tbuckley/cabot-search huggingface dataset:
Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery: A preclinical and clinical study
Authors: Zhigao Niu, Damiano La Zara, Lasse Blaabjerg, Jenni Pessi, Konstantinos Raptis, Anders Toftlev, Max Sauter, Philip Christophersen, Pierre-Louis Bardonnet, Vincent Andersson, Jian Xiong Wu, Matthäus Brandt, Li Fan, Zhuoran Wang, Franta Hubálek, Per-Olof Wahlund, Mathias Norrman, Kateryna Breusova, Marie Stine Hjaltason, Nicolai Rytter Mortensen, Lars Bardtrum, Birgitte Nissen, Kaisa Naelapää, Philip Jonas Sassene
Journal: Journal of Controlled Release (2024)

Current oral formulations of macromolecules including peptides typically rely on single permeation enhancer (PE) to promote absorption and thus bioavailability. In this work, we combined two PEs, namely sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and sodium caprate (C10), in one tablet formulation to potentially gain a synergistic effect for enhanced gastric absorption of a GLP-1 analogue and a PCSK9 inhibitor. Permeability tests on a gastric organoids-based cell model showed that the combination of SNAC and C10 can significantly improve peptide permeability compared to either SNAC or C10 alone. Tablet formulations were then designed, adjusting the total PE amount, relative ratio between SNAC and C10, and the peptide dose. To facilitate drug and PE release, a diluent was added. Upon oral administration in beagle dogs, the lead formulations made of SNAC/C10/diluent demonstrated higher bioavailability than either SNAC, SNAC/diluent and C10/diluent formulations for both peptides. Finally, the SNAC/C10/diluent formulation with PCSK9 inhibitor was tested in human, where it displayed similar bioavailability to the SNAC/diluent reference, thereby suggesting a low translatability between pre-clinical and clinical data when C10 was involved. This may be attributed to the difference in physiology, gastric pH environment as well as C10 concentration and colloidal form in the gastric lumen between dogs and humans. Hence, additional studies are needed for a better understanding of the clinical translation of C10-based peptide formulations.
Enhancing protective immunity against SARS-CoV-2 with a self-amplifying RNA lipid nanoparticle vaccine
Authors: Guibin Lin, Yan-Lai Tang, Zhengqiang Fu, Runjun Chen, Yan Liu, Zhanyan Liu, Xueli Kuang, Jing Sun, Jincun Zhao, Yuan Zhang
Journal: Journal of Controlled Release (2024)
Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer
Authors: Lisa N. Chesner, Fanny Polesso, Julie N. Graff, Jessica E. Hawley, Alexis K. Smith, Arian Lundberg, Rajdeep Das, Tanushree Shenoy, Martin Sjöström, Faming Zhao, Ya-Mei Hu, Simon Linder, William S. Chen, Reed M. Hawkins, Raunak Shrestha, Xiaolin Zhu, Adam Foye, Haolong Li, Lisa M. Kim, Megha Bhalla, Thomas O’loughlin, Duygu Kuzuoglu-Ozturk, Junjie T. Hua, Michelle L. Badura, Scott Wilkinson, Shana Y. Trostel, Andries M. Bergman, Davide Ruggero, Charles G. Drake, Adam G. Sowalsky, Lawrence Fong, Matthew R. Cooperberg, Wilbert Zwart, Xiangnan Guan, Alan Ashworth, Zheng Xia, David A. Quigley, Luke A. Gilbert, Felix Y. Feng, Amy E. Moran
Journal: Cancer Discovery (2024)

Immunotherapy options for immune cold tumors, like prostate cancer, are limited. We show that AR downregulates MHCI expression/antigen presentation and that AR inhibition improves T-cell responses and tumor control. This suggests that treatments combining AR inhibitors and checkpoint blockade may improve tumor immune surveillance and antitumor immunity in patients.
The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling
Authors: Maria Perez-Penco, Mikkel Byrdal, Lucia Lara de la Torre, Marta Ballester, Shawez Khan, Majken Siersbæk, Inés Lecoq, Cecilie Oelvang Madsen, Julie Westerlin Kjeldsen, Inge Marie Svane, Morten Hansen, Marco Donia, Julia Sidenius Johansen, Lars Rønn Olsen, Lars Grøntved, Inna Markovna Chen, Luis Arnes, Morten Orebo Holmström, Mads Hald Andersen
Journal: Cellular and Molecular Immunology (2024)

Abstract Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGFβ-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGFβ-specific immunity in PC. Here, we explored the importance of IL-6 for TGFβ-specific immunity in PC. In a murine model of PC, coadministration of the TGFβ-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGFβ-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGFβ-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.
Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric <i>NTRK</i> Fusion–Positive Solid Tumors (Children's Oncology Group ADVL1823)
Authors: Theodore W. Laetsch, Stephan Voss, Kathleen Ludwig, David Hall, Donald A. Barkauskas, Steven G. DuBois, Joan Ronan, Erin R. Rudzinski, Amanda Memken, Krystal Robinson, Joel Sorger, Joel M. Reid, Teena Bhatla, Brian D. Crompton, Alanna J. Church, Elizabeth Fox, Brenda J. Weigel
Journal: Journal of Clinical Oncology (2024)

PURPOSE The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion–positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion–positive solid tumors with response-adapted duration of therapy and local control. METHODS Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS). RESULTS Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities. CONCLUSION Larotrectinib is highly active in patients with newly diagnosed NTRK fusion–positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion–positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.
Molecular features of the serological IgG repertoire elicited by egg-based, cell-based, or recombinant haemagglutinin-based seasonal influenza vaccines: a comparative, prospective, observational cohort study
Authors: Juyeon Park, Foteini Bartzoka, Troy von Beck, Zhu-Nan Li, Margarita Mishina, Luke S Hebert, Jessica Kain, Feng Liu, Suresh Sharma, Weiping Cao, Devon J Eddins, Amrita Kumar, Jin Eyun Kim, Justin S Lee, Yuanyuan Wang, Evan A Schwartz, Axel F Brilot, Ed Satterwhite, Dalton M Towers, Eric McKnight, Jan Pohl, Mark G Thompson, Manjusha Gaglani, Fatimah S Dawood, Allison L Naleway, James Stevens, Richard B Kennedy, Joshy Jacob, Jason J Lavinder, Min Z Levine, Shivaprakash Gangappa, Gregory C Ippolito, Suryaprakash Sambhara, George Georgiou
Journal: The Lancet Microbe (2024)
Enhanced hepatitis B virus-specific immunity by combined neutralizing antibody therapy and DNA vaccination in a murine model of chronic hepatitis B infection
Authors: Maxime Beretta, Benjamin Vesin, Yu Wei, Cyril Planchais, Pierre Rosenbaum, Malika Ait-Goughoulte, Nadège Pelletier, David Hardy, Hugo Mouquet, Maryline Bourgine
Journal: Hepatology (2024)

Background and Aims: Successful treatment of chronic HBV infection remains a great challenge due to the difficulty in inducing efficient immune responses. Here, we investigated the therapeutic potential of DNA vaccination combined with a potent HBV broadly neutralizing antibody targeting the small surface viral antigen. Approach and Results: C57BL/6 mice were transduced with adeno-associated virus-HBV and were treated twice a week with HBV broadly neutralizing antibodies for 5 weeks. A DNA-based vaccine encoding the HBV core, envelope, and polymerase proteins was administered once to mice 3 weeks after initiating antibody therapy. The antiviral effects and antigen-specific immune responses were evaluated before and for 8 weeks after therapeutic vaccination. Vaccine administration with or without antibody treatment induced the development of functional HBV-specific CD8+ T cells and envelope-specific resident memory T cells in the liver. The combination of antibody treatment and DNA vaccination enhanced the recruitment of B and CD8+ T lymphocytes into the liver of HBV-carrier mice 2 weeks after vaccination. However, although still detectable 2 months after vaccination, HBV-specific CD8+ T cells showed an exhausted phenotype, suggesting that they are dysfunctional. In contrast, more effective control of antigenemia was observed following combination therapy, which was associated with the presence of HBs-specific memory B cells. Conclusions: Although the combination therapy did not result in a functional cure, our findings indicate it produced additive effects on the development of HBV-specific T cells in the liver immediately following treatment, offering a better insight into the mechanisms underlying hepatic tolerance.
Causes, patterns, and epidemiology of tattoo-associated infections since 1820
Authors: Sunghyun Yoon, Sandeep Kondakala, Soumana Daddy-Gaoh, Steven Foley, Ohgew Kweon, Seong-Jae Kim
Journal: The Lancet Microbe (2024)

Despite increased awareness and public health initiatives, the incidence of microbial infections related to tattoos has increased since 2000. Building on the first paper in this two-part Series, which detailed the microbiological aspects of tattoo-related infections over the past two centuries from 1820 to 2023, this second paper describes the patterns, causes, and other related epidemiological factors of these infections. Since 2000, bacterial outbreaks, particularly those caused by non-tuberculous mycobacteria, have increased, prompting a re-evaluation of tattoos as a serious public health risk. Insufficient hygiene practices have been the primary cause of microbial infections, with contaminated tattoo inks also contributing substantially, leading to 11 outbreaks and subsequent ink recalls. Although rare, the tattooing process can occasionally lead to life-threatening infections and fatalities. Tattoos by both professional and non-professional artists were associated with infections, suggesting that regulated environments do not necessarily eliminate risk. Additionally, individuals with compromised immune systems, especially those with HIV, were particularly vulnerable to infections such as Leishmania. Although permanent make-up is often perceived as safer than conventional tattoos, infections still occur, with 11 cases reported since 2010. Furthermore, polymicrobial infections involving multiple pathogens have posed challenges for diagnosis and treatment. Overall, these insights highlight the historical and emerging patterns of tattoo-related infections and can inform the development of more effective public health guidelines, enhance preventive measures, and guide future research on reducing the risks associated with tattoos.
Stard1 promotes cholestatic liver injury and disease progression by sensitizing to bile acid hepatotoxicity
Authors: Laura Conde de la Rosa, Laura Fábrega, Sandra Torres, Susana Nuñez, Vicent Ribas, Paula Segalés, Ricardo Espinosa-Escudero, Estel Solsona, María Jesús Monte, Alvaro Diaz-Gonzalez, José J. G. Marin, Carmen García-Ruiz, Jose C. Fernandez-Checa
Journal: Hepatology (2024)

Background and Aims: Cholestatic liver diseases (CLD) are often accompanied by hepatocellular injury, fibrosis, and cirrhosis due to the intracellular accumulation of solutes that cannot be excreted into bile, including bile acids (BAs). These are synthesized in hepatocytes from cholesterol mainly via the classic pathway and in a lower proportion through the mitochondrial acidic pathway. The latter requires STARD1-dependent cholesterol transport to the mitochondrial inner membrane for metabolism, whose contribution to BA-induced hepatotoxicity and CLD is unknown. Approach and Results: Here we show that patients with primary biliary cholangitis exhibit increased expression of STARD1 compared to control subjects. Mice with hepatocyte-specific Stard1 deletion ( Stard1 Δhep ) were more resistant to experimental models of complete (bile duct ligation, BDL) and chemical obstructive cholestasis-induced liver injury, inflammation and fibrosis than Stard1 f/f mice. Stard1 Δhep mice exhibited reduced hepatic BAs and mitochondrial cholesterol accumulation but increased mitochondrial GSH (mGSH) levels following BDL compared to Stard1 f/f mice. Pharmacological mGSH depletion sensitized primary mouse hepatocytes to a mix of BAs mimicking the profile seen in Stard1 f/f mice after BDL leading to increased inflammatory response and cytotoxicity. Conclusions: These findings highlight a role for STARD1 in cholestatic liver injury and suggest that its targeting may be of relevance for CLD.
Use of SGLT2i Versus DPP-4i as an Add-On Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery): A Cohort Study in Veterans With Diabetes
Authors: Katherine E. Griffin, Kathryn Snyder, Amir H. Javid, Amber Hackstadt, Robert Greevy, Carlos G. Grijalva, Christianne L. Roumie
Journal: Diabetes Care (2024)

To compare the risk of composite peripheral artery disease (PAD) surgical outcome, including peripheral revascularization and amputation procedures, between new users of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP-4is). This retrospective cohort study of U.S. veterans age ≥18 years with diabetes who received care from the Veterans Health Administration was performed from 1 October 2000 to 31 December 2021. Data were linked to Medicare, Medicaid, and the National Death Index. New use of SGLT2i or DPP-4i medications as an add-on to metformin, sulfonylurea, or insulin treatment alone or in combination was evaluated for an association with PAD surgical procedure for peripheral revascularization and amputation. A Cox proportional hazards model for time-to-PAD event analysis compared the risk of a PAD event between SGLT2is and DPP-4is in a propensity score-weighted cohort with a competing risk of death and allowance for events to occur up to 90 days or 360 days after stopping SGLT2is. The weighted cohort included 76,072 SGLT2i vs. 75,833 DPP-4i use episodes. The median age was 69 years, HbA1c was 8.4% (interquartile range [IQR] 7.5-9.4%), and the median diabetes duration was 10.1 (IQR 6.6-14.6) years. There were 874 and 780 PAD events among SGLT2i and DPP-4i users, respectively, for an event rate of 11.2 (95% CI 10.5-11.9) and 10.0 (9.4-10.6) per 1,000 person-years (adjusted hazard ratio [aHR] 1.18 [95% CI 1.08-1.29]). When PAD events were allowed for 360 days after SGLT2i use ended, the aHR was 1.16 (95% CI 1.06-1.26). SGLT2i as an add-on diabetes therapy was associated with an increased cause-specific hazard of PAD surgeries compared with DPP-4i.
The Complex Relationship Between Gut Microbiota and Alzheimer’s Disease: A Systematic Review
Authors: Xuan-Peng Zhou, Luan-Biao Sun, Wen-Hao Liu, Wu-Ming Zhu, Lin-Chun Li, Xin-Yuan Song, Jian-Peng Xing, Shuo-Hui Gao
Journal: Ageing Research Reviews (2024)

Alzheimer's disease (AD) is a progressive, degenerative disorder of the central nervous system. Despite extensive research conducted on this disorder, its precise pathogenesis remains unclear. In recent years, the microbiota-gut-brain axis has attracted considerable attention within the field of AD. The gut microbiota communicates bidirectionally with the central nervous system through the gut-brain axis, and alterations in its structure and function can influence the progression of AD. Consequently, regulating the gut microbiota to mitigate the progression of AD has emerged as a novel therapeutic approach. Currently, numerous studies concentrate on the intrinsic relationship between the microbiota-gut-brain axis and AD. In this paper, we summarize the multifaceted role of the gut microbiota in AD and present detailed therapeutic strategies targeting the gut microbiota, including the treatment of AD with Traditional Chinese Medicine (TCM), which has garnered increasing attention in recent years. Finally, we discuss potential therapeutic strategies for modulating the gut microbiota to alleviate the progression of AD, the current challenges in this area of research, and provide an outlook on future research directions in this field.
Safety, tolerability, pharmacokinetics, and neutralisation activities of the anti-HIV-1 monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS in adults without HIV in the USA (HVTN 136/HPTN 092): a first-in-human, open-label, randomised controlled phase 1 trial
Authors: Srilatha Edupuganti, Christopher B Hurt, Kathryn E Stephenson, Yunda Huang, Carmen A Paez, Chenchen Yu, Catherine Yen, Brett Hanscom, Zonglin He, Maurine D Miner, Theresa Gamble, Jack Heptinstall, Kelly E Seaton, Elizabeth Domin, Bob C Lin, Krisha McKee, Nicole Doria-Rose, Stephanie Regenold, Hans Spiegel, Maija Anderson, Nadia McClosky, Lily Zhang, Estelle Piwowar-Manning, Margaret E Ackerman, Michael Pensiero, Bonnie J Dye, Raphael J Landovitz, Kenneth Mayer, Marc Siegel, Magdalena Sobieszczyk, Stephen R Walsh, Lucio Gama, Dan H Barouch, David C Montefiori, Georgia D Tomaras, Cassie Grimsley Ackerley, Daniel Graciaa, Colleen Kelley, Nadine Rouphael, Sharon Curate-Ingram, Bette Korber, Kshitij Wagh, Nandini Sane, Jennifer Grossman, Sophie Hasan, Michelle Robinson, Jonathan Lucas, Marianne Gildea, Amber Babinec, Bethany Coomes, Julie Dumond, Justine Beck, Wairimu Chege, Xue Han, Jen Hanke, Carissa Karg, Laurie Rinn, Miriam Chicurel-Bayard, Shashikala Nagar, Hakeem White, W Scott Cooley, Gail Broder, Machel Hunt, Vanessa Cummings, Kristine Donaty, April Randhawa, Ramey Fair, Noshima Darden-Tabb, Richa Chaturvedi, Lindsey Baden, Amy Sherman, Jon Gothing, Andres Avila Paz, Julia Klopfer, Megan Powell, Anna Piermattei, August Heithoff, Joshua A. Weiner, Gabriela Kovacikova, Katherine S. Axelrod, Lu Zhang, Saman Baral, Nicole Yates, Kelvin Chiong, Irene Kuo, Jeanne Jordan, Madison Lintner, Kayley Langlands, Bitana Saintilma, Hannah Yellin, Madhu Balachandran, Manya Magnus, Jane Baumblatt, India Tindale, Samantha Fortier, Aleen Khodabakhshian, Nick Pierce, Maricela Gonzalez, Lisa Mark, Melinda Kuo, Ste'von Afemata
Journal: The Lancet HIV (2024)
Multiomics reveals tumor microenvironment remodeling in locally advanced gastric and gastroesophageal junction cancer following neoadjuvant immunotherapy and chemotherapy
Authors: Zhi Ji, Xia Wang, Jiaqi Xin, Lijun Ma, Duo Zuo, Hongli Li, Lan Su, Xinze Lv, Shaohua Ge, Le Zhang, Yong Liu, Yanhui Zhang, Tingting Ding, Ting Deng, Yi Ba, Rui Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Perioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors enhanced therapeutic efficacy. However, the mechanisms of response and resistance remain largely undefined. A detailed multiomic investigation is essential to elucidate these mechanisms. Methods We performed whole-exome sequencing, whole-transcriptome sequencing, multiplex immunofluorescence and single-cell RNA sequencing on matched pretreatment and post-treatment samples from 30 patients enrolled in an investigator-initiated Phase 2 clinical trial ( NCT04908566 ). All patients received neoadjuvant PD-1 inhibitors in combination with chemotherapy. A major pathologic response (MPR) was defined as the presence of no more than 10% residual viable tumor cells following treatment. Results Before treatment, the positive ratio of CD3+T cells in both the tumor parenchyma and stroma was significantly higher in the non-MPR group compared with the MPR group (p=0.042 and p=0.013, respectively). Least absolute shrinkage and selection operator regression was employed for feature gene selection and 13 genes were ultimately used to construct a predictive model for identifying MPR after surgery. The model exhibited a perfect area under curve (AUC) of 1.000 (95% CI: 1.000 to 1.000, p&lt;0.001). Post-treatment analysis revealed a significant increase in CD3+T cells, CD8+T cells and NK cells in the tumor stroma of MPR patients. In the tumor parenchyma, aside from a marked increase in CD8+T cells and NK cells, a notable reduction in macrophage was also observed (all p&lt;0.05). Importantly, forkheadbox protein 3 (FOXP3), the principal marker for regulatory T cells (Treg) cells, showed a significant decrease during treatment in MPR patients. FOXP3 expression in the non-MPR group was significantly higher than in the MPR group (p=0.0056) after treatment. Furthermore, single-cell RNA sequencing analysis confirmed that nearly all Treg cells were derived from the non-MPR group. Conclusions Our study highlights the critical role of dynamic changes within the tumor immune microenvironment in predicting the efficacy of neoadjuvant combined immunochemotherapy. We examined the disparities between MPR/non-MPR groups, shedding light on potential mechanisms of immune response and suppression. In addition to bolstering cytotoxic immune responses, specifically targeting Treg cells may be crucial for enhancing treatment outcomes.