tbuckley/cabot-search huggingface dataset:
Biotechnological Effects of Advanced Smart‐Bile Acid Cyclodextrin‐Based Nanogels for Ear Delivery and Treatment of Hearing Loss
Authors: Bozica Kovacevic, Susbin Raj Wagle, Corina Mihaela Ionescu, Thomas Foster, Maja Đanić, Momir Mikov, Armin Mooranian, Hani Al‐Salami
Journal: Advanced Healthcare Materials (2024)

Abstract Inner ear delivery requires safe and effective drug delivery vehicles incorporating high‐viscosity formulations with permeation enhancers. This study designs novel thermoresponsive‐smart polymer‐bile acid and cyclodextrin‐based nanogels for inner ear delivery. Nanogels are examined for their rheological and physical properties. The biocompatibility studies will be assessed on auditory and macrophage cell lines by investigating the impact of nanogels on cellular viability, mitochondrial respiration, glycolysis, intracellular oxidative stress, inflammatory profile, and macrophage polarization. Novel ther nanogels based on bile acid and beta‐cyclodextrin show preserved porous nanogels' inner structure, exhibit non‐Newtonian, shear‐thinning fluid behavior, have fast gelation at 37 °C and minimal albumin adsorption on the surface. The nanogels have minimal impact on cellular viability, mitochondrial respiration, glycolysis, intracellular oxidative stress, and inflammatory profile of the auditory cell line House Ear Institute‐Organ of Corti 1 after 24 h incubation. Nanogel exposure of 24 h to macrophage cell line RAW264.7 leads to decreased viability, mitochondrial dysfunction, and increased intracellular ROS and inflammatory cytokines. However, polarization changes from M2 anti‐inflammatory to M1 pro‐inflammatory macrophages are minimal, and inflammatory products of RAW264.7 macrophages do not overly disrupt the survivability of HEI‐OC1 cells. Based on these results, thermoresponsive bile acid and cyclodextrin nanogels can be potential drug delivery vehicles for inner ear drug delivery.
Synthesis on NIR‐II Multifunctional Imaging and Photothermal Therapy of a Novel Water‐Soluble Molecule
Authors: Mengyu Cao, Chang Wang, Fang Wang, Wentao Zou, Bing Yu, Hailin Cong, Youqing Shen
Journal: Advanced Healthcare Materials (2024)

The synthesis of water-soluble symmetric molecules with donor-acceptor-donor (D-A-D) structure is reported. The compound is connected by π bridge with 2-bromofluorene external polyethylene glycol 2000 as the shielding unit, and donor component and pyrrolopyrrole (DPP) as the acceptor unit. The D-A-D double donor fluorescent molecule P2-DPP is obtained by coupling reaction. The absorption peak and emission peak of the fluorescent molecule P2-DPP are 600 and 1020 nm, respectively. It has potential excellent imaging characteristics. It does not need to use nanoparticles formed by the DSPE-MPEG amphiphilic block to form micelles. The quantum yield reaches 0.6% and the penetration depth can reach 10 mm. The chemical is capable of achieving liver and renal metabolism. It has a good application prospect in the photothermal therapy of mouse tumors and realizes the integration of biological diagnosis and treatment.
Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study
Authors: Adam S. Kittai, David Bond, Ying Huang, Seema A. Bhat, Emily Blyth, John C. Byrd, Julio C. Chavez, Matthew S. Davids, Jamie P. Dela Cruz, Mark R. Dowling, Caitlyn Duffy, Carrie Ho, Caron Jacobson, Samantha Jaglowski, Nitin Jain, Kevin H. Lin, Cecelia Miller, Christine McCarthy, Zulfa Omer, Erin Parry, Manoj Rai, Kerry A. Rogers, Aditi Saha, Levanto Schachter, Hamish Scott, Jayastu Senapati, Mazyar Shadman, Tanya Siddiqi, Deborah M. Stephens, Vinay Vanguru, William Wierda, Jennifer A. Woyach, Philip A. Thompson
Journal: Journal of Clinical Oncology (2024)

PURPOSE Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION CAR-T demonstrates clinical efficacy for patients with RT.
Point-of-Care HbA1c in Clinical Practice: Caveats and Considerations for Optimal Use
Authors: David B. Sacks, M. Sue Kirkman, Randie R. Little
Journal: Diabetes Care (2024)

Hemoglobin A1c (A1C) is widely used for the diagnosis and management of diabetes. Accurate measurement of A1C is necessary for optimal clinical value. Assay standardization has markedly improved the accuracy and consistency of A1C testing. Devices to measure A1C at point of care (POC) are commercially available, allowing rapid results when the patient is seen. In this review, we describe how standardization of A1C testing was achieved, leading to high-quality results in clinical laboratories. We address the use of POC A1C testing in clinical situations and summarize the advantages and disadvantages of POC A1C testing. We emphasize the importance of considering the limitations of these devices and following correct testing procedures to ensure that accurate A1C results are obtained for optimal care of patients.
T cell help induces <i>Myc</i> transcriptional bursts in germinal center B cells during positive selection
Authors: Sharon Kagan Ben Tikva, Neta Gurwitz, Ehud Sivan, Dana Hirsch, Hadas Hezroni-Barvyi, Adi Biram, Lihee Moss, Noa Wigoda, Adi Egozi, Alan Monziani, Ofra Golani, Menachem Gross, Ariel Tenenbaum, Ziv Shulman
Journal: Science Immunology (2024)

Antibody affinity maturation occurs in secondary lymphoid organs within germinal centers (GCs). At these sites, B cells mutate their antibody-encoding genes in the dark zone, followed by preferential selection of the high-affinity variants in the light zone by T cells. The strength of the T cell–derived selection signals is proportional to the B cell receptor affinity and to the magnitude of subsequent Myc expression. However, because the lifetime of Myc mRNA and its corresponding protein is very short, it remains unclear how T cells induce sustained Myc levels in positively selected B cells. Here, by direct visualization of mRNA and active transcription sites in situ, we found that an increase in transcriptional bursts promotes Myc expression during B cell positive selection in GCs. Elevated T cell help signals predominantly enhance the percentage of cells expressing Myc in GCs as opposed to augmenting the quantity of Myc transcripts per individual cell. Visualization of transcription start sites in situ revealed that T cell help promotes an increase in the frequency of transcriptional bursts at the Myc locus in GC B cells located primarily in the LZ apical rim. Thus, the rise in Myc , which governs positive selection of B cells in GCs, reflects an integration of transcriptional activity over time rather than an accumulation of transcripts at a specific time point.
Spatially Segregated Macrophage Populations Predict Distinct Outcomes in Colon Cancer
Authors: Magdalena Matusiak, John W. Hickey, David G.P. van IJzendoorn, Guolan Lu, Lukasz Kidziński, Shirley Zhu, Deana R.C. Colburg, Bogdan Luca, Darci J. Phillips, Sky W. Brubaker, Gregory W. Charville, Jeanne Shen, Kyle M. Loh, Derick K. Okwan-Duodu, Garry P. Nolan, Aaron M. Newman, Robert B. West, Matt van de Rijn
Journal: Cancer Discovery (2024)

Abstract Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations reside in spatially segregated micro-environmental niches with conserved cellular compositions that are repeated across healthy and diseased tissue. We show that IL4I1+ macrophages phagocytose dying cells in areas with high cell turnover and predict good outcome in colon cancer. In contrast, SPP1+ macrophages are enriched in hypoxic and necrotic tumor regions and portend worse outcome in colon cancer. A subset of FOLR2+ macrophages is embedded in plasma cell niches. NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors. Our findings indicate that a limited number of unique human macrophage niches function as fundamental building blocks in tissue. Significance: This work broadens our understanding of the distinct roles different macrophage populations may exert on cancer growth and reveals potential predictive markers and macrophage population-specific therapy targets.
Pancreas-directed AAV8<i>-hSPINK1</i>gene therapy safely and effectively protects against pancreatitis in mice
Authors: Yuan-Chen Wang, Xiao-Tong Mao, Chang Sun, Ya-Hui Wang, Yi-Zhou Zheng, Si-Huai Xiong, Mu-Yun Liu, Sheng-Han Mao, Qi-Wen Wang, Guo-Xiu Ma, Di Wu, Zhao-Shen Li, Jian-Min Chen, Wen-Bin Zou, Zhuan Liao
Journal: Gut (2024)

Objective Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 ( hSPINK1 ) for pancreatitis therapy in mice. Design A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8- hSPINK1 ) to target the pancreas was constructed. Mice were treated with AAV8- hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8- hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8- hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T&gt;C mouse models). Results The constructed AAV8- hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×10 11 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8 -hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. Conclusion One-time injection of AAV8 -hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.
Regression From Early GDM to Normal Glucose Tolerance and Adverse Pregnancy Outcomes in the Treatment of Booking Gestational Diabetes Mellitus Study
Authors: David Simmons, Jincy Immanuel, William M. Hague, Helena Teede, Christopher J. Nolan, Michael J. Peek, Jeff R. Flack, Mark McLean, Vincent W. Wong, Emily J. Hibbert, Alexandra Kautzky-Willer, Jürgen Harreiter, Helena Backman, Emily Gianatti, Arianne Sweeting, Viswanathan Mohan, N. Wah Cheung, David Simmons, N. Wah Cheung, Jincy Immanuel, William M. Hague, Helena Teede, Christopher J. Nolan, Michael J. Peek, Jeff R. Flack, Mark McLean, Vincent Wong, Emily Hibbert, Emily Gianatti, Arianne Sweeting, Suzette Coat, Raiyomand Dalal, Georgia Soldatos, Suja Padmanabhan, Rohit Rajagopal, Victoria Rudland, Jürgen Harreiter, Alexandra Kautzky-Willer, Herbert Kiss, Helena Backman, Erik Schwarcz, Glynis Ross, Viswanathan Mohan, Ranjit Mohan Anjana, Uma Ram
Journal: Diabetes Care (2024)

OBJECTIVE To compare pregnancy outcomes among women with a normal oral glucose tolerance test (OGTT) before 20 weeks’ gestation (early) and at 24–28 weeks’ gestation (late) (no gestational diabetes mellitus, or No-GDM), those with early GDM randomized to observation with a subsequent normal OGTT (GDM-Regression), and those with GDM on both occasions (GDM-Maintained). RESEARCH DESIGN AND METHODS Women at &amp;lt;20 weeks’ gestation with GDM risk factors who were recruited for a randomized controlled early GDM treatment trial were included. Women with treated early GDM and late GDM (according to the World Health Organization’s 2013 criteria) were excluded from this analysis. Logistic regression compared pregnancy outcomes. RESULTS GDM-Regression (n = 121) group risk factor profiles and OGTT results generally fell between the No-GDM (n = 2,218) and GDM-Maintained (n = 254) groups, with adjusted incidences of pregnancy complications similar between the GDM-Regression and No-GDM groups. CONCLUSIONS Women with early GDM but normal OGTT at 24–28 weeks’ gestation had pregnancy outcomes that were similar to those of individuals without GDM. Identifying early GDM likely to regress would allow treatment to be avoided.
Should all patients with polymyalgia rheumatica have a vascular ultrasound assessment?
Authors: Sharon Cowley, Patricia Harkins, Colm Kirby, Richard Conway, David J Kane
Journal: Annals of the Rheumatic Diseases (2024)

There is a growing appreciation that both giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely interrelated conditions that have significant overlap in aetiology, clinical characteristics and treatment regimens. Subclinical GCA in PMR is becoming increasingly recognised, and there is evolving evidence that this may be a more aggressive disease phenotype than PMR. Ultrasound (US) lends itself well as a screening tool for GCA in PMR; it is inexpensive, non-invasive, widely available, lacks ionising radiation, may be performed at the bedside and is recommended by EULAR as a first-line investigation for suspected GCA. There is insufficient evidence to currently recommend that all patients with PMR should have a US assessment for vascular involvement. However, as clinical and laboratory parameters alone do not accurately diagnose patients with subclinical GCA, we suggest that vascular US will be increasingly performed by rheumatologists in practice to identify these patients with PMR, preferably as part of larger prospective outcome studies.
National Institute for Health and Care Excellence (NICE) guidance on monitoring and management of Barrett’s oesophagus and stage I oesophageal adenocarcinoma
Authors: Massimiliano di Pietro, Nigel J Trudgill, Melina Vasileiou, Gaius Longcroft-Wheaton, Alexander W Phillips, James Gossage, Philip V Kaye, Kieran G Foley, Tom Crosby, Sophie Nelson, Helen Griffiths, Muksitur Rahman, Gill Ritchie, Amy Crisp, Stephen Deed, John N Primrose
Journal: Gut (2024)

Barrett’s oesophagus is the only known precursor to oesophageal adenocarcinoma, a cancer with very poor prognosis. The main risk factors for Barrett’s oesophagus are a history of gastro-oesophageal acid reflux symptoms and obesity. Men, smokers and those with a family history are also at increased risk. Progression from Barrett’s oesophagus to cancer occurs via an intermediate stage, known as dysplasia. However, dysplasia and early cancer usually develop without any clinical signs, often in individuals whose symptoms are well controlled by acid suppressant medications; therefore, endoscopic surveillance is recommended to allow for early diagnosis and timely clinical intervention. Individuals with Barrett’s oesophagus need to be fully informed about the implications of this diagnosis and the benefits and risks of monitoring strategies. Pharmacological treatments are recommended for control of symptoms, but not for chemoprevention. Dysplasia and stage 1 oesophageal adenocarcinoma have excellent prognoses, since they can be cured with endoscopic or surgical therapies. Endoscopic resection is the most accurate staging technique for early Barrett’s-related oesophageal adenocarcinoma. Endoscopic ablation is effective and indicated to eradicate Barrett’s oesophagus in patients with dysplasia. Future research should focus on improved accuracy for dysplasia detection via new technologies and providing more robust evidence to support pathways for follow-up and treatment.
Impact of maternal risk factors on ethnic disparities in maternal mortality: a national population-based cohort study
Authors: Nicola Vousden, Kathryn Bunch, Sara Kenyon, Jennifer J. Kurinczuk, Marian Knight
Journal: The Lancet Regional Health - Europe (2024)

BackgroundEthnic disparities in maternal mortality are consistently reported. This study aimed to investigate the contribution of known risk factors including age, socioeconomic status, and medical comorbidities to observed ethnic disparities in the United Kingdom (UK).MethodsA cohort of all women who died during or up to six weeks after pregnancy in the UK 2009–2019 were identified through national surveillance. No single denominator population included data on all risk factors, therefore we used logistic regression modelling to compare to 1) routine population birth and demographic data (2015–19) (routine data comparator) and 2) combined control groups of four UK Obstetric Surveillance System studies (UKOSS) control comparator)).FindingsThere were 801 maternal deaths in the UK between 2009 and 2019 (White: 70%, Asian: 13%, Black: 12%, Chinese/Other: 3%, Mixed: 2%). Using the routine data comparator (n = 3,519,931 maternities) to adjust for demographics, including social deprivation, women of Black ethnicity remained at significantly increased risk of maternal death compared with women of white ethnicity (adjusted OR 2.43 (95% Confidence Interval 1.92–3.08)). The risk was greatest in women of Caribbean ethnicity (aOR 3.55 (2.30–5.48)). Among women of White ethnicity, risk of mortality increased as deprivation increased, but women of Black ethnicity had greater risk irrespective of deprivation. Using the UKOSS control comparator (n = 2210), after multiple adjustments including smoking, body mass index, and comorbidities, women of Black and Asian ethnicity remained at increased risk (aOR 3.13 (2.21–4.43) and 1.57 (1.16–2.12) respectively).InterpretationKnown risk factors do not fully explain ethnic disparities in maternal mortality. The impact of socioeconomic deprivation appears to differ between ethnic groups.FundingThis research is funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme, conducted through the Policy Research Unit in Maternal and Neonatal Health and Care, PR-PRU-127-21202.
Expansion and transmission dynamics of high risk carbapenem-resistant Klebsiella pneumoniae subclones in China: An epidemiological, spatial, genomic analysis
Authors: Qi Wang, Ruobing Wang, Shuyi Wang, Anru Zhang, Qiaoyan Duan, Shijun Sun, Longyang Jin, Xiaojuan Wang, Yawei Zhang, Chunlei Wang, Haiquan Kang, Zhijie Zhang, Kang Liao, Yinghui Guo, Liang Jin, Zhiwu Liu, Chunxia Yang, Hui Wang
Journal: Drug Resistance Updates (2024)

Carbapenem-resistant Klebsiella pneumonia (CRKP) is a global threat that varies by region. The global distribution, evolution, and clinical implications of the ST11 CRKP clone remain obscure. We conducted a multicenter molecular epidemiological survey using isolates obtained from 28 provinces and municipalities across China between 2011 and 2021. We integrated sequences from public databases and performed genetic epidemiology analysis of ST11 CRKP. Among ST11 CRKP, KL64 serotypes exhibited considerable expansion, increasing from 1.54% to 46.08% between 2011 and 2021. Combining our data with public databases, the phylogenetic and phylogeography analyses indicated that ST11 CRKP appeared in the Americas in 1996 and spread worldwide, with key clones progressing from China's southeastern coast to the inland by 2010. Global phylogenetic analysis showed that ST11 KL64 CRKP has evolved to a virulent, resistant clade with notable regional spread. Single-nucleotide polymorphism (SNP) analysis identified BMPPS (bmr3, mltC, pyrB, ppsC, and sdaC) as a key marker for this clade. The BMPPS SNP clade is associated with high mortality and has strong anti-phagocytic and competitive traits in vitro. The high-risk ST11 KL64 CRKP subclone showed strong expansion potential and survival advantages, probably owing to genetic factors.
Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020)
Authors: Olivier Paccoud, Marie Desnos-Ollivier, Florence Persat, Magalie Demar, Karine Boukris-Sitbon, Anne-Pauline Bellanger, Julie Bonhomme, Christine Bonnal, Françoise Botterel, Marie-Elisabeth Bougnoux, Sophie Brun, Sophie Cassaing, Estelle Cateau, Taieb Chouaki, Muriel Cornet, Eric Dannaoui, Nicole Desbois-Nogard, Marie-Fleur Durieux, Loïc Favennec, Arnaud Fekkar, Frederic Gabriel, Jean-Pierre Gangneux, Juliette Guitard, Lilia Hasseine, Antoine Huguenin, Solène Le Gal, Valérie Letscher-Bru, Caroline Mahinc, Florent Morio, Muriel Nicolas, Philippe Poirier, Stéphane Ranque, Gabrielle Roosen, Célia Rouges, Anne-Laure Roux, Milène Sasso, Alexandre Alanio, Olivier Lortholary, Fanny Lanternier, N. Brieu, C. Durand, D. Bertei, J.P. Bouchara, M. Pihet, S. Bland, J.P. Bru, M. Pulik, F. Le Turdu, H. Lefrand C, M. Ferrand, M. Larrouy, L. Millon, L. Delhaes, S. Imbert, I. Accoceberry, M.N. Bachelier, G. Nevez, D. Quinio, A. Le Coustumier, F. Carmagnol, B. Rivière, P. Boex, B. Podac, M. Moniot, C. Nourrisson, O. Augereau, J.P. Emond, G. Belkacem-Belkaki, J.L. Bacri, G. Berthelot, F. Dalle, E. Vallee, J. Bizet, L. Noussair, J.L. Herrmann, D. Maubon, C. Brocard, P. Guiffault, A. Layet, A. Morel, A. Angoulvant, P. Penn, A. Gigandon, B. Sendid, M. Cornu, M.L. Darde, A. Jaccard, B. Bouteille, D. Azjenberg, N. Prades, A.L. Bienvenu, T. Benoit-Cattin, A. Fiacre, S. Levy, A. Pitsch, M.H. Kiefer, A. Debourgogne, O. Moquet, J. Colot, L. Courtellemont, D. Poisson, V. Laurens, C. Kauffmann-Lacroix, P. Martres, G. Gargala, N. Godineau, S. Picot, C. Chassagne, N. Djibo, R. Devallière, M. Sabou, A.M. Camin-Ravenne, F. Bissuel, F. Janvier, X. Aubert, S. Chadapaud, X. Delbeck, A. Lafeuillade, X. Raoult, V. Baclet, C. Coignard, Y. Mouton, I. Ravaux, C. Eloy, A. Fur, L. Rezzouk, E. Mazards, O. Eloy, E. Chachaty, L. Mihaila, S. Dellion, O. Patey, A. Thouvenot, L. Limousin, A. Paugam, N. Desplaces, G. Raguin, E. Sitterlé, M. Blaize, M. Gits-Muselli, C. Hennequin, J.L. Poirot, S. Bretagne, Claire Lacroix, Samia Hamane
Journal: Clinical Microbiology and Infection (2024)
Renal complications in patients with predominantly antibody deficiency in the United States Immune Deficiency Network (USIDNET)
Authors: Emma Materne, Baijun Zhou, Daniel DiGiacomo, Jocelyn R. Farmer, Ramsay Fuleihan, Kathleen E. Sullivan, Charlotte Cunningham-Rundles, Zuhair K. Ballas, Daniel Suez, Sara Barmettler
Journal: Journal of Allergy and Clinical Immunology (2024)