tbuckley/cabot-search huggingface dataset:
Characteristics of liposomal encapsulation of an archetypal multi-kinase inhibitor in terms of antitumor activity and avoidance of systemic toxicity.
Authors: Rajesh Mukthavaram, Pengfei Jiang, Rohit Saklecha, Dmitri Simberg, Ila Bharati, Natsuko Nomura, Ying Chao, Sandra Pastorino, Sandeep C. Pingle, Valentina Fogal, Wolf Wrasidlo, Milan Theodore Makale, Santosh Kesari
Journal: Journal of Clinical Oncology (2015)

e13589 Background: Staurosporine (STS) class drugs exhibit a unique and broad spectrum inhibition of intracellular signaling pathways, and even low doses potently overcome the chemotherapy resistant cellular compartment of a wide range of tumors. The development of STS analogs, called “staralogs” has attracted much interest from academia, the pharmaceutical industry, and the NCI, and the 7-hydroxy analog UCN-01 has been the focus of 22 NIH sponsored Phase II/III clinical trials in solid tumors including glioblastoma (GBM). However, persistent pharmacokinetic and toxicity issues have uniformly prevented approval for clinical use. One solution may be liposomal drug reformulation which is increasingly being used with potent antitumor agents that failed translation. Methods: Liposomal loading of staralogs has proved inadequate so we sought to develop novel methods based on pH gradients, lipid composition, buffer composition and temperature regime, to achieve efficient loading of the class archetype, STS. We tested liposomal STS (LSTS) in two murine models of glioblastoma (GBM), a flank tumor and an orthotopic model that emulates the invasive natural history of GBM. We also assessed biodistribution and toxicity of LSTS using body weight, blood chemistry and liver enzymes. Results: We developed a novel method to attain > 95% liposomal loading of the class parent compound, STS as well as UCN-01. The liposomal STS (LSTS) formulation demonstrated: 1) striking suppression of murine flank tumors; 2) most recently penetration of the primary tumor and its invasive margin to yield greatly increased survival in a clinically relevant orthotopic GBM model, and; 3)no evidence of toxicity based on body weight, blood chemistry and liver enzymes, compared to free STS. Conclusions: This study demonstrated for the first time preferential tumor accumulation of LSTS and potent antitumor activity at a low systemic dose with no apparent toxicity. The present report provides the basis for pursuing comprehensive preclinical studies on the efficacy, pharmacokinetics, biodistribution, and toxicology of a range of encapsulated STS compounds for solid tumor therapy.
Primary small cell esophageal carcinoma (SCEC): A retrospective study of different treatment modalities.
Authors: Mohammad Alfayez, Vivienne MacLaren
Journal: Journal of Clinical Oncology (2015)

e15070 Background: Primary small cell carcinoma of the esophagus is a rare disease with very little known about its epidemiology or management. Here, we review the practice of treating SCEC through different treatment modalities at Beatson West of Scotland Cancer Centre Methods: Retrospective analysis of 25 patients with SCEC who were treated between 2001 and 2014 in our institution. All patients have histological diagnoses of SCEC. Data were collected based on age, gender, performance status, staging of the disease (limited stage (LS) vs. extensive stage (ES)), and modality of treatment. Different treatment modalities were delivered, which included palliative chemotherapy, sequential chemoradiation, or induction chemotherapy followed by concurrent chemoradiation. Results: The median age at diagnosis of SCEC was 73 years old. Diagnosis of SCEC is more common in men (60%) than in women. The tumour is more likely to be located in the distal part of the oesophagus (72%) than the middle part. Seventeen patients (68%) were diagnosed with LS-SCEC, while eight patients (32%) were diagnosed with ES-SECE. Two patients with ES-SCEC did not received any treatment while six patients received platinum-based palliative chemotherapy. Four patients with LS-SCEC received platinum-based chemotherapy only. Five patients received two cycles of induction platinum-based chemotherapy followed by radical-dose radiotherapy. Eight patients received sequential chemoradiation. The survival of patients with ES-SCEC and LS-SCEC who received chemotherapy only was 9.4 months (95% CI: 0-21.8) and 5.6 months (95% CI: 0-12.4) respectively. However, survival of patients who received sequential chemoradiation and induction chemotherapy followed by concurrent chemoradiation was 23 months (95% CI: 17.5-27.8) and 45 months (95% CI: 34.5-55.3) respectively. Interestingly, none of the patients have been reported to have brain metastasis. Conclusions: This retrospective study is the largest case series based on a western population with SCEC. The study showed combined modality therapy using platinum-based combination chemoradiation to the oesophagus improved survival with no need for extensive surgery.
Abstract P420: Chronic Pain in Adolescents and Adults With Congenital Heart Disease
Authors: Lina Brou, Lindsey Duca, Lisa Mckenzie, Christopher Rausch, Amber Khanna, David Kao, Tessa Crume
Journal: Circulation (2019)

Introduction: Chronic pain is a significant public health concern in the U.S., estimated to affect nearly 100 million people. While post-surgical pain associated with treatment of congenital heart disease (CHD) has been studied, the persistent prevalence of chronic pain among this growing population is unknown. Hypothesis: Our primary objective is to understand the burden of chronic pain among adolescents and adults with CHD in the Colorado Congenital Heart Defects Surveillance System (COCHD). Additionally, we will determine if chronic pain among individuals with CHD is associated with differing patterns of healthcare utilization and mental health diagnoses. Methods: We included 9,116 participants aged 11 to 64 years with a CHD lesion listed as a diagnostic code on an encounter occurring between January 1, 2011 to December 31, 2013. Chronic pain was defined as an encounter with ICD-9CM code (338.2-338.4) from a validated algorithm for identifying chronic pain in electronic medical record. Multivariable logistic regression was conducted to assess associations between chronic pain and the number of inpatient visits, cardiac procedures and mental health disorders, adjusted for CHD severity and age group. Results: Of the 9,116 participants identified with CHD between 2011-2013 in COCHD, 17.5% met the diagnostic criteria for chronic pain. Table 1 displays the differences in our cohort by chronic pain status. Chronic pain was associated with a 54% increase in the likelihood of a mental diagnosis (OR=1.54, 95%C.I.:1.43-1.66) and each increasing number of cardiac procedures that occurred during the 3 year study interval increased the likelihood of chronic pain by 25% (OR=1.25, 95%C.I.:1.21-1.30). Conclusion: Our study provides novel insight into the increasingly recognized public health issue of chronic pain within the growing population of adolescents and adults with CHD who have high lifetime healthcare utilization. Further studies will explore the complex relationship of mental illness, chronic pain and CHD.
Exceptional response and multisystem autoimmune-like toxicities associated with the same T cell clone in a patient with uveal melanoma treated with immune checkpoint inhibitors
Authors: Suthee Rapisuwon, Benjamin Izar, Cory Batenchuk, Alexandre Avila, Shaolin Mei, Peter Sorger, Jerry M. Parks, Sarah J. Cooper, David Wagner, Jay C. Zeck, Aline J. Charabaty, Michael B. Atkins
Journal: Journal for ImmunoTherapy of Cancer (2019)

Balancing the potential for durable remissions with autoimmune-like toxicities is a key clinical challenge in the use of immune checkpoint inhibitors (ICI). Certain toxicities are associated with an increased response rate; however, the molecular underpinnings of this association are poorly understood. Here, we report a patient with wide spread uveal melanoma who had an exceptional response to treatment with ipilimumab and nivolumab, but suffered severe immune-related sequelae, including central serous retinopathy with retinal detachment, tinnitus, and vitiligo resembling Vogt-Koyanagi-Harada disease, and refractory enteritis. TCR-sequencing of the primary tumor, a hepatic metastasis, duodenal biopsy and peripheral blood mononuclear cells, identified the identical T cell clone in all four tissues. This case provides preliminary evidence for cross-reactivity as a mechanism for the association between effect and toxicity of ICIs.
Abstract P363: Cardiovascular Health as a Mediator of Psychosocial Influences on CVD
Authors: Sarah S Singh, Stephanie J Frisbee
Journal: Circulation (2019)

Background: Negative psychosocial factors, such as high stress and poor social support, are strongly associated with disease outcomes, including CVD. Conceptually, it is plausible that better cardiovascular health (CVH) may blunt the association between psychosocial factors and incident CVD. However, few studies have investigated whether CVH, which includes biological and behavioral factors, is a potential pathway between psychosocial factors and CVD. Objective: To investigate whether the association between CVD and psychosocial factors is fully or partially mediated by CVH. Setting: This study was carried out in a nationally representative sample of Canadian adults aged 20 years and older. Data and Methods: This study is a cross-sectional design using data from the Canadian Community Health Survey (CCHS) 2015-2016 database. The CCHS is a nationwide, nationally representative survey that collects information on the health status, health care utilization and health determinants of the Canadian population. The study outcome was CVD, as measured by the self-reported presence of physician-diagnosed heart disease. The potential mediator was individual CVH, defined using the AHA CVH Index (CVHI) and determined using self-reported responses in CCHS. Psychosocial factors included self-reported responses to questions on life stress, work stress, sleep, social support and alcohol and drug use. A structural equation modeling (SEM) approach was then used to explore the mediational role of CVH in the association of CVD with psychosocial factors. Analyses were conducted in MPlus Version 8 software. Results: The majority of the population were males (51%), aged 40-60 (37%), with tertiary education (64%) and of the White race (79%). Overall, the mean CVH of the population was 4.5. Results suggested that CVH and all psychosocial factors, except for life stress predicted, CVD. Additionally, all psychosocial factors, except for life stress and drug use, predicted CVH. Standardized coefficients demonstrated that, of all psychosocial factors, work stress had the highest impact on both CVH (std coeff -0.22, p&lt;0.001) and CVD (std coeff -0.07, p&lt;0.0001). Further analyses demonstrated that CVHI partially mediated the association between CVD and work stress (std coeff -0.02, p&lt;0.001), sleep (std coeff -0.002, p&lt;0.001), alcohol use (std coeff -0.009, p&lt;0.001) and social support (std coeff -0.001, p=0.003). None of the associations were fully mediated by CVH. Conclusion: Results indicated that the association between psychosocial factors and CVD was partially mediated by CVH. That is, while better CVH weakened the association between psychosocial factors and CVD, the direct association between psychosocial factors and CVD remained. Further analyses should investigate whether accounting for individual characteristics such as age, sex and race may reveal full mediation through CVH.
Efficacy, safety, biomarkers, and phase II dose modeling in a phase I trial of the oral selective c-Met inhibitor tepotinib (MSC2156119J).
Authors: Gerald Steven Falchook, Razelle Kurzrock, Hesham M. Amin, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, Hongxia Zheng, Barbara Sarholz, Andreas Johne, David S. Hong
Journal: Journal of Clinical Oncology (2015)

2591 Background: Tumor c-Met overexpression is associated with tumor aggression and poor prognosis, making it a target for therapy. This phase I study (NCT01014936) in patients (pts) with advanced solid tumors provided data that allowed determination of a recommended phase II dose (RP2D) for the selective oral c-Met inhibitor tepotinib (MSC2156119J). Methods: Primary objectives were to determine the MTD and RP2D. Secondary endpoints included antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics. Pts received tepotinib according to one of three 3-weekly regimens (R): 30–230 mg/d d1–14 followed by 7-d rest (R1); 30–115 mg/d 3x/week (R2); or 300–1400mg/d d1–21 (R3). Interim PK and biomarker data were analyzed using a population modeling approach. Using these data and the exposure/target inhibition relationship established in mice, a human population PK model was developed to simulate c-Met inhibition profiles in humans and determine the biologically active dose of tepotinib. Results: As of 9/30/2014,143 pts had been enrolled (R1 = 42; R2 = 45; R3 = 56). The MTD was not reached at ≤ 1400 mg/day d1–21 (R3). Among the 56 pts treated with R3 (c-Met overexpressing 12; amplified 4; overexpressing and amplified 3), treatment-related adverse events (trAEs) were observed in 61%. Of these, > 75% experienced trAEs of worst grade 1/2. Seven pts (13%) experienced trAEs of worst grade ≥ 3: fatigue (2), peripheral edema (2), ALT increase (1), AST increase (1), hyponatremia (1), edema (1), and thrombocytopenia (1). Of the 56pts treated with R3, 2 had a PR and 7 had SD as their best overall response. Patients with PRs had tumors with c-Met overexpression or amplification, as did 2/7 pts with SD. A biologically active dose of 500 mg/d was selected as the RP2D based on a translational modeling approach, with simulations indicating that ≥ 95% pMET inhibition was required for tumor regression. Human population PK simulations suggested that tepotinib 500 mg daily could achieve continuous pMET inhibition of ≥ 95% in 90% of the population. Conclusions: Tepotinib is well tolerated and shows antitumor activity, particularly in pts with c-Met overexpressing/amplified tumors. Clinical trial information: NCT01014936.
Cancer-related fatigue in carcinoma urinary bladder patients receiving chemotherapy: A single institutional study from northern India.
Authors: Vineet Talwar, Varun Goel, Prasanta DASH
Journal: Journal of Clinical Oncology (2019)

361 Background: Fatigue is one of the most disabling phenomenon among patients receiving anti cancer treatment, which has profound effect on their Quality of life (QOL). Although clinicians across the globe acknowledge the importance of regular assessment of fatigue, however it is seldom being assessed and documented in clinical practice in India and very few studies have reported Cancer Related Fatigue among Indian population. Methods: For this study an exploratory design was adopted, using a purposive sampling method. Patients (N=206,) undergoing chemotherapy at Rajiv Gandhi Cancer Hospital and Research Center, Delhi, India; aged 18-83 years were included. The level of fatigue was assessed using 16- item Multidimensional assessment of Fatigue (MAF) scale and a semi structured in depth interview schedule. These interviews were recorded, transcribed and analyzed. Results: Irrespective of age, and education, 81% patients experience clinically significant fatigue. Extreme level of fatigue was reported by 29% patients requiring immediate clinical intervention while 52% patients reported moderate level of clinically significant fatigue. Top four psychosocial issues reported were: apprehension of CT side effects (23.5%), fear of pain (19%), Loss of appetite (17.5%) and anxiety during CT (13.5 %), followed by financial issues (11%). Among all patients, (49.5%) were aware of their diagnosis of which 8% were either fully aware or partially aware about the prognosis (23%). Conclusions: Fatigue remains one of the most important clinical parameters among majority of Carcinoma Urinary Bladder patients receiving chemotherapy, and is neither assessed by clinicians nor reported by majority of the patients. While almost one fourth of the patients report fear of chemotherapy as their pressing psychosocial concern, others report fear of pain, loss of appetite, manifest anxiety symptoms or report financial and logistics issue during CT. Various exercise, educational material and psychotherapeutic interventions should be developed to prepare and support them during their treatment for better preparedness of side effects and their management, reduced symptoms and better quality of life.
Citrullinated Inhibitor of <scp>DNA</scp> Binding 1 Is a Novel Autoantigen in Rheumatoid Arthritis
Authors: Ray A. Ohara, Gautam Edhayan, Stephanie M. Rasmussen, Takeo Isozaki, Henriette A. Remmer, Thomas M. Lanigan, Phillip L. Campbell, Andrew G. Urquhart, Jeffrey N. Lawton, Kevin C. Chung, David A. Fox, Jeffrey H. Ruth
Journal: Arthritis & Rheumatology (2019)

To explore the intrinsic role of inhibitor of DNA binding 1 (ID-1) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and to investigate whether ID-1 is citrullinated and autoantigenic in RA.RA patient serum ID-1 levels were measured before and after infliximab treatment. RA FLS were transfected with a clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 construct targeting ID-1 to examine the effects of ID-1 deletion. RA synovial fluid (SF) and homogenized synovial tissue (ST) were immunoprecipitated for ID-1 and measured for citrullinated residues using an enzyme-linked immunosorbent assay and Western blotting. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on in vitro-citrullinated recombinant human ID-1 (cit-ID-1) to localize the sites of citrullination. Normal and RA sera and SF were analyzed by immunodot blotting for anti-citrullinated protein antibodies (ACPAs) to cit-ID-1.RA patient serum ID-1 levels positively correlated with several disease parameters and were reduced after infliximab treatment. RA FLS displayed reduced growth and a robust increase in interleukin-6 (IL-6) and IL-8 production upon deletion of ID-1. ID-1 immunodepletion significantly reduced the levels of citrullinated residues in RA SF, and citrullinated ID-1 was detected in homogenized RA ST (n = 5 samples; P < 0.05). Immunodot blot analyses revealed ACPAs to cit-ID-1 but not to native ID-1, in RA peripheral blood (PB) sera (n = 30 samples; P < 0.001) and SF (n = 18 samples; P < 0.05) but not in normal PB sera. Following analyses of LC-MS/MS results for citrullination sites and corresponding reactivity in immunodot assays, we determined the critical arginines in ID-1 for autoantigenicity: R33, R52, and R121.Novel roles of ID-1 in RA include regulation of FLS proliferation and cytokine secretion as well as autoantigenicity following citrullination.
Клиническая эффективность урсодезоксихолевой кислоты в комплексном лечении больных ожирением и гастроэзофагеальной рефлюксной болезнью
Authors: Ye.S. Sirchak
Journal: GASTROENTEROLOGY (2019)

Актуальность. Нарушения в организме больных с ожирением носят системный метаболический характер, в том числе негативно влияют на состояние органов желудочно-кишечного тракта. Установлена связь ожирения с такими заболеваниями органов пищеварения, как стеатоз печени и поджелудочной железы, желчнокаменная болезнь, а также с гастроэзофагеальной рефлюксной болезнью (ГЭРБ). Назначение урсодезоксихолевой кислоты (УДХК) в составе комплексной терапии больных ожирением и ГЭРБ является патогенетически обоснованным с учетом ее способности влиять на метаболические процессы в организме, а также ее протективной роли в отношении слизистой оболочки верхних отделов желудочно-кишечного тракта при воздействии агрессивного рефлюктата. Цель: изучить клиническую эффективность препарата УДХК (Урсофальк) в комплексном лечении больных ожирением и ГЭРБ. Материалы и методы. Обследовано 94 больных с ожирением различной степени и ГЭРБ. Обследованные разделены на две клинические группы: I группа больных (n = 44) на фоне изменения образа жизни, соблюдения диетических рекомендаций получила стандартное лечение ГЭРБ с использованием ингибитора протонной помпы; II группа больных (n = 50), кроме вышеуказанного лечения, дополнительно получила препарат УДХК Урсофальк («Др. Фальк Фарма ГмбХ», Германия) в течение 3 месяцев. Результаты. ГЭРБ у больных ожирением с частотой до 40,9 % случаев проявляется внепищеводной симптоматикой. Назначение ингибитора протонной помпы в сочетании с УДХК у больных ожирением приводит к существенному снижению изжоги, проявлений дисфагии, а также внепищеводных проявлений рефлюксной болезни уже в конце 2–4 недели лечения. Комплексная терапия с использованием УДХК у обследованных больных также способствовала уменьшению массы тела (до 5 кг за один месяц лечения), преимущественно при ожирении I и II степеней. Выводы. Использование Урсофалька в комплексном лечении больных ГЭРБ при ожирении является патогенетически обоснованным средством уменьшения и нормализации клинических проявлений заболевания, особенно их внепищеводных форм. Комплексная терапия больных ГЭРБ и ожирением на фоне модификации образа жизни и диетических рекомендаций должна включать препарат УДХК для более быстрой, эффективной и безопасной нормализации массы тела с продолжительностью лечения минимум 3 месяца.
Macroporous Scaffolds: A 3D Macroporous Alginate Graphene Scaffold with an Extremely Slow Release of a Loaded Cargo for In Situ Long‐Term Activation of Dendritic Cells (Adv. Healthcare Mater. 5/2019)
Authors: Arjyabaran Sinha, Youngjin Choi, Minh Hoang Nguyen, Thanh Loc Nguyen, Seung Woo Choi, Jaeyun Kim
Journal: Advanced Healthcare Materials (2019)

In article number 1800571 by Jaeyun Kim and co-workers, a three-dimensional alginate scaffold embedded with reduced graphene oxide, characterized with high loading and slow release properties, is synthesized for long-term in situ modulation of dendritic cells to enhance vaccine efficacy. After mice are vaccinated with the scaffold loaded with immuno-active molecules, this scaffold suppresses tumor growth by significant activation of dendritic cells and cytotoxic T cells for a long time.