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First-in-human clinical studies

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https://www.readbyqxmd.com/read/29331971/a-study-protocol-for-a-non-randomised-comparison-trial-evaluating-the-feasibility-and-effectiveness-of-a-mobile-cognitive-behavioural-programme-with-integrated-coaching-for-anxious-adults-in-primary-care
#1
Eva Szigethy, Francis Solano, Meredith Wallace, Dina L Perry, Lauren Morrell, Kathryn Scott, Megan Jones Bell, Megan Oser
INTRODUCTION: Generalised anxiety disorder (GAD) and subclinical GAD are highly prevalent in primary care. Unmanaged anxiety worsens quality of life in patients seen in primary care practices and leads to increased medical utilisation and costs. Programmes that teach patients cognitive-behavioural therapy (CBT) techniques have been shown to improve anxiety and to prevent the evolution of anxiety symptoms to disorders, but access and engagement have hampered integration of CBT into medical settings...
January 13, 2018: BMJ Open
https://www.readbyqxmd.com/read/29331423/thymidylate-synthase-prompts-metastatic-progression-through-the-dtmp-associated-emt-process-in-pancreatic-ductal-adenocarcinoma
#2
Muxing Kang, Wen Zheng, Qing Chen, Wenjie Qin, Pengping Li, Shifei Huang, Yizhao Zhou, Lantian Wang, Haolei Cai, Wenjie Lu, Biao Jiang, Qingqu Guo, Jian Chen, Dylan Wan, Jianyu Rao, Yulian Wu
As a fundamental metabolic enzyme, anti-Thymidylate synthase (TS) strategy has been shown to be an effective therapy for human cancers. However, the genuine effects of TS in pancreatic ductal adenocarcinoma (PDA) are still conflicting. We systemically assessed the prognostic value and whether TS associated with malignant progression in PDA. Protein and mRNA expression level of TS were evaluated in en bloc PDA samples, the prognostic effect of TS expressed in cytoplasm or cytonuclear was determined separately in the first time...
January 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29331420/dacomitinib-antagonizes-multidrug-resistance-mdr-in-cancer-cells-by-inhibiting-the-efflux-activity-of-abcb1-and-abcg2-transporters
#3
Ying-Fang Fan, Wei Zhang, Leli Zeng, Zi-Ning Lei, Chao-Yun Cai, Pranav Gupta, Dong-Hua Yang, Qingbin Cui, Zuo-Dong Qin, Zhe-Sheng Chen, Louis D Trombetta
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR)...
January 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29331015/detection-of-human-disease-conditions-by-single-cell-morpho-rheological-phenotyping-of-blood
#4
Nicole Toepfner, Christoph Herold, Oliver Otto, Philipp Rosendahl, Angela Jacobi, Martin Kräter, Julia Stächele, Leonard Menschner, Maik Herbig, Laura Ciuffreda, Lisa Ranford-Cartwright, Michal Grzybek, Ünal Coskun, Elisabeth Reithuber, Genevieve Garriss, Peter Mellroth, Birgitta Henriques Normark, Nicola Tregay, Meinolf Suttorp, Martin Bornhäuser, Edwin R Chilvers, Reinhard Berner, Jochen Guck
Blood is arguably the most important bodily fluid and its analysis provides crucial health status information. A first routine measure to narrow down diagnosis in clinical practice is the differential blood count, determining the frequency of all major blood cells. What is lacking to advance initial blood diagnostics is an unbiased and quick functional assessment of blood that can narrow down the diagnosis and generate specific hypotheses. To address this need, we introduce the continuous, cell-by-cell morpho-rheological (MORE) analysis of diluted whole blood, without labeling, enrichment or separation, at rates of 1,000 cells/sec...
January 13, 2018: ELife
https://www.readbyqxmd.com/read/29330297/characterization-and-evidence-of-the-mir-888-cluster-as-a-novel-cancer-network-in-prostate
#5
Tsuyoshi Hasegawa, Garrison Glavich, Mary Pahuski, Aleena M Short, Oliver John Semmes, Lifang Yang, Vitold Galkin, Richard R Drake, Aurora Esquela-Kerscher
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of ~22 nucleotide non-coding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients but the mechanism of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330294/establishment-of-the-first-well-differentiated-human-pancreatic-neuroendocrine-tumor-model
#6
Daniel Benten, Yasmin Behrang, Ludmilla Unrau, Victoria Weissmann, Gerrit Wolters-Eisfeld, Susanne Burdak-Rothkamm, Felix R Stahl, Martin Anlauf, Patricia Grabowski, Markus Möbs, Jan Dieckhoff, Bence Sipos, Martina Fahl, Corinna Eggers, Daniel Perez, Maximilian Bockhorn, Jakob R Izbicki, Ansgar W Lohse, Joerg Schrader
Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired pre-clinical research in NET. Herein, we establish and characterize a lymph node-derived cell line (NT-3) from a male patient with well-differentiated pancreatic NET. Neuroendocrine differentiation and tumor biology was compared to existing NET cell lines BON and QGP-1...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330212/early-and-locally-advanced-metaplastic-breast-cancer-presentation-and-survival-by-receptor-status-in-surveillance-epidemiology-and-end-results-seer-2010-2014
#7
Mary C Schroeder, Priya Rastogi, Charles E Geyer, Lance D Miller, Alexandra Thomas
BACKGROUND: Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010-2014 with MBC or invasive ductal carcinoma (IDC)...
January 12, 2018: Oncologist
https://www.readbyqxmd.com/read/29330000/histotripsy-treatment-of-benign-prostatic-enlargement-using-the-vortx-rx-system-initial-human-safety-and-efficacy-outcomes
#8
T G Schuster, J T Wei, K Hendlin, R Jahnke, W W Roberts
OBJECTIVES: To assess clinical safety (primary) and efficacy (secondary) of histotripsy for treatment of symptomatic benign prostatic enlargement (BPE) in a first-in human study. METHODS: Twenty-five male subjects with moderate to severe lower urinary tract symptoms (LUTS), prostate size between 30 and 80 grams and no evidence of prostate cancer were enrolled at two sites in a prospective, single-arm study. Treatment consisted of acoustic energy delivery through the perineum with integrated real-time TRUS monitoring using the Vortx RX system...
January 9, 2018: Urology
https://www.readbyqxmd.com/read/29329556/cancer-immunotherapy-beyond-immune-checkpoint-inhibitors
#9
REVIEW
Julian A Marin-Acevedo, Aixa E Soyano, Bhagirathbhai Dholaria, Keith L Knutson, Yanyan Lou
Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized...
January 12, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29327978/in-vivo-cyp3a-activity-in-palliative-care-patients-study-protocol-for-a-single-arm-prospective-trial
#10
Marcus J P Geist, Hubert J Bardenheuer, Jürgen Burhenne, Gerd Mikus
BACKGROUND: Drug interactions are a common cause for escalation of debilitating symptoms in palliative care patients. CYP3A is the most relevant CYP enzyme in humans involved in metabolism of about half of all available pharmaceuticals. OBJECTIVE: To increase knowledge about the CYP3A enzyme and the impact of drug interactions on its activity to improve dosing in palliative care patients. DESIGN: The prospective clinical trial uses a secure method of analyzing CYP3A activity in humans: Administration of a marker substance followed by the determination of its blood concentrations as well as the concentrations of its metabolite at certain points of time and corresponding metabolic clearance calculations...
January 12, 2018: Journal of Palliative Medicine
https://www.readbyqxmd.com/read/29327671/tissue-engineered-heart-valves-a-call-for-mechanistic-studies
#11
Kevin Blum, Joseph Drews, Christopher K Breuer
Heart valve disease carries a substantial risk of morbidity and mortality. Outcomes are significantly improved by valve replacement, but currently-available mechanical and biological replacement valves are associated with complications of their own. Mechanical valves have a high rate of thromboembolism and require lifelong anticoagulation. Biological prosthetic valves have a much shorter lifespan, and are prone to tearing and degradation. Both types of valves lack the capacity for growth, making them particularly problematic in pediatric patients...
January 12, 2018: Tissue Engineering. Part B, Reviews
https://www.readbyqxmd.com/read/29327570/the-detour-procedure-no-more-need-for-conventional-bypass-surgery
#12
Dainis Krievins, Janis Savlovskis, Natalija Ezite, Andrew Hill, Kaspars Kisis, Marcis Gedins, Edgars Zellans, Andrew Holden
BACKGROUND: Long segment occlusive disease in the superficial femoral artery remains a treatment challenge despite advances in open surgical and endovascular approaches. We report initial clinical results of an entirely new procedure to perform femoropopliteal bypass using the DETOUR System to create a stentgraft bypass which originates in the SFA, travels through the femoral vein, and ends in the popliteal artery, bypassing the diseased segment. METHODS: Review the initial results of the first five patients at a single site enrolled in IRB-approved, prospective clinical study using the DETOUR System...
January 9, 2018: Journal of Cardiovascular Surgery
https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#13
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29326401/efficacy-and-tolerability-of-trastuzumab-emtansine-in-advanced-human-epidermal-growth-factor-receptor-2-positive-breast-cancer
#14
W Yeo, M Y Luk, I S Soong, T Ys Yuen, T Y Ng, F Kf Mo, K Chan, S Y Wong, J Tsang, C Leung, J Js Suen, R Kc Ngan
INTRODUCTION: The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in the Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond...
January 12, 2018: Hong Kong Medical Journal, Xianggang Yi Xue za Zhi
https://www.readbyqxmd.com/read/29326367/organic-anion-transporter-2-mediates-hepatic-uptake-of-tolbutamide-a-cytochrome-p450-2c9-probe-drug
#15
Yi-An Bi, Sumathy Mathialagan, Laurie Tylaska, Myra Fu, Julie Keefer, Anna Vildhede, Chester Costales, A David Rodrigues, Manthena Varma
Tolbutamide is primarily metabolized by cytochrome P450 (CYP)2C9, and thus, frequently applied as a clinical probe substrate for CYP2C9 activity. However, there is a marked discrepancy in the in vitro-in vivo extrapolation of its metabolic clearance implying potential for additional clearance mechanisms. The goal of this study was to evaluate the role of hepatic uptake transport in the pharmacokinetics of tolbutamide and identify the molecular mechanism thereof. Transport studies using singly-transfected cells expressing six major hepatic uptake transporters showed that tolbutamide is a substrate to organic anion transporter (OAT)2 alone -- with transporter affinity (Km) of 19...
January 11, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29326088/age-effects-of-distinct-immune-checkpoint-blockade-treatments-in-a-mouse-melanoma-model
#16
Álvaro Padrón, Vincent Hurez, Harshita B Gupta, Curtis A Clark, Sri Lakshmi Pandeswara, Bin Yuan, Robert S Svatek, Mary Jo Turk, Justin M Drerup, Rong Li, Tyler J Curiel
Cancer immunotherapy has shown remarkable recent progress. Immune checkpoint blocking antibodies have become the most successful anti-cancer agent class ever developed, with six distinct agents approved since 2011 for a wide variety of cancers. Although age is the biggest risk factor for cancer (aside from selected early-onset pediatric cancers), these agents were tested pre-clinically in young hosts, and there is remarkably little published on the effects of host age on treatment outcomes in pre-clinical studies or human clinical trials...
January 8, 2018: Experimental Gerontology
https://www.readbyqxmd.com/read/29324738/population-structure-analysis-of-the-neglected-parasite-thelazia-callipaeda-revealed-high-genetic-diversity-in-eastern-asia-isolates
#17
Xi Zhang, Ya Li Shi, Lu Lu Han, Chen Xiong, Shi Qi Yi, Peng Jiang, Zeng Xian Wang, Ji Long Shen, Jing Cui, Zhong Quan Wang
BACKGROUND: Thelazia callipaeda is the causative agent of thelaziasis in canids, felids and humans. However, the population genetic structure regarding this parasite remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we first explored the genetic variation of 32 T. callipaeda clinical isolates using the following multi-molecular markers: cox1, cytb, 12S rDNA, ITS1 and 18S rDNA. The isolates were collected from 13 patients from 11 geographical locations in China...
January 11, 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29324626/vascular-effects-of-adrenomedullin-and-the-anti-adrenomedullin-antibody-adrecizumab-in-sepsis
#18
Christopher Geven, Andreas Bergmann, Matthijs Kox, Peter Pickkers
Sepsis remains a major scientific and medical challenge, for which, apart from significant refinements in supportive therapy, treatment has barely changed over the last few decades. During sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock. The free circulating peptide adrenomedullin (ADM) is involved in regulation of the endothelial barrier function and tone of blood vessels. Several animal studies have shown that ADM administration improves outcome of sepsis...
January 10, 2018: Shock
https://www.readbyqxmd.com/read/29323621/vaccines-for-the-paramyxoviruses-and-pneumoviruses-successes-candidates-and-hurdles
#19
Charles J Russell, Eric A F Simões, Julia L Hurwitz
Human parainfluenza viruses (family Paramyxoviridae), human metapneumovirus, and respiratory syncytial virus (family Pneumoviridae) infect most infants and children within the first few years of life and are the etiologic agents for many serious acute respiratory illnesses. These virus infections are also associated with long-term diseases that impact quality of life, including asthma. Despite over a half-century of vaccine research, development, and clinical trials, no vaccine has been licensed to date for the paramyxoviruses or pneumoviruses for the youngest infants...
January 11, 2018: Viral Immunology
https://www.readbyqxmd.com/read/29323238/human-complement-receptor-type-1-cr1-protein-levels-and-genetic-variants-in-chronic-chagas-disease
#20
Thaisa Lucas Sandri, Kárita Cláudia Freitas Lidani, Fabiana Antunes Andrade, Christian G Meyer, Peter G Kremsner, Iara J de Messias-Reason, Thirumalaisamy P Velavan
Complement is an essential element in both innate and acquired immunity contributing to the immunopathogenesis of many disorders, including Chagas Disease (CD). Human complement receptor 1 (CR1) plays a role in the clearance of complement opsonized molecules and may facilitate the entry of pathogens into host cells. Distinct CR1 exon 29 variants have been found associated with CR1 expression levels, increased susceptibility and pathophysiology of several diseases. In this study, CR1 plasma levels were assessed by ELISA and CR1 variants in exon 29 by sequencing in a Brazilian cohort of 232 chronic CD patients and 104 healthy controls...
January 11, 2018: Scientific Reports
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