tbuckley/cabot-search huggingface dataset:
A pharmaceutical answer to nonadherence: Once weekly oral memantine for Alzheimer's disease
Authors: Rosemary Kanasty, Susan Low, Nupura Bhise, Jung Yang, Erick Peeke, Marlene Schwarz, James Wright, Bennett Carter, Saumya Moorthy, Tyler Grant, Ben DeBenedictis, Megan Bishoff, Craig Simses, Andrew M. Bellinger
Journal: Journal of Controlled Release (2019)

Adherence to medication regimens is a major barrier to effective treatment in many disease areas, notably in dementia which causes cognitive impairment that reduces patients' awareness of non-adherence and their ability to manage medication. The development of oral dosage forms that can be infrequently dosed, and therefore improve adherence rate and facilitate direct observed therapy, has been a goal for decades. We describe the first demonstration of an oral formulation that achieves >7-day gastric retention and sustained pharmacokinetics in the challenging dog model. Gastric retention requires physical resistance of the dosage form to gastric emptying forces, which are known to be stronger in dogs than in humans, making successful gastric retention in dogs a stringent test for predicting human translatability. This formulation of memantine hydrochloride is the first oral dosage form that achieves multi-day drug release with near zero-order kinetics and efficient delivery. In the dog model, relative memantine bioavailability approaches 100% with sustained plasma levels of memantine over seven days and profiles that can be tuned by varying components of the formulation. A single gastric resident dosage form achieves an AUC equivalent to 7 daily treatments with the marketed daily capsule, with a Cmax that is no higher than the daily product. PK modeling predicts that the gastroretentive formulation will maintain therapeutic blood levels in humans when administered once weekly. The formulation methodology presented here is applicable to many water soluble drugs and may enable the development of long-acting oral therapies for a wide variety of conditions.
Adrenaline and non-life threatening allergic reactions [2] (multiple letters)
Authors: Jo A. Douglass, Robyn E. O'Hehir, Daniela Zauli, Sara Zucchini, Alberto Grassi, Giorgio Ballardini, Francesco B. Bianchi, Sarah L. Johnston, Joe Unsworth, Mark M. Gompels
Journal: BMJ (2003)
Detect or not to detect very early stage hepatocellular carcinoma? The western perspective
Authors: Ju Dong Yang
Journal: Clinical and Molecular Hepatology (2019)

Very early stage hepatocellular carcinoma (HCC) is defined as a single tumor with the largest diameter of the lesion measuring 2 cm or less according to Barcelona Liver Cancer staging system. Detection of very early stage HCC is clinically important as it confers an excellent prognosis with the 5-year survival rates over 60 to 80% after patients receive curative treatments. While diagnosing HCC at a very early stage is crucial, it is technically challenging and may come with the physical or psychosocial harms related to diagnostic tests. It is further complicated by the fact that patients with very early stage HCC are not prioritized for liver transplant (LT) in the United States organ allocation system. When LT-eligible patients present with an indeterminate lesion measuring between 1 and 2 cm on the multiphasic computed tomography or magnetic resonance imaging, clinicians often observe patients carefully until the lesion grows up to 2 cm so that patients can be eligible to receive a Model for End-Stage Liver Disease (MELD) exception score for HCC in the United States. The European guideline recommends a routine biopsy of such lesion. In conclusion, attempting to detect very early stage HCC is difficult to achieve and controversial. Clinicians should take into account of the risk and the benefit of diagnostic tests, LT candidacy of patients and the local organ allocation system.
Magnetic Strategies for Nervous System Control
Authors: Michael G. Christiansen, Alexander W. Senko, Polina Anikeeva
Journal: Annual Review of Neuroscience (2019)

Magnetic fields pass through tissue undiminished and without producing harmful effects, motivating their use as a wireless, minimally invasive means to control neural activity. Here, we review mechanisms and techniques coupling magnetic fields to changes in electrochemical potentials across neuronal membranes. Biological magnetoreception, although incompletely understood, is discussed as a potential source of inspiration. The emergence of magnetic properties in materials is reviewed to clarify the distinction between biomolecules containing transition metals and ferrite nanoparticles that exhibit significant net moments. We describe recent developments in the use of magnetic nanomaterials as transducers converting magnetic stimuli to forms readily perceived by neurons and discuss opportunities for multiplexed and bidirectional control as well as the challenges posed by delivery to the brain. The variety of magnetic field conditions and mechanisms by which they can be coupled to neuronal signaling cascades highlights the desirability of continued interchange between magnetism physics and neurobiology.
Abstract 15380: Implication of the Transcription Factor FOXM1 in Pulmonary Arterial Hypertension
Authors: Caroline Lambert, Alice Bourgeois, Isabelle Trinh, Sandra Breuils-Bonnet, Valerie Nadeau, Guofei Zhou, Olivier Boucherat
Journal: Circulation (2017)

Introduction: Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature, defined by an elevated pulmonary vascular resistance, leading to right heart failure and premature death. PAH is characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis within pulmonary artery (PA) wall. Targeting the cancer-like of PASMCs represents an attractive therapeutic avenue to tackle PAH. The transcription factor FOXM1 is necessary for PASMC proliferation during lung morphogenesis and its overexpression is a key driver of cancer progression through the stimulation of DNA repair, cell proliferation and cell survival. Therefore, we hypothesized that FOXM1 expression is increased in PAH-PASMCs and contributes to vascular remodeling in PAH. Hypothesis: Using a multidisciplinary and translational approach we aimed to demonstrate that up-regulation of FOXM1 in PAH-PASMCs triggers proliferation and resistance to apoptosis. Methods and Results: FOXM1 is significan...
Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma
Authors: Rui-Yan Wu, Peng-Fei Kong, Liang-Ping Xia, Yun Huang, Zhi-Ling Li, Yun-Yun Tang, Yu-Hong Chen, Xuan Li, Ravichandran Senthilkumar, Hai-Liang Zhang, Ting Sun, Xue-Lian Xu, Yan Yu, Jia Mai, Xiao-Dan Peng, Dong Yang, Li-Huan Zhou, Gong-Kan Feng, Rong Deng, Xiao-Feng Zhu
Journal: Clinical Cancer Research (2019)

Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity.Flow cytometry-based screening was performed to identify kinase inhibitors that can block the IFNγ-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti-PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFNγ or ICB. By targeting the RET-Src axis, regorafenib potently inhibited JAK1/2-STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response.Our data unveiled a new mechanism of alleviating IFNγ-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.
Neurobiology of Self-Regulation: Longitudinal Influence of <i>FKBP5</i> and Intimate Partner Violence on Emotional and Cognitive Development in Childhood
Authors: Thorhildur Halldorsdottir, Dunja Kurtoic, Bertram Müller-Myhsok, Elisabeth B. Binder, Clancy Blair
Journal: American Journal of Psychiatry (2019)

Self-regulation includes the volitional and nonvolitional regulation of emotional, cognitive, and physiological responses to stimulation. It develops from infancy through individual characteristics and the environment, with the stress hormone system as a central player. Accordingly, the authors hypothesized that genes involved in regulating the stress system, such as FK506 binding protein 5 (FKBP5), interact with early-life stress exposure, such as exposure to intimate partner violence (IPV), to predict self-regulation indicators and associated outcomes, including behavioral and learning problems in school.Study participants were a longitudinal birth cohort of 910 children for whom FKBP5 genotypes were available and who were assessed for exposure to IPV during the first 2 years of life as well as multiple measures of self-regulation: stress-induced cortisol reactivity and fear-elicited emotional reactivity at 7, 15, and 24 months, executive function at 36, 48, and 60 months, and emotional and behavioral difficulties and reading and math achievement in school grades 1, 2, and 5. Data were analyzed using longitudinal clustering and ordinal logistic regression procedures followed by mixed linear modeling.Children with two copies of a risk FKBP5 haplotype and IPV exposure were significantly more likely to have a developmental trajectory characterized by high, prolonged stress-induced cortisol reactivity and emotional reactivity in toddlerhood, followed by low executive function at school entry and high emotional and behavior problems and low reading ability in the primary school grades.The interaction of FKBP5 and IPV affects the physiological response to stress early in life, with consequences for emotional and cognitive self-regulation. Targeting self-regulation may present an early intervention strategy for children facing genetic and environmental risk.
Genomic subtyping and therapeutic targeting of acute erythroleukemia
Authors: Ilaria Iacobucci, Ji Wen, Manja Meggendorfer, John K. Choi, Lei Shi, Stanley B. Pounds, Catherine L. Carmichael, Katherine E. Masih, Sarah M. Morris, R. Coleman Lindsley, Laura J. Janke, Thomas B. Alexander, Guangchun Song, Chunxu Qu, Yongjin Li, Debbie Payne-Turner, Daisuke Tomizawa, Nobutaka Kiyokawa, Marcus Valentine, Virginia Valentine, Giuseppe Basso, Franco Locatelli, Eric J. Enemark, Shirley K. Y. Kham, Allen E. J. Yeoh, Xiaotu Ma, Xin Zhou, Edgar Sioson, Michael Rusch, Rhonda E. Ries, Elliot Stieglitz, Stephen P. Hunger, Andrew H. Wei, L Bik To, Ian D. Lewis, Richard J. D’Andrea, Benjamin T. Kile, Anna L. Brown, Hamish S. Scott, Christopher N. Hahn, Paula Marlton, Deqing Pei, Cheng Cheng, Mignon L. Loh, Benjamin L. Ebert, Soheil Meshinchi, Torsten Haferlach, Charles G. Mullighan
Journal: Nature Genetics (2019)
Abstract GS1-02: Towards a human breast cell atlas
Authors: TK Seth, S Bai, M Hu, E Sei, A Wood, J Wiley, H Chen, A Contreras, M Teshome, B Lim, NE Navin
Journal: Cancer Research (2019)

Abstract The human breast tissue consists of lobules connected to a complex network of ducts that are evolutionarily designed to produce and transport milk to nourish offspring. Histopathology has identified 10 major cell types based on morphological features but have provided limited information on cell states - the transcriptional programs of cell types that reflect different biological functions. In this study, we have generated an unbiased 'cell atlas' of the normal human breast to define the cell types and cell states using single cell RNA sequencing methods. We performed 3' microdroplet based single cell RNA sequencing of 31,442 stromal cells from 11 women with pathologically normal breast tissues that were collected from mastectomies. Unbiased expression analysis identified three major cell types: epithelial cells (luminal and basal), fibroblasts and endothelial cells, in addition to several minor cell types: macrophages, T-cells, natural killer cells, pericytes and smooth muscle cells. Analysis of cell states of these cell types revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types. These data provide a valuable reference for the research community and will provide new insights into how normal cell types are transformed in the tumor microenvironment to promote or inhibit the progression of breast cancer. Citation Format: Seth TK, Bai S, Hu M, Sei E, Wood A, Wiley J, Chen H, Contreras A, Teshome M, Lim B, Navin NE. Towards a human breast cell atlas [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-02.
J Roger Owen
Authors: Sean Elyan, John Yarnold
Journal: BMJ (2019)

J Roger Owen trained in clinical oncology at the Middlesex and the Royal Marsden hospitals. He spent a year of his training in Paris, where he worked with Professor Bernard Pierquin and became expert in newly developed techniques of brachytherapy. Roger started work in Gloucestershire’s oncology centre in 1981. He brought with him a range of clinical skills learnt in London and Paris and critical research links with the Royal Marsden Hospital.

Invigorating this small cancer centre, he modernised treatment techniques across all modalities. He introduced a brachytherapy service, which he personally delivered with immense skill, and became the joint director of a successful international brachytherapy teaching course. He forged clinical and research links in Herefordshire and Worcestershire that ultimately led to the Three Counties Cancer Centre, with its heart in Cheltenham. As the founding clinical lead of the cancer network of the same name, he was instrumental in the burgeoning …
Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia
Authors: Alak Manna, Sonikpreet Aulakh, Prachi Jani, Salman Ahmed, Sharoon Akhtar, Marie Coignet, Michael Heckman, Zahara Meghji, Kirtipal Bhatia, Aarushi Sharma, Taimur Sher, Victoria Alegria, Fabio Malavasi, Eduardo N. Chini, Asher Chanan-Khan, Sikander Ailawadhi, Aneel Paulus
Journal: Clinical Cancer Research (2019)

CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied.We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT.In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model.Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.
Chemicals in Consumer Products Associated With Early Puberty
Authors: Jennifer Abbasi
Journal: JAMA (2019)

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Abstract 15222: Increased Risk of Cancer Death in Patients With Chronic Heart Failure -A Report From the CHART-2 Study-
Authors: Takuya Oikawa, Yasuhiko Sakata, Kotaro Nochioka, Masanobu Miura, Ruri Abe, Shintaro Kasahara, Masayuki Sato, Hajime Aoyanagi, Takashi Shiroto, Jun Takahashi, Satoshi Miyata, Hiroaki Shimokawa
Journal: Circulation (2017)

Introduction: Recent studies have reported that heart failure (HF) patients are at increased risk of cancer. However, no studies have examined the relationship between HF and cancer mortality. In t...
Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation
Authors: Claire D. Bourke, Ethan K. Gough, Godfrey Pimundu, Annie Shonhai, Chipo Berejena, Louise Terry, Lucas Baumard, Naheed Choudhry, Yusuf Karmali, Mutsa Bwakura-Dangarembizi, Victor Musiime, Joseph Lutaakome, Adeodata Kekitiinwa, Kuda Mutasa, Alexander J. Szubert, Moira J. Spyer, Jane R. Deayton, Magdalena Glass, Hyun Min Geum, Claire Pardieu, Diana M. Gibb, Nigel Klein, Thaddeus J. Edens, A. Sarah Walker, Amee R. Manges, Andrew J. Prendergast
Journal: Science Translational Medicine (2019)

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.
Risk factors for treatment failure in scabies
Authors: A. Aussy, E. Houivet, V. Hébert, H. Colas‐Cailleux, N. Laaengh, C. Richard, M. Ouvry, C. Boulard, S. Léger, N. Litrowski, J. Benichou, P. Joly
Journal: British Journal of Dermatology (2019)

Scabies is a major health problem worldwide. In developing countries, it can become infected, leading to heart and kidney disease. The prevalence of scabies is also increasing in developed countries, affecting 2‐4% of the population in Europe and USA. This is partly due to inadequate treatment. Reasons for treatment failure have been studied in hospitalised or bedbound patients, such as those with dementia in nursing homes, who are at high risk of scabies. However, treatment failure has not been studied in ambulatory individuals (i.e. who are mobile), who represent the majority of patients. The authors, based in university dermatology and biostatistics departments in Rouen, France, sought to identify predictors of treatment failure in patients who attended hospital or private dermatology clinics with a clinical diagnosis of scabies. They studied 210 patients, 98 of whom had been successfully treated and 112 who had evidence of persistent scabies 3 months after treatment. They found that a major cause of treatment failure was the use of only topical treatment (applied to the skin) with benzyl benzoate, or oral treatment (taken by mouth) with ivermectin, rather than a combination of the two. Another major cause was the use of a single dose of ivermectin rather than two consecutive doses. Other reasons for treatment failure included taking ivermectin with food rather than on an empty stomach, as recommended, inadequate treatment of relatives and close contacts, lack of written information about treatment and, perhaps, inadequate decontamination of furniture (a controversial subject). Increased frequency of application of benzyl benzoate did not seem to affect outcome, and the authors did not recommend this because of its irritancy. In conclusion, the authors felt there is a case for two consecutive doses of oral ivermectin rather than one, in addition to topical treatment. This has relevance worldwide, since single dose ivermectin is the recommended treatment in some countries.