tbuckley/cabot-search huggingface dataset:
Genital tract microbiota composition profiles and use of prebiotics and probiotics in gynaecological cancer prevention: review of the current evidence, the European Society of Gynaecological Oncology prevention committee statement
Authors: Anita Mitra, Murat Gultekin, Laura Burney Ellis, Nicolò Bizzarri, Sarah Bowden, Nadja Taumberger, Taja Bracic, Pedro Vieira-Baptista, Jalid Sehouli, Maria Kyrgiou
Journal: The Lancet Microbe (2023)

Female genital tract (FGT) microbiota has been associated with the development of gynaecological cancers. Thus, the possibility of whether manipulation of the FGT microbiota can help in the prevention of disease should be investigated. Various prebiotics, probiotics, and other non-clinician prescribed agents have been reported to have therapeutic effects in cervical disease. Numerous studies have reported an association between human papillomavirus infection and subsequent cervical dysplasia and a decrease in the abundance of Lactobacillus species. A continuum of microbiota composition is observed from the vagina to the upper parts of the FGT, but no evidence suggests that manipulation of the vaginal microbiota can help to modify the composition of other FGT compartments. Although prebiotics and probiotics have been reported to be beneficial, the studies are small and of varying design, and high-quality evidence to support their use is lacking. Currently, no studies have examined these therapeutics in other gynaecological malignancies. Thus, recommendation of probiotics, prebiotics, or other over-the-counter supplements for the prevention of gynaecological cancers warrants larger, well designed studies.
Case 39-2023: A 43-Year-Old Woman with Chronic Diarrhea, Hair Loss, and Nail and Skin Changes
Authors: Jimmy C T Lai, W K Claudia Wu, W S Agnes Chan, Louis H S Lau, Howard H W Leung
Journal: New England Journal of Medicine (2023)

A 43-year-old woman presented with chronic diarrhea and weight loss, as well as hair loss and nail and skin changes. Evaluation revealed electrolyte derangements and hypoalbuminemia. A diagnosis was made.
Methemoglobinemia Outbreak in a Neonatal ICU and Maternity Ward
Authors: Shun Takahashi, Takashi Ishige, Takumi Takizawa
Journal: New England Journal of Medicine (2023)

Acquired methemoglobinemia is a rare disorder of the oxygen-carrying capacity of hemoglobin caused by exposure to certain chemicals or medications. This letter reports an outbreak in a neonatal ICU and maternity ward.
Locally Acquired Melioidosis Linked to Environment — Mississippi, 2020–2023
Authors: Julia K. Petras, Mindy G. Elrod, Maureen C. Ty, Patrick Dawson, Kevin O’Laughlin, Jay E. Gee, Jennifer Hanson, Carla Boutwell, Gail Ainsworth, Cari A. Beesley, Elke Saile, Rebekah Tiller, Christopher A. Gulvik, Daphne Ware, Theresa Sokol, Gary Balsamo, Kathryn Taylor, Johanna S. Salzer, William A. Bower, Zachary P. Weiner, María E. Negrón, Alex R. Hoffmaster, Paul Byers
Journal: New England Journal of Medicine (2023)

Melioidosis, caused by
Reversible Host–Guest Crosslinks in Supramolecular Hydrogels for On‐Demand Mechanical Stimulation of Human Mesenchymal Stem Cells
Authors: Philipp Linke, Natalie Munding, Esther Kimmle, Stefan Kaufmann, Kentaro Hayashi, Masaki Nakahata, Yoshinori Takashima, Masaki Sano, Martin Bastmeyer, Thomas Holstein, Sascha Dietrich, Carsten Müller‐Tidow, Akira Harada, Anthony D. Ho, Motomu Tanaka
Journal: Advanced Healthcare Materials (2023)

Abstract Stem cells are regulated not only by biochemical signals but also by biophysical properties of extracellular matrix (ECM). The ECM is constantly monitored and remodeled because the fate of stem cells can be misdirected when the mechanical interaction between cells and ECM is imbalanced. A well‐defined ECM model for bone marrow‐derived human mesenchymal stem cells (hMSCs) based on supramolecular hydrogels containing reversible host–guest crosslinks is fabricated. The stiffness (Young's modulus E ) of the hydrogels can be switched reversibly by altering the concentration of non‐cytotoxic, free guest molecules dissolved in the culture medium. Fine‐adjustment of substrate stiffness enables the authors to determine the critical stiffness level E * at which hMSCs turn the mechano‐sensory machinery on or off. Next, the substrate stiffness across E * is switched and the dynamic adaptation characteristics such as morphology, traction force, and YAP/TAZ signaling of hMSCs are monitored. These data demonstrate the instantaneous switching of traction force, which is followed by YAP/TAZ signaling and morphological adaptation. Periodical switching of the substrate stiffness across E * proves that frequent applications of mechanical stimuli drastically suppress hMSC proliferation. Mechanical stimulation across E * level using dynamic hydrogels is a promising strategy for the on‐demand control of hMSC transcription and proliferation.
Contractile Asymmetry and Survival in Patients with Left Bundle Branch Block Treated with Cardiac Resynchronization Therapy
Authors: Nareen Kader, Liv Therese Holm-Nielsen, Bhupendar Tayal, Sam Riahi, Anders Sommer, Jens Cosedis Nielsen, Mads Brix Kronborg, Charlotte Stephansen, Niels Holmark Andersen, Niels Risum, Peter Søgaard, Tomas Zaremba
Journal:  (2023)

Abstract Aims Currently, electrical rather than mechanical parameters of delayed left ventricular (LV) activation are used for patient selection for cardiac resynchronization therapy (CRT). However, despite adhering to current guideline-based criteria, about one-third of heart failure (HF) patients fail to derive benefit from CRT. This study sought to investigate the prognostic survival significance of a recently introduced index of contractile asymmetry (ICA) based on the deformation of entire opposing LV walls in the context of selecting patients with HF and left bundle branch abnormality (LBBB) for CRT. Methods and results We analysed 367 patients with HF and LBBB undergoing CRT (31.6% females, 69 ± 9 years, ischaemic aetiology in 50.7%, LV ejection fraction 27 ± 6%). ICA was calculated using LV strain rate values from curved anatomical M-mode plots of apical 2D echocardiography images. The predictive value of ICA was assessed using Kaplan–Meier analysis and Cox proportional hazards models. During a median follow-up time of 5.54 years, death or cardiac transplantation occurred in 105 (28.6%) cases. Higher baseline ICA values in all apical views, particularly in the two-chamber view (ICA-2ch), were associated with increased event-free survival, and the unadjusted hazard ratio was 0.28 (95% confidence interval 0.18–0.46). Higher ICA-2ch (&amp;gt;0.319 s−1) consistently predicted survival across clinical subgroups and remained significant after covariate adjustment, while the event rate sharply increased in low ICA-2ch cases. Additionally, including ICA-2ch improved the predictive value of the multivariate risk model containing the typical LBBB pattern. Conclusion Pre-implant ICA suggests a quantitative prognostic threshold for both long-term survival and adverse outcomes following CRT implantation.
Diabetes in South Asians: Uncovering Novel Risk Factors With Longitudinal Epidemiologic Data: Kelly West Award Lecture 2023
Authors: Alka M. Kanaya
Journal: Diabetes Care (2023)

South Asian populations have a higher prevalence and earlier age of onset of type 2 diabetes and atherosclerotic cardiovascular diseases than other race and ethnic groups. To better understand the pathophysiology and multilevel risk factors for diabetes and cardiovascular disease, we established the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study in 2010. The original MASALA study cohort (n = 1,164) included 83% Asian Indian immigrants, with an ongoing expansion of the study to include individuals of Bangladeshi and Pakistani origin. We have found that South Asian Americans in the MASALA study had higher type 2 diabetes prevalence, lower insulin secretion, more insulin resistance, and an adverse body composition with higher liver and intermuscular fat and lower lean muscle mass compared with four other U.S. race and ethnic groups. MASALA study participants with diabetes were more likely to have the severe hyperglycemia subtype, characterized by β-cell dysfunction and lower body weight, and this subtype was associated with a higher incidence of subclinical atherosclerosis. We have found several modifiable factors for cardiometabolic disease among South Asians including diet and physical activity that can be influenced using specific social network members and with cultural adaptations to the U.S. context. Longitudinal data with repeat cardiometabolic measures that are supplemented with qualitative and mixed-method approaches enable a deeper understanding of disease risk and resilience factors. Studying and contrasting Asian American subgroups can uncover the causes for cardiometabolic disease heterogeneity and reveal novel methods for prevention and treatment.
Efficacy and Safety of Continuous Glucose Monitoring and Intermittently Scanned Continuous Glucose Monitoring in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Interventional Evidence
Authors: Samuel Seidu, Setor K. Kunutsor, Ramzi A. Ajjan, Pratik Choudhary
Journal: Diabetes Care (2023)

Traditional diabetes self-monitoring of blood glucose (SMBG) involves inconvenient finger pricks. Continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems offer CGM, enhancing type 2 diabetes (T2D) management with convenient, comprehensive data.
Prognostic Impact of Repeated NT-proBNP Measurements in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Michael A. Fuery, Eric S. Leifer, Marc D. Samsky, Sounok Sen, Christopher M. O’Connor, Mona Fiuzat, Justin Ezekowitz, Ileana Piña, David Whellan, Daniel Mark, G. Michael Felker, Nihar R. Desai, James L. Januzzi, Tariq Ahmad
Journal: JACC Heart Failure (2023)
Myocardial Fibrosis by Magnetic Resonance and Outcomes in Chagas Disease
Authors: Sergio A. Gómez-Ochoa, Lyda Z. Rojas, Juliana A. Hernández-Vargas, Silvia J. Trujillo-Cáceres, Alexandra Hurtado-Ortiz, Maricel Licht-Ardila, Michelle A. Guarín-Aragón, Carlos E. Rochitte, Carlos A. Morillo, Luis E. Echeverría
Journal: JACC. Cardiovascular imaging (2023)
Lesion level–dependent systemic muscle wasting after spinal cord injury is mediated by glucocorticoid signaling in mice
Authors: Markus E. Harrigan, Angela R. Filous, Christopher P. Vadala, Amy Webb, Maciej Pietrzak, Zarife Sahenk, Harald Prüss, Peter J. Reiser, Phillip G. Popovich, W. David Arnold, Jan M. Schwab
Journal: Science Translational Medicine (2023)

An incomplete mechanistic understanding of skeletal muscle wasting early after spinal cord injury (SCI) precludes targeted molecular interventions. Here, we demonstrated systemic wasting that also affected innervated nonparalyzed (supralesional) muscles and emerged within 1 week after experimental SCI in mice. Systemic muscle wasting caused muscle weakness, affected fast type 2 myofibers preferentially, and became exacerbated after high (T3) compared with low (T9) thoracic paraplegia, indicating lesion level–dependent (“neurogenic”) mechanisms. The wasting of nonparalyzed muscle and its rapid onset and severity beyond what can be explained by disuse implied unknown systemic drivers. Muscle transcriptome and biochemical analysis revealed a glucocorticoid-mediated catabolic signature early after T3 SCI. SCI-induced systemic muscle wasting was mitigated by (i) endogenous glucocorticoid ablation (adrenalectomy) and (ii) pharmacological glucocorticoid receptor (GR) blockade and was (iii) completely prevented after T3 relative to T9 SCI by genetic muscle-specific GR deletion. These results suggest that neurogenic hypercortisolism contributes to a rapid systemic and functionally relevant muscle wasting syndrome early after paraplegic SCI in mice.
TrkA-mediated sensory innervation of injured mouse tendon supports tendon sheath progenitor cell expansion and tendon repair
Authors: Masnsen Cherief, Jiajia Xu, Zhao Li, Robert J. Tower, Sowmya Ramesh, Qizhi Qin, Mario Gomez-Salazar, Ji-Hye Yea, Seungyong Lee, Stefano Negri, Mingxin Xu, Theodore Price, Adrian R. Kendal, Chen-Ming Fan, Thomas L. Clemens, Benjamin Levi, Aaron W. James
Journal: Science Translational Medicine (2023)

Peripheral neurons terminate at the surface of tendons partly to relay nociceptive pain signals; however, the role of peripheral nerves in tendon injury and repair remains unclear. Here, we show that after Achilles tendon injury in mice, there is new nerve growth near tendon cells that express nerve growth factor (NGF). Conditional deletion of the Ngf gene in either myeloid or mesenchymal mouse cells limited both innervation and tendon repair. Similarly, inhibition of the NGF receptor tropomyosin receptor kinase A (TrkA) abrogated tendon healing in mouse tendon injury. Sural nerve transection blocked the postinjury increase in tendon sensory innervation and the expansion of tendon sheath progenitor cells (TSPCs) expressing tubulin polymerization promoting protein family member 3. Single cell and spatial transcriptomics revealed that disruption of sensory innervation resulted in dysregulated inflammatory signaling and transforming growth factor–β (TGFβ) signaling in injured mouse tendon. Culture of mouse TSPCs with conditioned medium from dorsal root ganglia neuron further supported a role for neuronal mediators and TGFβ signaling in TSPC proliferation. Transcriptomic and histologic analyses of injured human tendon biopsy samples supported a role for innervation and TGFβ signaling in human tendon regeneration. Last, treating mice after tendon injury systemically with a small-molecule partial agonist of TrkA increased neurovascular response, TGFβ signaling, TSPC expansion, and tendon tissue repair. Although further studies should investigate the potential effects of denervation on mechanical loading of tendon, our results suggest that peripheral innervation is critical for the regenerative response after acute tendon injury.
Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects
Authors: Mariano Prado-Acosta, Seihwan Jeong, Alberto Utrero-Rico, Tatiana Goncharov, Joshua D. Webster, Ernst Holler, George Morales, Sergio Dellepiane, John E. Levine, Michael E. Rothenberg, Domagoj Vucic, James L. M. Ferrara
Journal: Science Translational Medicine (2023)

Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.
Liver macrophages and sinusoidal endothelial cells execute vaccine-elicited capture of invasive bacteria
Authors: Juanjuan Wang, Haoran An, Ming Ding, Yanhong Liu, Shaomeng Wang, Qian Jin, Qi Wu, Haodi Dong, Qile Guo, Xianbin Tian, Jiankai Liu, Jingfei Zhang, Tao Zhu, Junqiang Li, Zhujun Shao, David E. Briles, Jan-Willem Veening, Haifa Zheng, Linqi Zhang, Jing-Ren Zhang
Journal: Science Translational Medicine (2023)

Vaccination has substantially reduced the morbidity and mortality of bacterial diseases, but mechanisms of vaccine-elicited pathogen clearance remain largely undefined. We report that vaccine-elicited immunity against invasive bacteria mainly operates in the liver. In contrast to the current paradigm that migrating phagocytes execute vaccine-elicited immunity against blood-borne pathogens, we found that invasive bacteria are captured and killed in the liver of vaccinated host via various immune mechanisms that depend on the protective potency of the vaccine. Vaccines with relatively lower degrees of protection only activated liver-resident macrophage Kupffer cells (KCs) by inducing pathogen-binding immunoglobulin M (IgM) or low amounts of IgG. IgG-coated pathogens were directly captured by KCs via multiple IgG receptors FcγRs, whereas IgM-opsonized bacteria were indirectly bound to KCs via complement receptors of immunoglobulin superfamily (CRIg) and complement receptor 3 (CR3) after complement C3 activation at the bacterial surface. Conversely, the more potent vaccines engaged both KCs and liver sinusoidal endothelial cells by inducing higher titers of functional IgG antibodies. Endothelial cells (ECs) captured densely IgG-opsonized pathogens by the low-affinity IgG receptor FcγRIIB in a “zipper-like” manner and achieved bacterial killing predominantly in the extracellular milieu via an undefined mechanism. KC- and endothelial cell–based capture of antibody-opsonized bacteria also occurred in FcγR-humanized mice. These vaccine protection mechanisms in the liver not only provide a comprehensive explanation for vaccine-/antibody-boosted immunity against invasive bacteria but also may serve as in vivo functional readouts of vaccine efficacy.
Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with<i>FOXP3</i>mutations
Authors: Šimon Borna, Esmond Lee, Jason Nideffer, Akshaya Ramachandran, Bing Wang, Jeanette Baker, Melissa Mavers, Uma Lakshmanan, Mansi Narula, Amy Kang-hee Garrett, Janika Schulze, Sven Olek, Louis Marois, Yael Gernez, Monica Bhatia, Hey Jin Chong, Jolan Walter, Maleewan Kitcharoensakkul, Abigail Lang, Megan A. Cooper, Alice Bertaina, Maria Grazia Roncarolo, Eric Meffre, Rosa Bacchetta
Journal: Science Translational Medicine (2023)

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (T regs ) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and T reg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study T regs independently of their phenotype and to analyze T cell autoreactivity, we combined T reg -specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (T effs ) and T regs . In addition, a fraction of the expanded T regs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9–mediated FOXP3 knockout T regs and T regs from patients with IPEX indicated that the patients’ T regs gain a T H 2-skewed T eff -like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that T regs expressing nonmutated FOXP3 prevent the accumulation of autoreactive T effs and unstable T regs . These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.
Beyond cell cycle regulation: The pleiotropic function of CDK4 in cancer
Authors: Dorian V. Ziegler, Kanishka Parashar, Lluis Fajas
Journal: Seminars in Cancer Biology (2023)

CDK4, along with its regulatory subunit, cyclin D, drives the transition from G1 to S phase, during which DNA replication and metabolic activation occur. In this canonical pathway, CDK4 is essentially a transcriptional regulator that acts through phosphorylation of retinoblastoma protein (RB) and subsequent activation of the transcription factor E2F, ultimately triggering the expression of genes involved in DNA synthesis and cell cycle progression to S phase. In this review, we focus on the newly reported functions of CDK4, which go beyond direct regulation of the cell cycle. In particular, we describe the extranuclear roles of CDK4, including its roles in the regulation of metabolism, cell fate, cell dynamics and the tumor microenvironment. We describe direct phosphorylation targets of CDK4 and decipher how CDK4 influences these physiological processes in the context of cancer.
Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial
Authors: Yoshiaki Oda, Yuji Kumagai, Manabu Kanai, Yasuhiro Iwama, Iori Okura, Takeshi Minamida, Yukihiro Yagi, Toru Kurosawa, Benjamin Greener, Ye Zhang, Judd L Walson
Journal: The Lancet Infectious Diseases (2023)
Recent developments on using pyruvate kinase activators as a new approach for treating sickle cell disease
Authors: Dina S. Parekh, William A. Eaton, Swee Lay Thein
Journal: Blood (2023)

Pyruvate kinase (PK) is a key enzyme in glycolysis, the sole source of adenosine triphosphate, which is essential for all energy-dependent activities of red blood cells. Activating PK shows great potential for treating a broad range of hemolytic anemias beyond PK deficiency, because they also enhance activity of wild-type PK. Motivated by observations of sickle-cell complications in sickle-trait individuals with concomitant PK deficiency, activating endogenous PK offers a novel and promising approach for treating patients with sickle-cell disease.
Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget’s disease of bone
Authors: Jonathan Phillips, Deepak Subedi, Steff C Lewis, Catriona Keerie, Owen Cronin, Mary Porteous, David Moore, Roseanne Cetnarskyj, Lakshminarayan Ranganath, Peter L Selby, Tolga Turgut, Geeta Hampson, Rama Chandra, Shu Ho, Jon Tobias, Steven Young-Min, Malachi J McKenna, Rachel K Crowley, William D Fraser, Jonathan C Y Tang, Luigi Gennari, Rannuccio Nuti, Maria Luisa Brandi, Javier Del Pino-Montes, Jean-Pierre Devogelaer, Anne Durnez, Giovanni Carlo Isaia, Marco Di Stefano, Nuria Guanabens, Josep Blanch Rubio, Markus J Seibel, John P Walsh, Sarah L Rea, Mark A Kotowicz, Geoffrey C Nicholson, Emma L Duncan, Gabor Major, Anne Horne, Nigel Gilchrist, Stuart H Ralston
Journal: Annals of the Rheumatic Diseases (2023)

Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment.