tbuckley/cabot-search huggingface dataset:
proANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action
Authors: Thibault Michel, Hélène Nougué, Jérôme Cartailler, Guillaume Lefèvre, Malha Sadoune, François Picard, Alain Cohen-Solal, Damien Logeart, Jean-Marie Launay, Nicolas Vodovar
Journal: Circulation Research (2022)

Background: Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). Methods: Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. Results: We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay –a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. Conclusions: These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.
Part II: Cutaneous manifestations of peripheral vascular disease
Authors: Aishwarya Raja, Jamie Karch, Allen F. Shih, Henriette De La Garza, Antonio Jesus De Zepeda Diaz, Mayra B.C. Maymone, Tania J. Phillips, Eric Secemsky, Neelam Vashi
Journal: Journal of the American Academy of Dermatology (2022)
Caspase-11 interaction with NLRP3 potentiates the noncanonical activation of the NLRP3 inflammasome
Authors: Julien Moretti, Baosen Jia, Zachary Hutchins, Soumit Roy, Hilary Yip, Jiahui Wu, Meimei Shan, Samie R. Jaffrey, Jörn Coers, J. Magarian Blander
Journal: Nature Immunology (2022)
Association of 30-ft US-Mexico Border Wall in San Diego With Increased Migrant Deaths, Trauma Center Admissions, and Injury Severity
Authors: Amy E. Liepert, Allison E. Berndtson, Linda L. Hill, Jessica L. Weaver, Laura N. Godat, Todd W. Costantini, Jay J. Doucet
Journal: JAMA Surgery (2022)

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Immune cell infiltration pattern in non-small cell lung cancer PDX models is a model immanent feature and correlates with a distinct molecular and phenotypic make-up
Authors: Eva Oswald, Daniel Bug, Anne Grote, Kanstantsin Lashuk, Nassim Bouteldja, Dorothee Lenhard, Anne Löhr, Anke Behnke, Volker Knauff, Anna Edinger, Kerstin Klingner, Simone Gaedicke, Gabriele Niedermann, Dorit Merhof, Friedrich Feuerhake, Julia Schueler
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The field of cancer immunology is rapidly moving towards innovative therapeutic strategies, resulting in the need for robust and predictive preclinical platforms reflecting the immunological response to cancer. Well characterized preclinical models are essential for the development of predictive biomarkers in the oncology as well as the immune-oncology space. In the current study, gold standard preclinical models are being refined and combined with novel image analysis tools to meet those requirements. Methods A panel of 14 non-small cell lung cancer patient-derived xenograft models (NSCLC PDX) was propagated in humanized NOD/Shi-scid/IL-2Rnull mice. The models were comprehensively characterized for relevant phenotypic and molecular features, including flow cytometry, immunohistochemistry, histology, whole exome sequencing and cytokine secretion. Results Models reflecting hot (&gt;5% tumor-infiltrating lymphocytes/TILs) as opposed to cold tumors (&lt;5% TILs) significantly differed regarding their cytokine profiles, molecular genetic aberrations, stroma content, and programmed cell death ligand-1 status. Treatment experiments including anti cytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death 1 or the combination thereof across all 14 models in the single mouse trial format showed distinctive tumor growth response and spatial immune cell patterns as monitored by computerized analysis of digitized whole-slide images. Image analysis provided for the first time qualitative evaluation of the extent to which PDX models retain the histological features from their original human donors. Conclusions Deep phenotyping of PDX models in a humanized setting by combinations of computational pathology, immunohistochemistry, flow cytometry and proteomics enables the exhaustive analysis of innovative preclinical models and paves the way towards the development of translational biomarkers for immuno-oncology drugs.
COVID-19 Vaccine–Induced Multisystem Inflammatory Syndrome With Polyserositis Detected by FDG PET/CT: Reply
Authors: Soo Jin Lee, Sang-Heon Kim
Journal: Clinical Nuclear Medicine (2022)

Department of Nuclear Medicine, Hanyang University College of Medicine, Seoul, Korea. Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea [email protected] Conflicts of interest and sources of funding: None declared.
<scp>CAR‐T</scp> cell therapy targeting B cell maturation antigen is effective for relapsed/refractory multiple myeloma, including cases with poor performance status
Authors: Juan Du, Runhong Wei, Songfu Jiang, Hua Jiang, Lu Li, Wanting Qiang, Haiyan He, Lin Shi, Qiuling Ma, Kang Yu, Xiaoyuan Zhang, Hanyi Ding, Xuedong Sun, Fang Xiang, Lin Zhu, Zhi Cheng, Weijun Fu
Journal: American Journal of Hematology (2022)

In this open-label, single-arm, phase I/II clinical trial, we evaluated the efficacy of anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in 49 relapsed/refractory multiple myeloma (RRMM) patients, including 20 with Eastern Cooperative Oncology Group (ECOG) grade 3-4. After HDS269B infusion (9 × 106 CAR+ cells/kg), 17 patients (34.69%, 11 ECOG 0-2, 6 ECOG 3-4) developed cytokine release syndrome [grade 1-2: 14 patients (28.57%); grade 3: 3 patients (6.12%)]. The objective response rate (ORR) was 77%, with a complete response (CR) achieved in 47%. Ongoing response >12 months occurred in 15 patients, and was extended beyond 38 months in one patient. The median progression-free survival (PFS) and overall survival (OS) were 10 months (95% CI 5.3-14.7) and 29 months (95% CI 10.0-48.0), respectively. The PFS (12 months) and OS (18 months) rates were 41.64% and 62.76%, respectively. In patients with ECOG 0-2 and 3-4, ORR was 79.31% (23/29) and 75.0% (15/20) and PFS were 15 months (95% CI 5.4-24.6) and 4 months (95% CI 0-11.7), respectively. OS was not reached in ECOG 0-2 patients, but was 10.5 months (95% CI 0-22) in ECOG 3-4 patients. Single-cell sequencing indicated that treatment efficacy might be related to mTORC1 signaling. Thus, HDS269B therapy is safe and effective for RRMM patients, even those with ECOG 3-4.
Molecular Pathways and Mechanisms of BRAF in Cancer Therapy
Authors: Poulikos I. Poulikakos, Ryan J. Sullivan, Rona Yaeger
Journal: Clinical Cancer Research (2022)

With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF-mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/MAPK pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.
A novel in vitro model to study the metabolic differences between stem cell-derived human hepatocyte-like cells and primary human hepatocytes eliminating genetic interdonor variability
Authors: Varvara Kirchner, Eunyoung Tak, Gi-Won Song, Edward LeCluyse, Valerie Soldatow, Sung-Gyu Lee, Laura Niedernhofer, Jakub Tolar, Timothy Pruett
Journal: International Journal of Surgery (2022)
Author Correction: Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
Authors: Panagiotis Galanos, George Pappas, Alexander Polyzos, Athanassios Kotsinas, Ioanna Svolaki, Nickolaos N. Giakoumakis, Christina Glytsou, Ioannis S. Pateras, Umakanta Swain, Vassilis L. Souliotis, Alexandros G. Georgakilas, Nicholas Geacintov, Luca Scorrano, Claudia Lukas, Jiri Lukas, Zvi Livneh, Zoi Lygerou, Dipanjan Chowdhury, Claus Storgaard Sørensen, Jiri Bartek, Vassilis G. Gorgoulis
Journal: Genome biology (2022)
Actively separated microneedle patch for sustained-release of growth hormone to treat growth hormone deficiency
Authors: Li Yang, Qingyun Liu, Xinhui Wang, Nansha Gao, Xiuzhen Li, Hongzhong Chen, Lin Mei, Xiaowei Zeng
Journal: Acta Pharmaceutica Sinica B (2022)

Growth hormone deficiency (GHD) has become a serious healthcare burden, and presents a huge impact on the physical and mental health of patients. Here, we developed an actively separated microneedle patch (PAA/NaHCO3-Silk MN) based on silk protein for sustained release of recombinant human growth hormone (rhGH). Silk protein, as a friendly carrier material for proteins, could be constructed in mild full-water conditions and ensure the activity of rhGH. After manually pressing PAA/NaHCO3-Silk MN patch to skin for 1 min, active separation is achieved by absorbing the interstitial fluid (ISF) to trigger HCO3‒ in the active backing layer to produce carbon dioxide gas (CO2). In rats, the MN patch could maintain the sustained release of rhGH for more than 7 days, and produce similar effects as daily subcutaneous (S.C.) injections of rhGH in promoting height and weight with well tolerated. Moreover, the PAA/NaHCO3-Silk MN patch with the potential of painless self-administration, does not require cold chain transportation and storage possess great economic benefits. Overall, the PAA/NaHCO3-Silk MN patch can significantly improve patient compliance and increase the availability of drugs, meet current unmet clinical needs, improve clinical treatment effects of GHD patients.
Foreign-Body Aspiration in a Child
Authors: Katarzyna M. Saar, Christopher R. Grindle
Journal: New England Journal of Medicine (2022)

A 12-month-old girl presented to the emergency department with a history of coughing and stridor after a choking episode. A chest radiograph showed right-lung opacification and volume loss, rightward shift of the mediastinum, and left-lung hyperinflation.
Association of Prenatal Care Expansion With Use of Antidiabetic Agents During Pregnancies Among Latina Emergency Medicaid Recipients With Gestational Diabetes
Authors: Maria I. Rodriguez, Ann Martinez Acevedo, Jonas J. Swartz, Aaron B. Caughey, Amy Valent, K. John McConnell
Journal: JAMA Network Open (2022)

Access to necessary prenatal care is not guaranteed through Medicaid for some people with low income based on their immigration status. Although states have the option to extend emergency Medicaid coverage for prenatal care, many states have not expanded coverage.
Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy
Authors: Julio Garcia-Aguilar, Sujata Patil, Marc J. Gollub, Jin K. Kim, Jonathan B. Yuval, Hannah M. Thompson, Floris S. Verheij, Dana M. Omer, Meghan Lee, Richard F. Dunne, Jorge Marcet, Peter Cataldo, Blase Polite, Daniel O. Herzig, David Liska, Samuel Oommen, Charles M. Friel, Charles Ternent, Andrew L. Coveler, Steven Hunt, Anita Gregory, Madhulika G. Varma, Brian L. Bello, Joseph C. Carmichael, John Krauss, Ana Gleisner, Philip B. Paty, Martin R. Weiser, Garrett M. Nash, Emmanouil Pappou, José G. Guillem, Larissa Temple, Iris H. Wei, Maria Widmar, Sabrina Lin, Neil H. Segal, Andrea Cercek, Rona Yaeger, J. Joshua Smith, Karyn A. Goodman, Abraham J. Wu, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2022)

PURPOSE Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.
Inaccuracy of pulse oximetry in darker-skinned patients is unchanged across 32 years
Authors: Martin J. Tobin, Amal Jubran
Journal: European Respiratory Journal (2022)

<b>The structure of pulse oximeters has changed tremendously over time, but inaccurate readings of oxygen saturation in black patients have not improved across 32 years and manufacturers do not report efforts to resolve the problem</b>https://bit.ly/3KYc7Zo
Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection
Authors: David Wasilewski, Josefine Radke, Ran Xu, Matthias Raspe, Anna Trelinska-Finger, Tizian Rosenstock, Paul Poeser, Elisa Schumann, Judith Lindner, Frank Heppner, David Kaul, Norbert Suttorp, Peter Vajkoczy, Nikolaj Frost, Julia Onken
Journal: JAMA Network Open (2022)

Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce.To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection.This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated.Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection.Median overall survival.From the whole cohort of patients with NSCLC (N = 384), 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001).Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients.
Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control
Authors: Hannah P. Gideon, Travis K. Hughes, Constantine N. Tzouanas, Marc H. Wadsworth, Ang Andy Tu, Todd M. Gierahn, Joshua M. Peters, Forrest F. Hopkins, Jun-Rong Wei, Conner Kummerlowe, Nicole L. Grant, Kievershen Nargan, Jia Yao Phuah, H. Jacob Borish, Pauline Maiello, Alexander G. White, Caylin G. Winchell, Sarah K. Nyquist, Sharie Keanne C. Ganchua, Amy Myers, Kush V. Patel, Cassaundra L. Ameel, Catherine T. Cochran, Samira Ibrahim, Jaime A. Tomko, Lonnie James Frye, Jacob M. Rosenberg, Angela Shih, Michael Chao, Edwin Klein, Charles A. Scanga, Jose Ordovas-Montanes, Bonnie Berger, Joshua T. Mattila, Rajhmun Madansein, J. Christopher Love, Philana Ling Lin, Alasdair Leslie, Samuel M. Behar, Bryan Bryson, JoAnne L. Flynn, Sarah M. Fortune, Alex K. Shalek
Journal: Immunity (2022)

Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.
Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation
Authors: Leah K. Billingham, Joshua S. Stoolman, Karthik Vasan, Arianne E. Rodriguez, Taylor A. Poor, Marten Szibor, Howard T. Jacobs, Colleen R. Reczek, Aida Rashidi, Peng Zhang, Jason Miska, Navdeep S. Chandel
Journal: Nature Immunology (2022)

Abstract The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
Robotic and open resection of the liver and bile ducts for perihilar cholangiocarcinoma. Comparative analysis of the short-term outcomes
Authors: Natalia Elizarova, Mikhail Efanov, Ruslan Alikhanov, Ivan Kazakov, Olga Melekhina, Yuliya Kulezneva, Anna Koroleva, Andrey Vankovich, Igor Khatkov
Journal: International Journal of Surgery (2022)