regarding early and accurate diagnosis and treatment.
Health needs of older people and age-inclusive health care in humanitarian emergencies in low-income and middle-income countries: a systematic review
Authors: Elburg van Boetzelaer, Lekha Rathod, Patrick Keating, Umberto Pellecchia, Sunita Sharma, Jason Nickerson, Judith van de Kamp, Oscar H Franco, James Smith, Favila Escobio, Joyce L Browne
Journal: The Lancet Healthy Longevity (2024)
X-Chromosome–Linked miRNAs Regulate Sex Differences in Cardiac Physiology
Authors: James I. Emerson, Wei Shi, Jose Paredes-Larios, William G. Walker, Josiah E. Hutton, Ileana M. Cristea, William F. Marzluff, Frank L. Conlon
Journal: Circulation Research (2024)

Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states. We identified microRNA (miRNAs/miR) with sex-differential expression in mouse hearts. Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males. We show miRNA, miR-871, is responsible for decreased expression of the protein SRL (sarcalumenin) in females. SRL is involved in calcium signaling, and we show it contributes to differences in electrophysiology between males and females. miR-871 overexpression mimics the effects of the cardiac physiology of conditional cardiomyocyte-specific Srl-null mice. Inhibiting miR-871 with an antagomir in females shortened ventricular repolarization. The human orthologue of miR-871, miR-888, coevolved with the SRL 3' untranslated region and regulates human SRL. These data highlight the importance of sex-differential miRNA mechanisms in mediating sex-specific functions and their potential relevance to human cardiac diseases.
Correction to “Kasraie S, Niebuhr M, Kopfnagel V, Dittrich‐Breiholz O, Kracht M, Werfel T. Macrophages From Patients With Atopic Dermatitis Show a Reduced CXCL10 Expression in Response to Staphylococcal α‐Toxin”
Journal: Allergy (2024)
Phase 2 Open-Label Trial of Brentuximab Vedotin with Pembrolizumab in PD-1 Pretreated Metastatic Non-Small Cell Lung Cancer and Metastatic Cutaneous Melanoma
Authors: Sylvia Lee, Omid Hamid, Robert Jotte, Yousef Zakharia, Theresa Medina, Amanda Gillespie-Twardy, Inderjit Mehmi, Sunandana Chandra, Graham Watson, Patrick Ward, Marya Chaney, Hailing Lu, Jason Berndt, Brian P. O'Connor, Kapil Rathi, Eeman Shaikh, C. Lance. Cowey
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells (Tregs) that express CD30 and re-sensitize tumors to anti-(PD-1) therapy. This study evaluated responses to BV+pembrolizumab post PD-1 and explored corresponding biomarkers. Methods: 55 patients with metastatic non-small cell lung cancer (NSCLC) and 58 with metastatic cutaneous melanoma received ≥1 dose of BV+pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1-7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor. Results: For the secondary refractory metastatic NSCLC cohort (RECIST v1.1), ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (iRECIST), ORR was 24%, median iPFS was 4.44 months, and median OS was 21.9 months. Overall, median duration of OS follow-up was 17.2 months (95% CI 14.62, 22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in Tregs. Paired tumor biopsies from baseline and Cycle 3 Day 1 showed a trend of increased CD8 T cell infiltration, especially in responding patients. Conclusions: BV+pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.
The impact of interethnic lipidomic variation in falciparum malaria
Authors: Wael Abdrabou, Saruul Zorigt, Issiaka Soulama, Dariga Bolatbay, Mame Massar Dieng, Jakub Jurkovic, Samuel Sindié Sermé, Salif Sombié, Noelie Bere Henry, Désiré Kargougou, Sam Aboubacar Coulibaly, Aïssatou Diawara, Youssef Idaghdour
Journal: Journal of Infection (2024)
Serum miR-365b-5p/miR-222-5p as a potential diagnostic biomarker for long-term weight loss in patients with morbid obesity after bariatric surgery
Authors: Virginia Mela, Flores Martín-Reyes, Wilfredo Oliva-Olivera, Antonio Cantarero-Cuenca, Ana Sánchez-García, Raquel Sancho-Marín, Andrés González-Jimenez, Mónica Tomé, Francisco J Moreno-Ruiz, Rocío Soler-Humanes, José L Fernández-Serrano, Francisco J Tinahones, Eduardo García-Fuentes, Lourdes Garrido-Sánchez
Journal: Metabolism (2024)