tbuckley/cabot-search huggingface dataset:
Resilience to diabetic retinopathy
Authors: Anara Serikbaeva, Yanliang Li, Simon Ma, Darvin Yi, Andrius Kazlauskas
Journal: Progress in Retinal and Eye Research (2024)

Chronic elevation of blood glucose at first causes relatively minor changes to the neural and vascular components of the retina. As the duration of hyperglycemia persists, the nature and extent of damage increases and becomes readily detectable. While this second, overt manifestation of diabetic retinopathy (DR) has been studied extensively, what prevents maximal damage from the very start of hyperglycemia remains largely unexplored. Recent studies indicate that diabetes (DM) engages mitochondria-based defense during the retinopathy-resistant phase, and thereby enables the retina to remain healthy in the face of hyperglycemia. Such resilience is transient, and its deterioration results in progressive accumulation of retinal damage. The concepts that co-emerge with these discoveries set the stage for novel intellectual and therapeutic opportunities within the DR field. Identification of biomarkers and mediators of protection from DM-mediated damage will enable development of resilience-based therapies that will indefinitely delay the onset of DR.
HtrA3 paves the way for MSC migration and promotes osteogenesis
Authors: Yaru Guo, Siqin Ma, Dandan Wang, Feng Mei, Yusi Guo, Boon Chin Heng, Shihan Zhang, Ying Huang, Yan Wei, Ying He, Wenwen Liu, Mingming Xu, Xuehui Zhang, Lili Chen, Xuliang Deng
Journal: Bioactive Materials (2024)

Mesenchymal stem cell (MSC) migration determines the healing capacity of bone and is crucial in promoting bone regeneration. Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enzymes. However, the underlying mechanisms of how enzymolysis paves the way for MSCs to migrate from their niche to the defect area is still not fully understood. Here, this study shows that high-temperature requirement A3 (HtrA3) overcomes the physical barrier and provides anchor points through collagen IV degradation, paving the way for MSC migration. HtrA3 is upregulated in MSCs at the leading edge of bone defect during the early stage of healing. HtrA3 degrades the surrounding collagen IV, which increases the collagen network porosity and increases integrin β1 expression. Subsequently, integrin β1 enhances the mechanotransduction of MSCs, thus remodeling the cytoskeleton, increasing cellular stiffness and nuclear translocation of YAP, eventually promoting the migration and subsequent osteogenic differentiation of MSCs. Local administration of recombinant HtrA3 in rat cranial bone defects significantly increases new bone formation and further validates the enhancement of MSC migration. This study helps to reveal the novel roles of HtrA3, explore potential targets for regenerative medicine, and offer new insights for the development of bioactive materials.
Gamified Behavioral Science Intervention to Enhance Trial Enrollment
Authors: Ankeet S. Bhatt, Safia Chatur, Brian L. Claggett, James Lay-Flurrie, Prabhakar Viswanathan, Orly Vardeny, Mikhail N. Kosiborod, Kavita Sharma, Scott D. Solomon, Muthiah Vaduganathan
Journal: JACC Heart Failure (2024)
Neutralization activity of HCWs’ sera after Omicron XBB.1.5-adapted monovalent COVID-19 mRNA vaccination
Authors: Masayuki Amano, Yasuko Ichikawa, Shota Matsumoto, Nobuyo Higashi-Kuwata, Yuki Takamatsu, Shuzo Matsushita, Shinya Shimada, Hiroaki Mitsuya
Journal: Journal of Infection (2024)
Prevalence and predictors of residual antibiotics in children's blood in community settings in Tanzania
Authors: Theopista Lotto, Sabine Renggli, Eliangiringa Kaale, Honorati Masanja, Beatrice Ternon, Laurent Arthur Décosterd, Valérie D'Acremont, Blaise Genton, Alexandra V. Kulinkina
Journal: Clinical Microbiology and Infection (2024)

Objective Children account for a significant proportion of antibiotic consumption in low- and middle-income countries, with overuse occurring in formal and informal health sectors. This study assessed the prevalence and predictors of residual antibiotics in the blood of children in Mbeya and Morogoro regions of Tanzania. Methods The cross-sectional community-based survey used two-stage cluster sampling to include children aged under 15 years. For each child, information on recent illness, healthcare-seeking behavior, and use of antibiotics, as well as a dried blood spot sample, were collected. The samples underwent tandem mass spectrometry analysis to quantify the concentrations of 15 common antibiotics. Associations between survey variables and presence of residual antibiotics were assessed using mixed-effects logistic regression. Results In total, 1742 children were surveyed, and 1699 analyzed. The overall prevalence of residual antibiotics in the blood samples was 17.4% (296/1699), the highest among children under the age of five years. The most frequently detected antibiotics were trimethoprim (144/1699; 8.5%), sulfamethoxazole (102/1699; 6.0%), metronidazole (61/1699; 3.6%) and amoxicillin (43/1699; 2.5%). The strongest predictors of residual antibiotics in the blood were observed presence of antibiotics at home (aOR=2.9; 95% CI: 2.0–4.1) and reported consumption of antibiotics in the last two weeks (aOR=2.5; 95% CI: 1.6–3.9). However, half (145/296) of the children who had residual antibiotics in their blood, some with multiple antibiotics, had no reported history of illness or antibiotic consumption in the last two weeks, and antibiotics were not found at home. Discussion This study demonstrated a high prevalence of antibiotic exposure among children in Tanzanian communities, albeit likely underestimated, especially for compounds with short half-lives. A significant proportion of antibiotic exposure was unexplained and may have been due to unreported self-medication or environmental pathways. Incorporating biomonitoring into surveillance strategies can help better understand exposure patterns and design antibiotic stewardship interventions.
Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study
Authors: Elisabeth Dovern, Mesire Aydin, Mette D. Hazenberg, Man Wai Tang, Elisabeth M. Suijk, Gerianne M. Hoogendoorn, Charlotte F. J. Van Tuijn, Jean‐Louis Kerkhoffs, Caroline E. Rutten, Sacha S. Zeerleder, Josu de la Fuente, Bart J. Biemond, Erfan Nur
Journal: American Journal of Hematology (2024)

Abstract Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19–49], 13 females) were transplanted. Median follow‐up was 46.0 months (IQR 21.8–57.9). One‐year overall survival and event‐free survival (graft failure or death) were both 95% (95% confidence interval 86–100). Mean donor myeloid and T‐cell chimerism 1‐year post‐transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid‐responsive grade II intestinal acute graft‐versus‐host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event‐free survival and robust donor T‐cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov : NCT05249452.
Inducing Long Lasting B Cell and T Cell Immunity Against Multiple Variants of SARS‐CoV‐2 Through Mutant Bacteriophage Qβ—Receptor Binding Domain Conjugate
Authors: Zibin Tan, Canchai Yang, Po‐han Lin, Sherif Ramadan, Weizhun Yang, Zahra Rashidi, Shuyao Lang, Fatemeh Shafieichaharberoud, Jia Gao, Xingling Pan, Nachy Soloff, Xuanjun Wu, Steven Bolin, Dohun Pyeon, Xuefei Huang
Journal: Advanced Healthcare Materials (2024)

More than 3 years into the global pandemic, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a significant threat to public health. Immunities acquired from infection or current vaccines fail to provide long term protection against subsequent infections, mainly due to their fast-waning nature and the emergence of variants of concerns (VOCs) such as Omicron. To overcome these limitations, SARS-CoV-2 Spike protein receptor binding domain (RBD)-based epitopes are investigated as conjugates with a powerful carrier, the mutant bacteriophage Qβ (mQβ). The epitope design is critical to eliciting potent antibody responses with the full length RBD being superior to peptide and glycopeptide antigens. The full length RBD conjugated with mQβ activates both humoral and cellular immune systems in vivo, inducing broad spectrum, persistent, and comprehensive immune responses effective against multiple VOCs including Delta and Omicron variants, rendering it a promising vaccine candidate.
TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia
Authors: Mariko Morii, Sho Kubota, Mihoko Iimori, Takako Yokomizo-Nakano, Ai Hamashima, Jie Bai, Akiho Nishimura, Masayoshi Tasaki, Yukio Ando, Kimi Araki, Goro Sashida
Journal: Leukemia (2024)
Redefining Iron Deficiency in Patients With Chronic Heart Failure
Authors: Milton Packer, Stefan D. Anker, Javed Butler, John G.F. Cleland, Paul R. Kalra, Robert J. Mentz, Piotr Ponikowski, Khawaja M. Talha
Journal: Circulation (2024)

A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.
New York Heart Association functional class and implantable cardioverter‐defibrillator in non‐ischaemic heart failure with reduced ejection fraction: Extended follow‐up of the <scp>DANISH</scp> trial
Authors: Munise N. Karacan, Seiko N. Doi, Adelina Yafasova, Jens Jakob Thune, Jens C. Nielsen, Jens Haarbo, Niels E. Bruun, Finn Gustafsson, Hans Eiskjær, Christian Hassager, Jesper H. Svendsen, Dan E. Høfsten, Steen Pehrson, Lars Køber, Jawad H. Butt
Journal: European Journal of Heart Failure (2024)

Abstract Aims Current guidelines recommend implantable cardioverter‐defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II–III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long‐term effects of primary prevention ICD implantation according to NYHA class in an extended follow‐up study of the DANISH trial. Methods and results The DANISH trial randomized 1116 patients with non‐ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all‐cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow‐up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long‐term rate of all‐cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20–1.93) and cardiovascular death (HR 1.95 [1.47–2.60]). ICD implantation, compared with usual care, did not reduce the long‐term rate of all‐cause mortality (all participants: HR 0.89 [95% CI 0.74–1.08]; NYHA class II: HR 0.85 [0.64–1.13]; NYHA class III/IV: HR 0.89 [0.69–1.14]; p interaction = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70–1.09]; NYHA class II: HR 0.78 [0.54–1.12]; NYHA class III/IV: HR 0.89 [0.67–1.19]; p interaction = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40–0.92]; NYHA class II: HR 0.73 [0.40–1.36]; NYHA class III/IV: HR 0.52 [0.29–0.94]; p interaction = 0.39). Conclusions In patients with non‐ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class. Clinical Trial Registration: ClinicalTrials.gov NCT00542945.
BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism
Authors: Quanjun Yang, Xinting Zhu, Ping Huang, Chunyan Li, Leng Han, Yonglong Han, Run Gan, Bo Xin, Yixing Tu, Shumin Zhou, Ting Yuan, Juan Hao, Chunqiong Li, Li Zhang, Lei Shi, Cheng Guo
Journal: Molecular Therapy (2024)

Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.
Prophylactic vaccination inducing anti-Env antibodies can result in protection against HTLV-1 challenge in macaques
Authors: Midori Nakamura-Hoshi, Hiroshi Ishii, Takushi Nomura, Masako Nishizawa, Trang Thi Thu Hau, Nozomi Kuse, Midori Okazaki, Akira Ainai, Tadaki Suzuki, Hideki Hasegawa, Takeshi Yoshida, Kenzo Yonemitsu, Yuriko Suzaki, Yasushi Ami, Hiroyuki Yamamoto, Tetsuro Matano
Journal: Molecular Therapy (2024)

Human T cell leukemia/T-lymphotropic virus type 1 (HTLV-1) infection occurs by cell-to-cell transmission and can induce fatal adult T cell leukemia. Vaccine development is critical for the control of HTLV-1 transmission. However, determining whether vaccine-induced anti-Env antibodies can prevent cell-to-cell HTLV-1 transmission is challenging. Here, we examined the protective efficacy of a vaccine inducing anti-Env antibodies against HTLV-1 challenge in cynomolgus macaques. Eight of 10 vaccinated macaques produced anti-HTLV-1 neutralizing antibodies (NAbs) and were protected from an intravenous challenge with 10
Efficacy and safety of three antiretroviral therapy regimens for treatment-naive African adults living with HIV-2 (FIT-2): a pilot, phase 2, non-comparative, open-label, randomised controlled trial
Authors: Serge P Eholie, Didier K Ekouevi, Corine Chazallon, Charlotte Charpentier, Eugène Messou, Zelica Diallo, Jacques Zoungrana, Albert Minga, Ndeye Fatou Ngom Gueye, Denise Hawerlander, Fassery Dembele, Géraldine Colin, Boris Tchounga, Sophie Karcher, Jérome Le Carrou, Annick Tchabert-Guié, Thomas-d'Aquin Toni, Abdoul-Salam Ouédraogo, Guillaume Bado, Coumba Toure Kane, Moussa Seydi, Armel Poda, Ephrem Mensah, Illah Diallo, Youssouf Joseph Drabo, Xavier Anglaret, Françoise Brun-Vezinet, Xavier Anglaret, Lambert Assoumou, Guillaume Bado, Emmanuel Bissagnene, Fabrice Bonnet, Carlos Britto, Françoise Brun Vezinet, Charlotte Charpentier, Corine Chazallon, Henri Chenal, Geneviève Chêne, Remy Chenier, Gwenaelle Clouet, Géraldine Colin, Gilles Collin, Valérie Conte, Christine Danel, Laure-Amélie De Monteynard, Fassery Dembele, Zelica Diallo, Illah Diallo, Lambert Dohoun, Youssouf Joseph Drabo, Serge Paul Eholié, Didier Koumavi Ekouevi, Fatoumata Fadiga, Delphine Gabillard, Pierre Marie Girard, Geoffrey S. Gottlieb, Denise Hawerlander, Sophie Karcher, Benjamin Kariyiare, Mame Basty Koita Fall, Romuald Konan, Antoine Kouame, Serge-Olivier Kouley, Gabriele Laborde Bolen, Roland Landman, Jérome Le Carrou, Anne Geneviève Marcelain, Sophie Matheron, Ephrem Mensah, Noémie Mercier, Assoua Messou, Eugène Messou, Albert Minga, Cheick Tidiane N'dour, Celestin N'chot, Bara Ndiaye, Ndeye Fatou Ngom Gueye, Larissa N'guessan-Koffi, Eric Ouattara, Abdoul-Salam Ouédraogo, Vincent Palokinam Pitche, Gilles Peytavin, Jean Christophe Plantier, Armel Poda, Mireille Prince-David, Yasmine Raffali, Claire Rekacewicz, Christine Rouzioux, Mounerou Salou, Lassana Sangare, Adrien Bruno Sawadogo, Moussa Seydi, Désiré Somé, Séphora Tamegnon, Annick Tchabert-Guié, Boris Tchounga, Thomas d'Aquin Toni, Coumba Toure Kane, Pierre Touret, Jean-Richard Traoré, Marco Antonio Vitoria de Avila, Seydou Yaméogo, Cyrille Yao Yapi, Jacques Zoungrana
Journal: The Lancet HIV (2024)
Leveraging the pleural space for anticancer therapies in pleural mesothelioma
Authors: Kevin G Blyth, Prasad S Adusumilli, Philippe Astoul, Liz Darlison, Y C Gary Lee, Aaron S Mansfield, Stefan J Marciniak, Nick Maskell, Vasiliki Panou, Tobias Peikert, Najib M Rahman, Marjorie G Zauderer, Daniel Sterman, Dean A Fennell
Journal: The Lancet Respiratory Medicine (2024)
Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial
Authors: Andrea Necchi, Mathieu Roumiguié, Ashish M Kamat, Neal D Shore, Joost L Boormans, Ahmet Adil Esen, Thierry Lebret, Shuya Kandori, Dean F Bajorin, Laurence E M Krieger, Scot A Niglio, Edward M Uchio, Ho Kyung Seo, Ronald de Wit, Eric A Singer, Petros Grivas, Hiroyuki Nishiyama, Haojie Li, Pranshu Baranwal, Margot Van den Sigtenhorst-Fijlstra, Ekta Kapadia, Girish S Kulkarni
Journal: The Lancet Oncology (2024)
Targeting cellular cathepsins inhibits hepatitis E virus entry
Authors: Mara Klöhn, Thomas Burkard, Juliana Janzen, Jil A. Haase, André Gömer, Rebecca Fu, George Ssebyatika, Maximilian K. Nocke, Richard J. P. Brown, Thomas Krey, Viet Loan Dao Thi, Volker Kinast, Yannick Brüggemann, Daniel Todt, Eike Steinmann
Journal: Hepatology (2024)

Background and Aims: HEV is estimated to be responsible for 70,000 deaths annually, yet therapy options remain limited. In the pursuit of effective antiviral therapies, targeting viral entry holds promise and has proven effective for other viruses. However, the precise mechanisms and host factors required during HEV entry remain unclear. Cellular proteases have emerged as host factors required for viral surface protein activation and productive cell entry by many viruses. Hence, we investigated the functional requirement and therapeutic potential of cellular protease during HEV infection. Approach and Results: Using our established HEV cell culture model and subgenomic HEV replicons, we found that blocking lysosomal cathepsins (CTS) with small molecule inhibitors impedes HEV infection without affecting replication. Most importantly, the pan-cathepsin inhibitor K11777 suppressed HEV infections with an EC 50 of ~0.02 nM. Inhibition by K11777, devoid of notable toxicity in hepatoma cells, was also observed in HepaRG and primary human hepatocytes. Furthermore, through time-of-addition and RNAscope experiments, we confirmed that HEV entry is blocked by inhibition of cathepsins. Cathepsin L (CTSL) knockout cells were less permissive to HEV, suggesting that CTSL is critical for HEV infection. Finally, we observed cleavage of the glycosylated ORF2 protein and virus particles by recombinant CTSL. Conclusions: In summary, our study highlights the pivotal role of lysosomal cathepsins, especially CTSL, in the HEV entry process. The profound anti-HEV efficacy of the pan-cathepsin inhibitor K11777, especially with its notable safety profile in primary cells, further underscores its potential as a therapeutic candidate.
CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-β
Authors: Boning Niu, Tianyi Tian, Lu Wang, Yinmei Tian, Tian Tian, Yuanyuan Guo, Hu Zhou, Zhiping Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1