tbuckley/cabot-search huggingface dataset:
High Pleural Pressure Prevents Alveolar Overdistension and Hemodynamic Collapse in Acute Respiratory Distress Syndrome with Class III Obesity. A Clinical Trial
Authors: Roberta De Santis Santiago, Maddalena Teggia Droghi, Jacopo Fumagalli, Francesco Marrazzo, Gaetano Florio, Luigi G. Grassi, Susimeire Gomes, Caio C. A. Morais, Ozires P. S. Ramos, Maurizio Bottiroli, Riccardo Pinciroli, David A. Imber, Aranya Bagchi, Kenneth Shelton, Abraham Sonny, Edward A. Bittner, Marcelo B. P. Amato, Robert M. Kacmarek, Lorenzo Berra, Adriana Sayuri Hirota, Daniela Davis Madureira Iope, Carolina Eimi Kajiyama, Andrea Fonseca, Otilia Batista, Silvia Cristina Leopoldino, Carlo Valsecchi, Erick Leon, Kathryn Hibbert, Charles C. Hardin, Kim Connelly, Daniel Fisher, Grant Michael Larson, Emanuele Vassena, Raffaele Di Fenza, Stefano Gianni, Bijan Safaee Fakhr, Jeanine Wiener-Kronish, Brian Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Obesity is characterized by elevated pleural pressure (Ppl) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine the effects of a lung recruitment maneuver (LRM) in the presence of elevated Ppl on hemodynamics, left and right ventricular pressure, and pulmonary vascular resistance. We hypothesized that elevated Ppl protects the cardiovascular system against high airway pressure and prevents lung overdistension.Methods: First, an interventional crossover trial in adult subjects with ARDS and a body mass index ≥ 35 kg/m2 (n = 21) was performed to explore the hemodynamic consequences of the LRM. Second, cardiovascular function was studied during low and high positive end-expiratory pressure (PEEP) in a model of swine with ARDS and high Ppl (n = 9) versus healthy swine with normal Ppl (n = 6).Measurements and Main Results: Subjects with ARDS and obesity (body mass index = 57 ± 12 kg/m2) after LRM required an increase in PEEP of 8 (95% confidence interval [95% CI], 7-10) cm H2O above traditional ARDS Network settings to improve lung function, oxygenation and [Formula: see text]/[Formula: see text] matching, without impairment of hemodynamics or right heart function. ARDS swine with high Ppl demonstrated unchanged transmural left ventricular pressure and systemic blood pressure after the LRM protocol. Pulmonary arterial hypertension decreased (8 [95% CI, 13-4] mm Hg), as did vascular resistance (1.5 [95% CI, 2.2-0.9] Wood units) and transmural right ventricular pressure (10 [95% CI, 15-6] mm Hg) during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized the [Formula: see text]/[Formula: see text] ratio.Conclusions: High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. In addition, patients with ARDS and class III obesity hemodynamically tolerate LRM with high airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT02503241).
Abstract 4346: Training Minority Community Leaders on Prostate Cancer. Effect of an Educational Strategy in Los Angeles, CA &amp; Tallahassee, FL
Authors: Carolina Aristizabal
Journal: Cancer Research (2020)

Abstract Background: Certain groups are disproportionately impacted by prostate cancer (PCa) compared to other racial/ethnic groups such as Blacks. While the burden of PCa in Hispanics is low, there is limited understanding of the disparities in subpopulations of Hispanics. We developed and culturally adapted, and updated all the scientific data, translated, implemented and evaluated a Prostate Cancer Advocacy Training (PCAT) for Hispanic populations. Methods: Culturally and language specific content on PCa cause, risk factors, epidemiology, detection, diagnosis and treatment was delivered through a workshop and simultaneously broadcasted in Spanish in Los Angeles County (n=29) and in English in Tallahassee, Florida (n=9). Pre- and post-test surveys assessed impact. Results: The following pre vs. post differences were statistically significant (p &amp;lt; 0.05), in knowledge (5.0±1.6 vs 6.3±1.1) and advocacy intentions (3.9±0.9 vs 4.3±0.8). On correctly identifying warning signs for PCa (50% vs 87%), intent to inform and educate patients, family, and friends about PCa within the next three months, (69% vs 95%), to ensure that high quality research is sensitive to the priorities of patients (63% vs 84%), to help increase patient recruitment, compliance and retention for clinical trials within the next month (62% vs 84%), intent to engage in PCa patient education within the next three months, (67% vs 92%); and in engaging in PCa community outreach within the next three months, (67% vs 94%) There were no significant differences due to race/ethnicity. Conclusion: The PCAT led to increased knowledge, awareness, and intention to engage patients and community health workers in advocacy and engagement regarding PCa in the next three months. Results suggest that delivering culturally and language specific educational information increases engagement of Hispanic and African American patient/community advocates. This has implications for reducing cancer health disparities. Citation Format: Carolina Aristizabal. Training Minority Community Leaders on Prostate Cancer. Effect of an Educational Strategy in Los Angeles, CA &amp; Tallahassee, FL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4346.
Gene Therapy Based on Nucleic Acid Nanostructure
Authors: Xiaohui Wu, Tiantian Wu, Jianbing Liu, Baoquan Ding
Journal: Advanced Healthcare Materials (2020)

Abstract During the past decades, nucleic acids have been employed for the construction of versatile nanostructures with well‐defined shapes and sizes. Owing to the remarkable programmability, addressability, and biocompatibility, nucleic acid nanostructures are extensively applied in biomedical researches, such as bioimaging, biosensing, and drug delivery. In particular, nucleic acid nanostructures can act as promising candidates for the delivery of gene‐related nucleic acid drugs based on the inherent homology. In this review, the recent progress in the design of multifunctional nucleic acid nanocarriers for gene therapy through antisense, RNA interference, gene editing, and gene expression is summarized. Furthermore, the challenges and future opportunities of nucleic acid nanotechnology in biomedical applications will be discussed.
Older adults with cancer and their caregivers — current landscape and future directions for clinical care
Authors: Sindhuja Kadambi, Kah Poh Loh, Richard Dunne, Allison Magnuson, Ronald Maggiore, Jason Zittel, Marie Flannery, Julia Inglis, Nikesha Gilmore, Mostafa Mohamed, Erika Ramsdale, Supriya Mohile
Journal: Nature Reviews Clinical Oncology (2020)
Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension
Authors: Roberto Badagliacca, Michele D’Alto, Stefano Ghio, Paola Argiento, Vincenzo Bellomo, Natale Daniele Brunetti, Gavino Casu, Marco Confalonieri, Marco Corda, Michele Correale, Carlo D’Agostino, Lucrezia De Michele, Giuseppe Galgano, Alessandra Greco, Carlo Lombardi, Giovanna Manzi, Valentina Mercurio, Massimiliano Mulè, Giuseppe Paciocco, Silvia Papa, Emanuele Romeo, Laura Scelsi, Davide Stolfo, Patrizio Vitulo, Robert Naeije, Carmine Dario Vizza
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144–363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
Abstract 1131: Preventive effect of Celecoxib in Sorafenib-related hand-foot syndrome in hepatocellular carcinoma patients, a single-center, open-label, randomized, controlled clinical phase III trial
Authors: JIANCONG CHEN
Journal: Cancer Research (2020)

Abstract Background: Skin toxicity, especially hand-foot syndrome (HFS), is one of the most common sorafenib-induced adverse events (AEs) in hepatocellular carcinoma (HCC) patients, leading to treatment interruption and failure. Mucocutaneous inflammation may cause HFS; therefore, we investigated whether celecoxib can alleviate HFS, improve patients' quality of life and increase survival when administered in conjunction with active therapy. Methods: Our randomized, open-label study prospectively enrolled 116 advanced HCC patients receiving sorafenib as targeted therapy from July 2015 to July 2016. All patients were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib with or without celecoxib. Sorafenib-related AEs were recorded, Survival was compared between the two groups. Results: Compared to the Sorafenib group, the SoraCele group had lower incidence rates of ≥ grade 2 and grade 3 HFS (63.8% vs 29.3%, P &amp;lt; 0.001; 19.0% vs 3.4%, P = 0.008, respectively), hair loss, rash and abdominal pain. Kaplan-Meier analysis revealed a lower risk of ≥ grade 2 HFS (HR, 0.384; P = 0.002) and a lower dose reduction/interruption rate (46.6% to 15.5%, P &amp;lt; 0.001) in the SoraCele group. Cox proportional hazards regression analysis demonstrated that celecoxib was the only independent predictive factor of developing ≥ grade 2 HFS (HR, 0.414; P = 0.004). Longer progression-free survival (PFS) was also observed in the SoraCele group (P = 0.039), although overall survival was not prolonged (P = 0.305). Conclusions: Sorafenib+Celecoxib administration alleviated sorafenib-related skin toxicity. Longer PFS was achieved in clinical practice, although overall survival was not prolonged (ClinicalTrials.gov: NCT02961998). Keywords: hand-foot syndrome; celecoxib; sorafenib; hepatocellular carcinoma Citation Format: JIANCONG CHEN. Preventive effect of Celecoxib in Sorafenib-related hand-foot syndrome in hepatocellular carcinoma patients, a single-center, open-label, randomized, controlled clinical phase III trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1131.
Abstract 1928: Study of copy number amplification and chemo-response in triple negative breast cancer
Authors: Jordan Mark Grainger, Jia Yu, Krishna R. Kalari, Peter Vedell, Kevin Thompson, Matthew P. Goetz, Vera J. Suman, Judy C. Boughey, Liewei Wang
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. With currently no targeted therapies for TNBC, identification of novel biomarkers to improve chemo-response is vital. Recently, copy number amplifications (CNAs) have been implicated in treatment response in several diseases including breast cancer. Our clinical studies have associated a 5 Mb CNA in TNBC patients with chemo-response, which may elucidate novel biomarkers and treatment strategies for TNBC. Analysis of RNAseq and Whole Exome Sequencing data from 42 TNBC patient tumors enrolled in the BEAUTY Study, identified a 5 Mb CNA on chromosome 8q which associated with pathological complete response following taxane and anthracycline chemotherapy. By performing siRNA knockdown cytotoxicity studies in TNBC cell lines for genes within this amplified region, we identified RDH10 as a potential novel biomarker for increasing chemo-sensitivity. RDH10 is the rate limiting step in the synthesis of all-trans retinoic acid (ATRA). Previous studies have demonstrated ATRA to be a potent inhibitor of PIN1, a key regulator of several oncogenic signaling pathways, amplified in TNBC. We discovered overexpression of RDH10 to increase endogenous levels of ATRA, contributing to the degradation of PIN1 and taxane sensitivity. A rescue experiment with PIN1 was able to restore the chemo-resistance phenotype. Similarly, we found treating TNBC cells with ATRA phenocopied RDH10's effect on PIN1 and improved chemo-sensitivity. Furthermore, analyses of chemo-responsive PDX tumors containing the 5 Mb CNA, overexpressed RDH10 and exhibited lower levels of PIN1 when compared to non-responders. In conclusion, RDH10 amplification increases endogenous levels of ATRA and degrades PIN1 in TNBC. ATRA-mediated degradation of PIN1 sensitizes TNBC to chemotherapy, suggesting RDH10 as a novel biomarker for chemo-response and ATRA as a novel treatment to improve chemo-sensitivity. Citation Format: Jordan Mark Grainger, Jia Yu, Krishna R. Kalari, Peter Vedell, Kevin Thompson, Matthew P. Goetz, Vera J. Suman, Judy C. Boughey, Liewei Wang. Study of copy number amplification and chemo-response in triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1928.
Abstract 5811: Combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors in breast cancer via RB-independent pathway
Authors: Kamal Pandey
Journal: Cancer Research (2020)

Abstract Objective: FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) are widely used to treat metastatic hormone receptor-positive (HR+) breast cancer. Despite the excellent disease control with CDK4/6 inhibitors, acquired resistance emerges in almost all cases. The strategies to combat the resistance are not yet defined. We investigated therapeutic strategies as well as mechanisms of resistance to CDK4/6 inhibitors in breast cancer. Methods: Palbociclib resistant cells (MCF7-PR and T47D-PR) were generated from the parental MCF and T47D cell lines by treating them with gradually increasing concentration of palbociclib for over 9 months. Cell viability assay, cell cycle, and western blot were performed to confirm the acquired resistance. Microarray analyses were carried out to identify altered gene expression. We validated the overexpressed genes by qRT-PCR and western blot and further confirmed the significant inhibition by CDK2 siRNA in combination with palbociclib both in vitro and in vivo. Results: Palbociclib-resistant MCF7 and T47D cells had about 10 fold higher half maximal inhibitory concentration (IC50), compared with parental cells. Morphological changes and alteration in EMT markers were observed in resistant cells. Loss of RB and overexpression of cyclin E1 confirmed that the cells gained resistance. Overexpression of C-MYC was observed in resistant cells compared to sensitive counterparts. Furthermore, from analysis of pleural effusion samples from HR+ breast cancer patients, we confirmed again that loss of RB and overexpression of cyclin E are significantly correlated with resistance to CDK4/6 inhibitors. Mechanistically, we found that, cyclin E-CDK2 mediated phosphorylation of C-MYC was responsible for suppressing C-MYC induced senescence. To overcome CDK4/6 inhibitor resistance, combined inhibition of CDK2 and CDK4/6 showed a synergistic effect in palbociclib-resistant in vitro and in vivo model. Further, combination-treated group showed significantly higher β-galactosidase expression compared to no- treatment control or palbociclib alone treated group. Conclusion: The synergistic anti-proliferative effect of the combined inhibition of CDK2 and CDK4/6 overcame acquired resistance to CDK4/6 inhibitors via RB-independent pathway, that is, suppressing C-MYC. These findings could pave the way for the development of next generation CDK2 inhibitor in CDK4/6 inhibitor-resistant breast cancer, which is characterized by overexpressed cyclin E and C-MYC. Keywords: CDK4/6, hormone receptor-positive breast cancer, drug resistance Citation Format: Kamal Pandey. Combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors in breast cancer via RB-independent pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5811.
Abstract 4058: TheraT - a highly versatile arenavirus based vector platform for intravenous and intratumoral cancer immunotherapy
Authors: Josipa Raguz, Sarah Schmidt, Theresa Kleisner, Manuel Zerbs, Goran Bekic, Sonja Feher, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Henning Lauterbach, Klaus Orlinger
Journal: Cancer Research (2020)

Abstract The unprecedented success of checkpoint blockade therapies clearly demonstrates the power of the immune system to fight cancer. Yet, only a minority of cancer patients respond with long-term control of the tumor or even cure, necessitating the development of other treatment modalities. Hookipa Pharma developed a novel attenuated, replication-competent viral vector platform (TheraT) that induces powerful cytotoxic T lymphocyte responses against foreign and self-antigens. In a preclinical model for human papilloma virus 16 (HPV16) associated cancer (TC-1), we evaluated immunogenicity and efficacy upon systemic and intratumoral application of TheraT vectors based on the arenaviruses lymphocytic choriomeningitis virus (LCMV) and pichinde virus (PICV). Both HB-201 (LCMV) and HB-202 (PICV) product candidates encode a non-oncogenic but highly antigenic E6/E7 fusion protein from HPV16. Independent of the route of administration, single administration of HB-201 or HB-202 induced potent peripheral E7-specific CD8+ T cell responses and led to efficient tumor growth control. Survival of TheraT treated animals was significantly longer compared to buffer treated animals. Similarly, single systemic as well as intratumoral application of HB-201 or HB-202 induced major infiltration of CD8+ T cells into the tumor microenvironment. Combination of intravenous HB-201 and anti-PD1 was well tolerated but did not further enhance efficacy in this model, implicating the presence of other immune evasion factors. In conclusion, replication-attenuated TheraT is safe, highly immunogenic and shows excellent therapeutic efficacy after single intravenous and intratumoral application. These data underline the potential and versatility of this novel vector platform. Mechanistic studies in various mouse tumor models are underway. Phase 1/2 clinical trial initiation of HB-201 monotherapy is planned for end of 2019 and preparations for an IND filing for a combination trial of HB-201 and HB-202 in H1 2020 have been initiated. Citation Format: Josipa Raguz, Sarah Schmidt, Theresa Kleisner, Manuel Zerbs, Goran Bekic, Sonja Feher, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Henning Lauterbach, Klaus Orlinger. TheraT - a highly versatile arenavirus based vector platform for intravenous and intratumoral cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4058.
Human NK cell deficiency as a result of biallelic mutations in MCM10
Authors: Emily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan M. Schmit, Sagar L. Patil, Nicole C. Guilz, Malini Mukherjee, Ashley E. Pezzi, Jolanta Chmielowiec, Swetha Tatineni, Ivan K. Chinn, Zeynep Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Asbjørg Stray-Pedersen, Rachel E. Bradley, Mo Moody, Philip P. Connor, Adrian G. Heaps, Colin Steward, Pinaki P. Banerjee, Richard A. Gibbs, Malgorzata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, Jordan S. Orange
Journal: Journal of Clinical Investigation (2020)

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.