tbuckley/cabot-search huggingface dataset:
Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3β/β-catenin pathway
Authors: Shu-Jie Zhao, Fan-Qi Kong, Jian Jie, Qing Li, Hao Liu, An-Di Xu, Ya-Qing Yang, Bin Jiang, Dong-Dong Wang, Zhong-Qiu Zhou, Peng-Yu Tang, Jian Chen, Qian Wang, Zheng Zhou, Qi Chen, Guo-Yong Yin, Han-Wen Zhang, Jin Fan
Journal: Theranostics (2019)

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. Methods: The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo. The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. Results: In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3β/β-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. Conclusion: Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.
SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited cobalamin disorders
Authors: Rose Ghemrawi, Carole Arnold, Shyue-Fang Battaglia-Hsu, Grégory Pourié, Isabelle Trinh, Christine Bassila, Charif Rashka, Arnaud Wiedemann, Justine Flayac, Aurélie Robert, Natacha Dreumont, François Feillet, Jean-Louis Guéant, David Coelho
Journal: Metabolism (2019)
Extracellular vesicle-based drug delivery systems for cancer treatment
Authors: Sierra Walker, Sara Busatto, Anthony Pham, Ming Tian, Annie Suh, Kelsey Carson, Astrid Quintero, Maria Lafrence, Hanna Malik, Moises X Santana, Joy Wolfram
Journal: Theranostics (2019)

Extracellular vesicles (EVs) are naturally occurring cell-secreted nanoparticles that play important roles in many physiological and pathological processes. EVs enable intercellular communication by serving as delivery vehicles for a wide range of endogenous cargo molecules, such as RNAs, proteins, carbohydrates, and lipids. EVs have also been found to display tissue tropism mediated by surface molecules, such as integrins and glycans, making them promising for drug delivery applications. Various methods can be used to load therapeutic agents into EVs, and additional modification strategies have been employed to prolong circulation and improve targeting. This review gives an overview of EV-based drug delivery strategies in cancer therapy.
Control of Meiotic and Mitoic Progression by the F-Box Protein NIPA In Vivo.
Authors: Anna L. Illert, Hiroyuki Kawaguchi, Letitia Quintanilla-Fend, Florian Bassermann, Christine von Klitzing, Petra Seipel, Misuteru Hiwatari, Stephan W. Morris, Christian Peschel, Duyster Justus
Journal: Blood (2006)
Improved patient access and outcomes with the integration of an eConsult program (teledermatology) within a large academic medical center
Authors: Rebecca F. Wang, John Trinidad, Jeffrey Lawrence, Llana Pootrakul, L. Arick Forrest, Kevin Goist, Edward Levine, Shalina Nair, Milisa Rizer, Andrew Thomas, Randell Wexler, Benjamin H. Kaffenberger
Journal: Journal of the American Academy of Dermatology (2019)
Helen Salisbury: Ageing and inequality
Authors: Helen Salisbury
Journal: BMJ (2019)

“Don’t get old, doctor,” my patients often advise me. However, we always end up agreeing that the alternative is worse. When patients in their 90s complain that they can no longer manage the two mile walk into town and the two miles back without their knees hurting, I try to avoid any “so wonderful for your age” comments, which they must hear repeatedly. Instead, we discuss painkillers and why they probably don’t need surgery yet. These patients are impressive women (and the occasional man), often caring for others and being lynchpins of the community.

If you work …
BMJ Awards 2020: nominations open with four new categories including climate action and women’s health
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Nominations have opened for the 2020 BMJ Awards, which will once again celebrate outstanding achievements in medicine.

Doctors have until Friday 17 January 2020 to submit entries on behalf of themselves or colleagues. This year the awards have 16 categories, including four new ones, across a range of specialties and domains.

Now in their 12th year, the awards recognise the inspirational work of healthcare teams around the country and …
Cardiometabolic risk in survivors of childhood cancer who received hematopoietic cell transplant (HCT)
Authors: K. S. Baker, A. S. Kelly, A. Petryk, A. R. Sinaiko, L. M. Steffen, A. Moran, D. Mulrooney, D. R. Dengel, K. Gujral, X. Zhou, J. Steinberger
Journal: Journal of Clinical Oncology (2009)

6532 Background: Evidence suggests that survivors of childhood cancer are at increased risk for cardiovascular disease (CVD) and type 2 diabetes with even higher risk in those who received HCT. The purpose of this study was to compare the cardiometabolic risk factor profile in HCT patients and healthy sibling controls. Methods: Measures of insulin resistance (euglycemic hyperinsulinemic clamp adjusted for lean body mass [Mlbm], low Mlbm represents insulin resistance), fasting glucose, insulin, lipids, anthropometry, blood pressure (BP), and carotid artery compliance and distensibility (lower values represent arterial stiffness) were determined in 87 children and young adults (current age 27.3 yr, 57% male) who had received HCT for hematologic malignancy during childhood (mean age at HCT 11.8 yr) and 55 healthy sibling controls (current age=25.2 yr, 51% male). Linear regression models were used to evaluate risk factors between groups after adjusting for age, gender, pubertal stage, body mass index (BMI), and carotid lumen diameter (stiffness measures only). Results: Metabolic syndrome (ATP III criteria for adults, modified criteria for children) was present in 13 (14.9%) HCT survivors and 4 (7.3%) controls (p=0.19). Thirty-one (35.6%) survivors and 9 (16.4%) controls had two or more components of the metabolic syndrome (p=0.11). There were no differences between groups for BMI, waist circumference, percent body fat, or BP. HCT survivors had higher triglycerides, fasting glucose and insulin, lower HDL cholesterol, arterial distensibility, and were more insulin resistant (Table). Conclusions: HCT survivors have increased cardiometabolic risk factors independent of obesity suggesting that cancer itself and/or associated treatment exposures have a direct influence on CVD risk and that early screening and management of cardiometabolic risk factors should be considered in HCT survivors. [Table: see text] No significant financial relationships to disclose.
Abstract #2702: Morinda citrifolia (Noni) induces apoptosis via the TLR4 pathway in breast cancer cells
Authors: Sabrenia Parker, Tisheeka Steed, Tongrui Liu, Ruth O'Regan, Myron Williams, Kevin Kimbro
Journal: Cancer Research (2009)

Morinda citrifolia (Noni) is a popular complementary and alternative medicine (CAM)-related botanical. This tropical tree has been used as a food supplement and as herbal medicine throughout the Pacific for over 2000 years. The nutraceuticals in Noni extracts may enhance cancer treatment; however, the underlying molecular mechanism(s) of action has not been clearly delineated. With the long-term goal of improving clinical management of breast cancer (BrCa), the current proposal seeks to dissect the molecular mechanisms of Noni on BrCa cells via the toll-like receptor 4 (TLR4) pathway. We show that a butanol (BuOH) extract (>1mg/ml) from Noni (e.g. BuNoni) has a cytotoxic effect on BrCa cells i.e., MDA-MB-231, in vitro. Microarray analysis of MDA-MB-231 cells treated with 1mg/ml BuNoni for 2 hours, indicate the toll-like receptor pathway as a target for the BuNoni extract. This action is supported by the inhibition of cell death via a TLR4 antagonist, Rhodobacter sphaeroides lipopolysaccaride (LPS-RS) in a dose dependent manner. The 2 mg/ml BuNoni treatment exhibited a greater than 50% cell death at 48 hours, but the cell recovery rises to more than 64% survival of the control when LPS-RS is used in conjunction with BuNoni treatment. Further analysis support the mechanism of cell death through a lack of necrosis activity as measured by lactate dehydrogenase release and as seen in FACS analysis with 68.8% of cells undergoing early and late stage apoptosis using 2 mg/ml BuNoni treatment and approximately 21.52% apoptosis when BuNoni treatment is used in combination with LPS-RS. Taken together, these results indicate that a butanol extract of Noni is cytotoxic to BrCa cells by enhancing apoptosis through interaction with TLR4.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2702.
Hypersensitivity pneumonitis: Main features characterization in a Portuguese cohort
Authors: V. Santos, N. Martins, C. Sousa, M. Jacob, E. Padrão, N. Melo, P. Caetano Mota, H.N. Bastos, S. Guimarães, C. Souto Moura, O. Sokhatska, R. Cunha, J. Pereira, A. Morais
Journal: Pulmonology (2019)

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) which varies in prevalence across the world, depending on disease definition, diagnostic methods, exposure type and intensity, geographical environments, agricultural and industrial practices, and host risk factors. This study aimed to deepen knowledge about HP's clinical characteristics, diagnosis and functional and imaging features in a cohort of HP patients from the North of Portugal. To achieve this goal, a retrospective assessment of the clinical and diagnostic data was carried out, and patients were classified and compared according to disease presentation (acute, sub-acute and chronic HP forms). Of the 209 HP patients included (mean age 58.3 ± 16.0 years), 52.6% were female and 73.7% presented a chronic form. Most patients had prior exposure to birds (76.6%). Dyspnoea and cough were the most frequently experienced symptoms, but no statistically significant differences were found between groups (p = 0.089, p = 0.418, respectively). Fever was most common in acute HP form (p < 0.001). The most common patterns found in Chest CT were ground glass (p = 0.002) in acute/subacute presentation, and reticulation (p < 0.001) in chronic form, while mosaic attenuation, although was also frequently observed, no statistically significant differences were found between groups (p = 0.512). The most common functional pattern was restrictive (38% of patients, 73.7% with chronic HP form). Bronchoalveolar lavage lymphocytes were higher in acute and subacute forms although not reaching statistical significance (p = 0.072), with lowest CD4/CD8 ratio (p = 0.001) in acute forms. Thus, given the significant disease heterogeneity, further studies with different populations and ambient exposures are needed to achieve a better stratification of the exposure risk, to provide proper implementation of avoidance methods and a precise diagnostic and therapeutic approach.
Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia
Authors: Libin Pan, Pei Han, Shurong Ma, Ran Peng, Can Wang, Weijia Kong, Lin Cong, Jie Fu, Zhengwei Zhang, Hang Yu, Yan Wang, Jiandong Jiang
Journal: Acta Pharmaceutica Sinica B (2019)

The progression of hyperuricemia disease is often accompanied by damage to renal function. However, there are few studies on hyperuricemia nephropathy, especially its association with intestinal flora. This study combines metabolomics and gut microbiota diversity analysis to explore metabolic changes using a rat model as well as the changes in intestinal flora composition. The results showed that amino acid metabolism was disturbed with serine, glutamate and glutamine being downregulated whilst glycine, hydroxyproline and alanine being upregulated. The combined glycine, serine and glutamate could predict hyperuricemia nephropathy with an area under the curve of 1.00. Imbalanced intestinal flora was also observed. Flavobacterium, Myroides, Corynebacterium, Alcaligenaceae, Oligella and other conditional pathogens increased significantly in the model group, while Blautia and Roseburia, the short-chain fatty acid producing bacteria, declined greatly. At phylum, family and genus levels, disordered nitrogen circulation in gut microbiota was detected. In the model group, the uric acid decomposition pathway was enhanced with reinforced urea liver-intestine circulation. The results implied that the intestinal flora play a vital role in the pathogenesis of hyperuricemia nephropathy. Hence, modulation of gut microbiota or targeting at metabolic enzymes, i.e., urease, could assist the treatment and prevention of this disease.
Schizophrenia—An Overview
Authors: Robert A. McCutcheon, Tiago Reis Marques, Oliver D. Howes
Journal: JAMA Psychiatry (2019)

<h3>Importance</h3> Schizophrenia is a common, severe mental illness that most clinicians will encounter regularly during their practice. This report provides an overview of the clinical characteristics, epidemiology, genetics, neuroscience, and psychopharmacology of schizophrenia to provide a basis to understand the disorder and its treatment. This educational review is integrated with a clinical case to highlight how recent research findings can inform clinical understanding. <h3>Observations</h3> The first theme considered is the role of early-life environmental and genetic risk factors in altering neurodevelopmental trajectories to predispose an individual to the disorder and leading to the development of prodromal symptoms. The second theme is the role of cortical excitatory-inhibitory imbalance in the development of the cognitive and negative symptoms of the disorder. The third theme considers the role of psychosocial stressors, psychological factors, and subcortical dopamine dysfunction in the onset of the positive symptoms of the disorder. The final theme considers the mechanisms underlying treatment for schizophrenia and common adverse effects of treatment. <h3>Conclusions and Relevance</h3> Schizophrenia has a complex presentation with a multifactorial cause. Nevertheless, advances in neuroscience have identified roles for key circuits, particularly involving frontal, temporal, and mesostriatal brain regions, in the development of positive, negative, and cognitive symptoms. Current pharmacological treatments operate using the same mechanism, blockade of dopamine D<sub>2</sub>receptor, which contribute to their adverse effects. However, the circuit mechanisms discussed herein identify novel potential treatment targets that may be of particular benefit in symptom domains not well served by existing medications.
A Novel Role for Factor VIII and Other Coagulation Factors in Organ Size Control
Authors: Anna Aronovich, Dalit Tchorsh, Elias Shezen, Chava Rosen, Yael Klionsky, Sivan Cohen, Orna Tal, Uri Martinovich, Helena Katchman, Smadar Eventov-Friedman, Ninette Amariglio, Jasmine Jacob-Hirsch, Gideon Rechavi, Yair Reisner
Journal: Blood (2008)
Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses
Authors: Min-Nung Huang, Lowell T. Nicholson, Kristen A. Batich, Adam M. Swartz, David Kopin, Sebastian Wellford, Vijay K. Prabhakar, Karolina Woroniecka, Smita K. Nair, Peter E. Fecci, John H. Sampson, Michael D. Gunn
Journal: Journal of Clinical Investigation (2019)

Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic CD8+ DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43-containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction-mediated Ag transfer pathway between monocytes and CD8+ DCs and suggest that administration of tumor Ag-loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers.
Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles
Authors: Velislava N. Petrova, Bevan Sawatsky, Alvin X. Han, Brigitta M. Laksono, Lisa Walz, Edyth Parker, Kathrin Pieper, Carl A. Anderson, Rory D. de Vries, Antonio Lanzavecchia, Paul Kellam, Veronika von Messling, Rik L. de Swart, Colin A. Russell
Journal: Science Immunology (2019)

Measles causes immunosuppression by restricting naïve B cell diversity and eliminating previously established B memory cells.
HLSC-Derived Extracellular Vesicles Attenuate Liver Fibrosis and Inflammation in a Murine Model of Non-alcoholic Steatohepatitis
Authors: Stefania Bruno, Chiara Pasquino, Maria Beatriz Herrera Sanchez, Marta Tapparo, Federico Figliolini, Cristina Grange, Giulia Chiabotto, Massimo Cedrino, Maria Chiara Deregibus, Ciro Tetta, Giovanni Camussi
Journal: Molecular Therapy (2019)

Extracellular vesicles (EVs) are membrane vesicles released virtually by all cell types. Several studies have shown that stem cell-derived EVs may mimic both in vitro and in vivo the biological effects of the cells. We recently demonstrated that non-alcoholic steatohepatitis (NASH) is inhibited by treatment with human liver stem cells (HLSCs). The aim of the present study was to evaluate whether EVs released by HLSCs influence the progression of NASH, induced by a diet deprived of methionine and choline, in immunocompromised mice. EV treatment was initiated after 2 weeks of diet with a biweekly administration of three different doses. Bio-distribution evaluated by optical imaging showed a preferential accumulation in normal and, in particular, in fibrotic liver. EV treatment significantly improved liver function and reduced signs of liver fibrosis and inflammation at both morphological and molecular levels. In particular, we observed that, out of 29 fibrosis-associated genes upregulated in NASH liver, 28 were significantly downregulated by EV treatment. In conclusion, HLSC-derived EVs display anti-fibrotic and anti-inflammatory effects in a model of chronic liver disease, leading to an improvement of liver function. Extracellular vesicles (EVs) are membrane vesicles released virtually by all cell types. Several studies have shown that stem cell-derived EVs may mimic both in vitro and in vivo the biological effects of the cells. We recently demonstrated that non-alcoholic steatohepatitis (NASH) is inhibited by treatment with human liver stem cells (HLSCs). The aim of the present study was to evaluate whether EVs released by HLSCs influence the progression of NASH, induced by a diet deprived of methionine and choline, in immunocompromised mice. EV treatment was initiated after 2 weeks of diet with a biweekly administration of three different doses. Bio-distribution evaluated by optical imaging showed a preferential accumulation in normal and, in particular, in fibrotic liver. EV treatment significantly improved liver function and reduced signs of liver fibrosis and inflammation at both morphological and molecular levels. In particular, we observed that, out of 29 fibrosis-associated genes upregulated in NASH liver, 28 were significantly downregulated by EV treatment. In conclusion, HLSC-derived EVs display anti-fibrotic and anti-inflammatory effects in a model of chronic liver disease, leading to an improvement of liver function.
The Landscape of Atypical and Eukaryotic Protein Kinases
Authors: Georgi K. Kanev, Chris de Graaf, Iwan J.P. de Esch, Rob Leurs, Thomas Würdinger, Bart A. Westerman, Albert J. Kooistra
Journal: Trends in Pharmacological Sciences (2019)

Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.
U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation
Authors: Koji Haratani, Kimio Yonesaka, Shiki Takamura, Osamu Maenishi, Ryoji Kato, Naoki Takegawa, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, Masayuki Takeda, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Junji Tsurutani, Kazuto Nishio, Katsumi Doi, Masaaki Miyazawa, Kazuhiko Nakagawa
Journal: Journal of Clinical Investigation (2019)

Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3–targeting (HER3–targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.