tbuckley/cabot-search huggingface dataset:
Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: An open-label randomized controlled trial in Lesotho
Authors: Alain Amstutz, Bienvenu Lengo Nsakala, Fiona Vanobberghen, Josephine Muhairwe, Tracy Renée Glass, Tilo Namane, Tlali Mpholo, Manuel Battegay, Thomas Klimkait, Niklaus Daniel Labhardt
Journal: PLoS Medicine (2020)

Background Current World Health Organization (WHO) antiretroviral therapy (ART) guidelines define virologic failure as two consecutive viral load (VL) measurements ≥1,000 copies/mL, triggering empiric switch to next-line ART. This trial assessed if patients with sustained low-level HIV-1 viremia on first-line ART benefit from a switch to second-line treatment. Methods and findings This multicenter, parallel-group, open-label, superiority, randomized controlled trial enrolled patients on first-line ART containing non-nucleoside reverse transcriptase inhibitors (NNRTI) with two consecutive VLs ≥100 copies/mL, with the second VL between 100–999 copies/mL, from eight clinics in Lesotho. Consenting participants were randomly assigned (1:1), stratified by facility, demographic group, and baseline VL, to either switch to second-line ART (switch group) or continued first-line ART (control group; WHO guidelines). The primary endpoint was viral suppression (<50 copies/mL) at 36 weeks. Analyses were by intention to treat, using logistic regression models, adjusted for demographic group and baseline VL. Between August 1, 2017, and August 7, 2019, 137 individuals were screened, of whom 80 were eligible and randomly assigned to switch (n = 40) or control group (n = 40). The majority of participants were female (54 [68%]) with a median age of 42 y (interquartile range [IQR] 35–51), taking tenofovir disoproxil fumarate/lamivudine/efavirenz (49 [61%]) and on ART for a median of 5.9 y (IQR 3.3–8.6). At 36 weeks, 22/40 (55%) participants in the switch versus 10/40 (25%) in the control group achieved viral suppression (adjusted difference 29%, 95% CI 8%–50%, p = 0.009). The switch group had significantly higher probability of viral suppression across different VL thresholds (<20, <100, <200, <400, and <600 copies/mL) but not for <1,000 copies/mL. Thirty-four (85%) participants in switch group and 21 (53%) in control group experienced at least one adverse event (AE) (p = 0.002). No hospitalization or death or other serious adverse events were observed. Study limitations include a follow-up period too short to observe differences in clinical outcomes, missing values in CD4 cell counts due to national stockout of reagents during the study, and limited generalizability of findings to other than NNRTI-based first-line ART regimens. Conclusions In this study, switching to second-line ART among patients with sustained low-level HIV-1 viremia resulted in a higher proportion of participants with viral suppression. These results endorse lowering the threshold for virologic failure in future WHO guidelines. Trial registration The trial is registered at ClinicalTrials.gov, NCT03088241.
A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy
Authors: Brian H. Santich, Sarah M. Cheal, Mahiuddin Ahmed, Michael R. McDevitt, Ouathek Ouerfelli, Guangbin Yang, Darren R. Veach, Edward K. Fung, Mitesh Patel, Daniela Burnes Vargas, Aiza A. Malik, Hong-Fen Guo, Pat B. Zanzonico, Sebastien Monette, Adam O. Michel, Charles M. Rudin, Steven M. Larson, Nai K. Cheung
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index. Experimental Design: The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA–BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses. Results: SADA–BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA–BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver. Conclusions: The SADA–BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA–BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose. See related commentary by Capala and Kunos, p. 377
Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques and dampens atherosclerosis progression
Authors: Fabrizia Bonacina, Elisa Martini, Monika Svecla, Jasmine Nour, Marco Cremonesi, Giangiacomo Beretta, Annalisa Moregola, Fabio Pellegatta, Veronica Zampoleri, Alberico Luigi Catapano, Marinos Kallikourdis, Giuseppe Danilo Norata
Journal: Cardiovascular Research (2020)

Abstract Aim Loss of immunosuppressive response supports inflammation during atherosclerosis. We tested whether adoptive cell therapy (ACT) with Tregulatory cells (Tregs), engineered to selectively migrate in the atherosclerotic plaque, would dampen the immune-inflammatory response in the arterial wall in animal models of familial hypercholesterolaemia (FH). Methods and results FH patients presented a decreased Treg suppressive function associated to an increased inflammatory burden. A similar phenotype was observed in Ldlr −/− mice accompanied by a selective increased expression of the chemokine CX3CL1 in the aorta but not in other districts (lymph nodes, spleen, and liver). Treg overexpressing CX3CR1 were thus generated (CX3CR1+-Tregs) to drive Tregs selectively to the plaque. CX3CR1+-Tregs were injected (i.v.) in Ldlr −/− fed high-cholesterol diet (western type diet, WTD) for 8 weeks. CX3CR1+-Tregs were detected in the aorta, but not in other tissues, of Ldlr −/− mice 24 h after ACT, corroborating the efficacy of this approach. After 4 additional weeks of WTD, ACT with CX3CR1+-Tregs resulted in reduced plaque progression and lipid deposition, ameliorated plaque stability by increasing collagen and smooth muscle cells content, while decreasing the number of pro-inflammatory macrophages. Shotgun proteomics of the aorta showed a metabolic rewiring in CX3CR1+-Tregs treated Ldlr −/− mice compared to controls that was associated with the improvement of inflammation-resolving pathways and disease progression. Conclusion ACT with vasculotropic Tregs appears as a promising strategy to selectively target immune activation in the atherosclerotic plaque.
Lower Cardiorespiratory Fitness Is Associated With a Smaller and Stiffer Heart
Authors: Marcello Ricardo Paulista Markus, Till Ittermann, Christine Julia Drzyzga, Martin Bahls, Sabine Schipf, Ulrike Siewert-Markus, Sebastian Edgar Baumeister, Ralf Ewert, Henry Völzke, Elisabeth Steinhagen-Thiessen, Robin Bülow, Heribert Schunkert, Ramachandran S. Vasan, Stephan Burkhard Felix, Marcus Dörr
Journal: JACC. Cardiovascular imaging (2020)
Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering
Authors: Ting Su, Mengying Zhang, Qiankun Zeng, Wenhao Pan, Yijing Huang, Yuna Qian, Wei Dong, Xiaoliang Qi, Jianliang Shen
Journal: Bioactive Materials (2020)

Polysaccharide hydrogels are widely used in tissue engineering because of their superior biocompatibility and low immunogenicity. However, many of these hydrogels are unrealistic for practical applications as the cost of raw materials is high, and the fabrication steps are tedious. This study focuses on the facile fabrication and optimization of agarose-polydopamine hydrogel (APG) scaffolds for skin wound healing. The first study objective was to evaluate the effects of polydopamine (PDA) on the mechanical properties, water holding capacity and cell adhesiveness of APG. We observed that APG showed decreased rigidity and increased water content with the addition of PDA. Most importantly, decreased rigidity translated into significant increase in cell adhesiveness. Next, the slow biodegradability and high biocompatibility of APG with the highest PDA content (APG3) was confirmed. In addition, APG3 promoted full-thickness skin defect healing by accelerating collagen deposition and promoting angiogenesis. Altogether, we have developed a straightforward and efficient strategy to construct functional APG scaffold for skin tissue engineering, which has translation potentials in clinical practice.
Complete Right-to-Left Shunt in Lung Perfusion Scintigraphy
Authors: Falk Gühne, Robert Drescher, Ferdinand Ndum, Philipp Seifert, Martin Freesmeyer
Journal: Clinical Nuclear Medicine (2020)

Lung scintigraphy was performed to rule out pulmonary embolism in a 37-year-old woman suffering from dyspnea and hypoxemia after routine diagnostics failed to find the underlying disease. Perfusion scans did not show tracer uptake within the lungs despite ventilation scans being unremarkable. Instead, the result suggested a complete right-to-left shunt, which was a conundrum. With the assistance of CT an uncommon congenital vessel aberration turned out to be the cause of this exceptional scintigraphy finding, as well as the yet unexplained hypoxemia.
A meta‐review of “lifestyle psychiatry”: the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders
Authors: Joseph Firth, Marco Solmi, Robyn E. Wootton, Davy Vancampfort, Felipe B. Schuch, Erin Hoare, Simon Gilbody, John Torous, Scott B. Teasdale, Sarah E. Jackson, Lee Smith, Melissa Eaton, Felice N. Jacka, Nicola Veronese, Wolfgang Marx, Garcia Ashdown‐Franks, Dan Siskind, Jerome Sarris, Simon Rosenbaum, André F. Carvalho, Brendon Stubbs
Journal: World Psychiatry (2020)

There is increasing academic and clinical interest in how “lifestyle factors” traditionally associated with physical health may also relate to mental health and psychological well‐being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta‐review of the top‐tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta‐analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta‐reviews, and two meta‐analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress‐related disorders, schizophrenia, bipolar disorder, and attention‐deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non‐pharmacological sleep‐focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.
18F-FDG PET/CT Helps Differentiate Peripheral Nerve Myeloid Sarcoma From a Presumed Benign Nerve Sheath Tumor
Authors: Jeeban P. Das, Christopher C. Riedl, Gary A. Ulaner
Journal: Clinical Nuclear Medicine (2020)

Abstract A 21-year-old man with NF1 (neurofibromatosis type 1) mutation and in remission from acute myeloid leukemia presented with a painless mass in the left upper limb. MRI showed a soft-tissue mass involving the ulnar nerve presumed to be a nerve sheath tumor. 18 F-FDG PET/CT was performed demonstrating high FDG avidity in the mass, prompting a biopsy. Histopathology and immunohistochemistry of the biopsy sample demonstrated myeloid sarcoma of the ulnar nerve. This case highlights the role of 18 F-FDG PET/CT in raising the suspicion of malignancy in otherwise presumably benign lesions of the nerve.
Expression and clinical significance of PD-L1, B7-H3, B7-H4 and VISTA in craniopharyngioma
Authors: Yuelong Wang, Jiaojiao Deng, Lin Wang, Tingyue Zhou, Jinlong Yang, Zerong Tian, Jinhao Yang, Hongxu Chen, Xin Tang, Shasha Zhao, Liangxue Zhou, Aiping Tong, Jianguo Xu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Craniopharyngioma (CP) is a common refractory tumor of the central nervous system. However, little is known about the expression and clinical significance of B7 family ligands/receptors in CP patients. Thus, we conducted the present study to address this issue in a cohort of 132 CP cases.We mapped and quantified the expression of B7 family ligands/receptors molecules programmed cell death ligand 1 (PD-L1), B7-H3, B7-H4 and V-domain Ig-containing suppressor of T cell activation (VISTA) in 89 adamantinomatous-type CP and 43 papillary-type CP samples using immunohistochemistry and immunofluorescence. Associations between the marker levels, clinicopathological variables and survival were evaluated.The positive rates of PD-L1, B7-H3, B7-H4 and VISTA in the cohort of 132 CP cases were 76.5%, 100%, 40.2% and 80.3%, respectively. The cut-off values of PD-L1, B7-H3, B7-H4 and PD-L1 expression were determined by survival receiver operating characteristic (ROC) package, which was 70, 182, 0 and 20, respectively. Elevated expressions of PD-L1, B7-H3, B7-H4 and VISTA were significantly associated with some clinicopathological characteristics. Kaplan-Meier analysis indicated that higher VISTA expressions correlated with better overall survival (OS) and progression-free survival (PFS) (p=0.0053 and p=0.0066, respectively). Multivariate Cox regression analysis indicated that VISTA was an independent prognostic factor for OS (p=0.018) but not for PFS (p=0.898).We found variable expression of PD-L1, B7-H3, B7-H4 and VISTA proteins in CPs. The results suggest that the expression level of VISTA may be used as an important indicator to predict the OS and PFS of CPs. B7 family ligands/receptors could be potential immunotherapeutic targets when treating CPs.
Accelerating the Global Development of Pediatric Cancer Drugs: A Call to Coordinate the Submissions of Pediatric Investigation Plans and Pediatric Study Plans to the European Medicines Agency and US Food and Drug Administration
Authors: Gregory Reaman, Dominik Karres, Franca Ligas, Giovanni Lesa, Denise Casey, Lori Ehrlich, Koen Norga, Richard Pazdur
Journal: Journal of Clinical Oncology (2020)
Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study
Authors: Kazuhiro Kakimi, Hirokazu Matsushita, Keita Masuzawa, Takahiro Karasaki, Yukari Kobayashi, Koji Nagaoka, Akihiro Hosoi, Shinnosuke Ikemura, Kentaro Kitano, Ichiro Kawada, Tadashi Manabe, Tomohiro Takehara, Toshiaki Ebisudani, Kazuhiro Nagayama, Yukio Nakamura, Ryuji Suzuki, Hiroyuki Yasuda, Masaaki Sato, Kenzo Soejima, Jun Nakajima
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC. Methods NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (&gt;1×10 9 ) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly &gt;4 months. Results Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor. Conclusions Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint. Trial registration number UMIN000006128
Ensuring Adequate Palliative and Hospice Care During COVID-19 Surges
Authors: Jean Abbott, Daniel Johnson, Matthew Wynia
Journal: JAMA (2020)

Jihae Lee, MD; Liliya Abrukin, MD, MPH; Stefan Flores, MD; Nicholas Gavin, MD, MBA, MS; Marie-Laure Romney, MD, MBA; Craig D. Blinderman, MD, MA; Shunichi Nakagawa, MD
Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models
Authors: Pui Y. Lee-Law, Paula Olaizola, Francisco J. Caballero-Camino, Laura Izquierdo-Sanchez, Pedro M. Rodrigues, Alvaro Santos-Laso, Mikel Azkargorta, Felix Elortza, Maria L. Martinez-Chantar, Maria J. Perugorria, Patricia Aspichueta, Marco Marzioni, Nicholas F. LaRusso, Luis Bujanda, Joost P.H. Drenth, Jesus M. Banales
Journal: Journal of Hepatology (2020)

Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting.Levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry.Most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis.Cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy.Protein SUMOylation is a dynamic post-translational event implicated in numerous cellular processes. This study revealed dysregulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adenosylmethionine (SAMe), a natural UBC9-dependent SUMOylation inhibitor, halted polycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients.
Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I
Authors: Hao Zeng, Lingling Wang, Jiawei Zhang, Ting Pan, Yinghua Yu, Jingxia Lu, Ping Zhou, Hua Yang, Ping Li
Journal: Acta Pharmaceutica Sinica B (2020)

Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3β signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3β/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale.