tbuckley/cabot-search huggingface dataset:
Fructose-1,6-bisphosphatase loss modulates STAT3-dependent expression of PD-L1 and cancer immunity
Authors: Bo Wang, Yingke Zhou, Jun Zhang, Xin Jin, Heshui Wu, Haojie Huang
Journal: Theranostics (2019)

Rationale: Abnormal expression of programmed death-1 (PD-1) ligand-1(PD-L1) in cancer cells plays a crucial role in cancer immune evasion and progression.The immune checkpoint molecules PD-1 and PD-L1 have been targeted for cancer treatment with significant benefits for cancer patients.However, the response rate is relatively low in certain types of cancer and the underlying mechanism remains poorly understood.Better understanding of the molecular mechanism of PD-L1 expression regulation in cancer cells is urgently needed to improve the treatment response rate and overall survival of patients.Fructose-1, 6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is implicated in human cancer due to its frequent loss in various cancer types.Methods: Expression of FBP1 and PD-L1 was analyzed in various cancer cell lines.Western blot and RT-qPCR were performed to determine whether FBP1 regulates PD-L1 expression.Co-immunoprecipitation and glutathione S-transferase (GST) pulldown assay were employed to define the underlying regulatory mechanisms.Immunohistochemistry was conducted to determine the correlation between FBP1 and PD-L1 expression in a cohort of patients.A cancer syngeneic mouse model was utilized to examine how FBP1 affects tumor immunity. Results:We demonstrated that in a manner independent of its enzymatic activity FBP1 downregulates the expression of PD-L1 in various cell lines of different cancer types including pancreatic and prostate cancer.We further showed that this regulation occurs at the transcriptional level and is mediated by FBP1 inhibition of signal transducer and activator of transcription-3 (STAT3)-dependent PD-L1 transcription.Moreover, FBP1 and PD-L1 protein expression were negatively correlated in pancreatic ductal adenocarcinoma (PDAC) specimens from a cohort of patients.Most importantly, we demonstrated that decreased FBP1 expression promotes tumor growth and resistance to immune checkpoint blockade therapy in mice.Conclusions: Our findings reveal a new tumor suppressor function of FBP1 in inhibiting PD-L1 expression and enhancing cancer immunity.They also suggest that FBP1-deficient human cancers could be therapeutically targeted by PD-1/PD-L1-based immune checkpoint blockade therapy.
Preparing for the Next Pandemic — The WHO’s Global Influenza Strategy
Authors: Mark Eccleston-Turner, Alexandra Phelan, Rebecca Katz
Journal: New England Journal of Medicine (2019)

Given the ongoing threat posed by influenza, the WHO earlier this year released its Global Influenza Strategy 2019–2030. Although the strategy is a welcome step, additional challenges will test its effectiveness unless efforts are made to ensure that they are addressed.
Predictable clinical responses to sorafenib in stage IV uveal melanoma.
Authors: Eckhart Kaempgen, Martina Schmid, Michael Erdmann, Petra Keikavoussi, Deike Strobel, Beatrice Schuler-Thurner, Gerold Schuler
Journal: Journal of Clinical Oncology (2012)

e19032 Background: Uveal melanoma is an orphan disease with poor prognosis, once metastasized. There is currently no approved systemic treatment and all clinical trials so far failed to significantly improve OS in stage IV uveal melanoma patients (see results of the EORTC 18021 trial, abstract 95725). Sorafenib is a pleiotropic kinase inhibitor targeting tumor metabolism and related neoangiogenesis. Although sorafenib failed as monotherapy in metastasized melanoma, results from small phase II trials have indicated synergism with chemotherapy in some patients. We therefore offered compassionate use treatment with sorafenib to patients with documented progressive stage IV uveal melanoma after fotemustine iv or HIA treatment (EORTC 18021 trial). Methods: Sorafenib 400 mg orally bid was combined with fotemustine 100 mg/m² at 3 week intervals to treat a total of 7 patients with metastatic uveal melanoma. Patients were closely followed by repeated analyses of serum tumor markers and ultrasound scans of liver metastases. Complete staging by CT/MR scans was done every 3 months. Results: 3 of 7 patients with initially elevated tumormarkers showed an early rapid drop in serum MIA and/or S100 within two weeks of sorafenib treatment followed by partial responses and long term stabilization of the disease up to 20 months. Responder patients could also be identified by a rapid drop in tumorperfusion as shown by contrast enhanced ultrasound of liver metastases. Due to hematologic toxicity treatment had to be modified in all responder patients. Neither reduction of sorafenib dosage to 200 mg orally bid nor omittance of fotemustine treatment resulted in early disease progression, pinpointing potential high sorafenib responsiveness in uveal melanoma patients. Conclusions: Patients with stage IV uveal melanoma may benefit from treatment with the kinase inhibitor sorafenib. Our observations suggest selection of responder patients by early drop of elevated tumor markers S100 / MIA and early drop in tumor perfusion. Stimulated by these data a first phase II trial investigating sorafenib in uveal melanoma patients has been initiated in Germany (ClinicalTrials.gov NCT0137702: A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma (STREAM).
Gender dysphoria: same old media tropes
Authors: Michael J Shaw
Journal: BMJ (2019)

Investigative journalism has an inherent publication bias. Rather than shedding light on the relevant sociopolitical, ethical, and scientific issues, Cohen and Barnes seem to view the complexity of gender dysphoria in adolescence through a narrow media lens.1

Characteristic media tropes, particularly in headlines, use inflammatory or alarmist language, emphasise age or other perceived vulnerability, sometimes use sexualised terms, and focus on interventions …
Creatinine Clearance in Sickle Cell Anemia Is Modulated by Genes in the TGF-β/BMP Pathway.
Authors: Vikki G. Nolan, Anne C. Rybicki, Clinton T. Baldwin, Herbert T. Cohen, Adeboye H. Adewoye, Diego F. Wyszynski, Mary E. Fabry, Ronald L. Nagel, Martin H. Steinberg
Journal: Blood (2005)
Identification of ID4 as a Cooperating Second Hit for T Cell Lymphoma Development in PU.1 UREΔ/Δ Mice.
Authors: Bronwyn M. Owens, Li Yu, Ulrich Steidl, Jeffrey L. Kutok, Linda K. Clayton, Katharina Wagner, Hiromi Iwasaki, Chunhui Liu, Björn Hackanson, Koichi Akashi, Christoph Plass, Daniel G. Tenen, Frank Rosenbauer
Journal: Blood (2005)
Glucose and Counterregulatory Responses to Exercise in Adults With Type 1 Diabetes and Impaired Awareness of Hypoglycemia Using Closed-Loop Insulin Delivery: A Randomized Crossover Study
Authors: Melissa H. Lee, Sara Vogrin, Barbora Paldus, Dilshani Jayawardene, Hannah M. Jones, Sybil A. McAuley, Varuni Obeyesekere, Judith Gooley, André La Gerche, Richard J. MacIsaac, Vijaya Sundararajan, Alicia J. Jenkins, Glenn M. Ward, David N. O’Neal
Journal: Diabetes Care (2019)

To evaluate exercise-related glucose and counterregulatory responses (CRR) in adults with type 1 diabetes with impaired awareness of hypoglycemia (IAH) using hybrid closed-loop (HCL) insulin delivery to maintain glucose homeostasis.Twelve participants undertook 45-min high-intensity intermittent exercise (HIIE) and moderate-intensity exercise (MIE) in random order. The primary outcome was continuous glucose monitoring (CGM) time in range (70-180 mg/dL) for 24-h post-exercise commencement.CGM time in range was similar for HIIE and MIE (median 79.5% [interquartile range 73.2, 87.6] vs. 76.1% [70.3, 83.9], P = 0.37), and time with levels <54mg/dL post-exercise commencement was 0%. HIIE induced greater increases in cortisol (P = 0.002), noradrenaline (P = 0.005), and lactate (P = 0.002), with no differences in adrenaline, dopamine, growth hormone, or glucagon responses.IAH adults using HCL undertaking HIIE and MIE exhibit heterogeneity in CRR. Novel findings were a preserved cortisol response and variable catecholamine responses to HIIE.
Gelatin Templated Polypeptide Co‐Cross‐Linked Hydrogel for Bone Regeneration
Authors: Yusen Qiao, Xingzhi Liu, Xichao Zhou, Hongbo Zhang, Wen Zhang, Wei Xiao, Guoqing Pan, Wenguo Cui, Hélder A. Santos, Qin Shi
Journal: Advanced Healthcare Materials (2019)

Polypeptides with short chains of amino acid monomers have been widely applied in the clinic because of their various biological functions. However, the easily-inactivated characteristics and burst releasing of the peptides limit their application in vivo. Here, a novel osteogenic polypeptide hydrogel (GelMA-c-OGP) is created by co-cross-linking template photo-cross-linked gelatin (GelMA) with photo-cross-linkable osteogenic growth peptides (OGP) using ultraviolet radiation. GelMA enables the formation of hydrogel with photo-cross-linkable OGP with good mechanical properties and also promotes bone regeneration. GelMA-c-OGP hydrogel accelerates the bone formation procedure of osteogenic precursor cells by significantly enhancing the expression of osteogenic-related genes BMP-2, OCN, and OPN, and increasing the precipitation of calcium salts in osteoblasts. Similarly, GelMA-c-OGP hydrogel promotes bone regeneration in vivo. Furthermore, it is observed that more collagen fibers connect cortical bones in the GelMA-c-OGP implanted group than the control group by hematoxylin-eosin and immunohistochemical staining of Collagen I and TGF-β. The co-cross-linked OGP polypeptide converts from liquid to solid hydrogel with transient UV light in situ, which also can strengthen the mechanical property of the defect bone and avoid burst osteogenic peptide, releasing during the bone defect healing period. Overall, this hydrogel delivering system has a significant impact on bone defect healing compared with traditional methods.
Glivec/STI571 Treatment Stimulates Megakaryopoiesis and Normalizes PDGF Receptor beta Kinase Expression in Thrombocytopenic Patients with Myeloid Metaplasia with Myelofibrosis.
Authors: Marie Caroline le Bousse-Kerdiles, Christophe Desterke, Bernadette Guerton, Denis Clay, Hans Hasselbalch, Heinz Gisslinger, Jurgen Thiele, Hans Kvasnicka, Giovanni Barosi
Journal: Blood (2005)
Intra-operative atrial refractory periods in relation to atrial fibrillation history and the presence of mitral regurgitation
Authors: RG Tieleman, van Isabelle Gelder, AE Tuinenburg, BA Schoonderwoerd, JG Grandjean, PJ De Kam, RG Huet, J Van der Maaten, Hjgm Crijns
Journal: Circulation (1999)
HOX11L2 expression linked to t(5;14)(q35;q32) is not associated with poor prognosis in childhood T-ALL treated in EORTC trials 58 881 and 58 951
Authors: H Cave, S Suciu, C Preudhomme, B Poppe, A Robert, A Uyttebroek, M Malet, P Boutard, Y Benoit, L Mauvieux, P Lutz, F Mechinaud, N Grardel, F Mazingue, MP Pages, Y Bertrand, E Plouvier, G Brunie, C Waterkeyn, Anne Hagemeijer-Hausman, F Speleman, M Lessard, E Vilmer, J Otten, N Dastugue
Journal: Blood (2002)
The Prevalence of Pulmonary Hypertension and the Related Factors in Hemodialysis Patients
Authors: Sedighi Omid, Golshani Samad, Sharifpoor Ali, Mahjoob Fatemeh
Journal: European Respiratory Journal (2012)

Background and purpose:  Pulmonary hypertension (PH) has been reported in hemodialysis patients, but there are scant studies about its prevalence and mechanisms. The aim of this study was to determine the prevalence of pulmonary hypertension in hemodialysis patients and to study some of its possible etiologic factors.   Materials and methods:  In this cross-sectional study, the prevalence of pulmonary hypertension was determined by Doppler echocardiogram in 100 patients on hemodialysis via arteriovenous fistula at least for 6 months. Âll the patients underwent a thorough clinical evaluation. The laboratory findings including mean of three-month hemoglobin and serum level of calcium, phosphorus, albumin, alkaline phosphatase, parathormone (PTH), triglyceride and cholesterol were all recorded. Pulmonary hypertension was defined as systolic pulmonary artery pressure higher than 35 mmHg.   Results:  Pulmonary hypertension was detected in 44 patients (44%) with a mean systolic pulmonary artery pressure of 52.09±7.33 mmHg. No significant differences were found between those with and without pulmonary hypertension with regard to age, gender, duration of hemodialysis and all the biological parameters.   Conclusion:  This study demonstrates a high prevalence of pulmonary hypertension among patients receiving chronic hemodialysis via arteriovenous fistula.
Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis
Authors: Atsushi Takahashi-Kanemitsu, Christopher T. Knight, Masanori Hatakeyama
Journal: Cellular and Molecular Immunology (2019)

Abstract Chronic infection with Helicobacter pylori cagA -positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and -independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a “hit-and-run” process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the “hit-and-run” process of gastric carcinogenesis.
The BMJ Christmas 2019 appeal: a health centre is not a health centre if it doesn’t have clean water
Authors: Dan Jones
Journal: BMJ (2019)

WaterAid/James Kiyimba

In Kharumwa Hospital in northwestern Tanzania doctors such as Casmir Lubango (pictured) have seen clean water and good sanitation transform the healthcare they provide. Lubango’s hospita­­­l used often to run out of clean water or had to use it sparingly, until the international charity WaterAid helped bring a reliable source to the hospital, as well as decent toilets and hygiene training.

“I’m happy we have enough water at the health centre now,” said Lubango. “Personal hygiene among patients has greatly improved. Our wards are congested but very clean.

“Improved access to water and good hygiene practices in a hospital environment means infection prevention and control. There are no longer sepsis cases, due to improved hygiene.

“These things combined have won us the trust and confidence …
Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma
Authors: Robyn A. Wong, Xujun Luo, Mimi Lu, Zhenyi An, Daphne A. Haas-Kogan, Joanna J. Phillips, Kevan M. Shokat, William A. Weiss, Qi Wen Fan
Journal: Cancer Research (2019)

Abstract The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. Significance: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.
Milestones in nephrology: Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle's loop of rabbit kidney.
Authors: Greger R, Schlatter E, Hebert Sc
Journal: Journal of the American Society of Nephrology (2001)

Previous data from our laboratory have shown that active transport in the cortical thick ascending limb of Henle's loop (cTAL), as measured by the short circuit current (I sc , μA.cm -2 ), requires the presence of Na +  and Cl - . The data were compatible with the model of secondarily active Cl -  reabsorption involving the cotransport of Na +  and Cl -  across the luminal membrane. The data suggested, furthermore, that 1 Na +  and 2 Cl -  interact with the luminal carrier. In the present study it was tested whether this reabsorptive mechanism also requires the presence of luminal K + . Isolated cTAL segments (n=40) were perfused at high flow rates with a modified Ringer's solution. Removal of K +  from the lumen reduced I sc  significantly from 215 to 133 μA.cm -2 . Addition of Ba 2+  (10 -3  mol.l -1 ) which blocks the K + conductance of the luminal membrane, to the K + -containing lumen perfusate decreased I sc  significantly from 234 to 141 μA.cm -2 . Combination of both manoeuvres: perfusion with a K + -free and Ba 2+ -containing solution almost abolished I sc  from a control of 237 to 56 μA.cm -2 . The results are compatible with the view that in rabbit cTAL the luminal carrier interacts with all 3 ions, possibly 1 Na + , 2 Cl - , and 1 K + . K +  recycles across the luminal membrane through its conductive pathway.
Using Haplotype Information for Conservation Genomics
Authors: Maeva Leitwein, Maud Duranton, Quentin Rougemont, Pierre-Alexandre Gagnaire, Louis Bernatchez
Journal: Trends in Ecology & Evolution (2019)

The particular combinations of alleles that define haplotypes along individual chromosomes can be determined with increasing ease and accuracy by using current sequencing technologies. Beyond allele frequencies, haplotype data collected in population samples contain information about the history of allelic associations in gene genealogies, and this is of tremendous potential for conservation genomics. We provide an overview of how haplotype information can be used to assess historical demography, gene flow, selection, and the evolutionary outcomes of hybridization across different timescales relevant to conservation issues. We address technical aspects of applying such approaches to nonmodel species. We conclude that there is much to be gained by integrating haplotype-based analyses in future conservation genomics studies.
Malnutrition in the third world. II
Authors: A. S. Truswell
Journal: BMJ (1985)

The global incidence of xerophthalmia a late manifestation of vitamin A deficiency is estimated at 500000 new cases/year half of which result in blindness.  The highest incidence is in East Asia.  Severe xerophthalmia is largely confined to infants and young children.  Its stages include night blindness conjunctival xerosis Bitots spots corneal xerosis and corneal ulceration or keratomalacia.  The pathogenesis of severe vitamin A deficiency in Third World countries consists of low maternal intake of vitamin A and carotene very low neonatal liver stores of vitamin A low vitamin A and carotene concentrations in breast milk poor absorption and transport of vitamin A due to protein-energy malnutrition and precipitation of clinical deficiency by infection.  There are 4 strategies of prevention:  nutrition education vitamin A for mothers periodic dosing of young children and fortification of staple foods with vitamin A.  Vitamin A has been given priority by the World Health Organization (WHO) for prevention programs.  Iodine deficiency disorders estimated to affect 400000000 people have also been given priority.  Endemic goitres a consequence of inadequate iodine intake persist in many parts of the Third World.  Iodized salt is effective only where there are roads shops and a cash economy.  Recommended for remote communities is injection of iodized poppyseed oil to all women of childbearing age to prevent cretinism.  Nutritional anemia is another WHO priority.  Its 2 most common causes are iron deficiency and folate deficiency.
Association of β-Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients With Heart Failure With a Preserved Ejection Fraction
Authors: Daniel N. Silverman, Timothy B. Plante, Margaret Infeld, Peter W. Callas, Stephen P. Juraschek, Geoff B. Dougherty, Markus Meyer
Journal: JAMA Network Open (2019)

<h3>Importance</h3> β-Blockers are prescribed to most patients with heart failure (HF) with a preserved ejection fraction (HFpEF), but their effect on HFpEF remains unclear. <h3>Objective</h3> To determine the association of β-blocker use with HF hospitalizations and cardiovascular disease (CVD) mortality, overall and in strata of patients with an ejection fraction (EF) of 50% or greater or less than 50%. <h3>Design, Setting, and Participants</h3> For 1761 participants from North and South America enrolled in the multicenter, double-blinded Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist randomized clinical trial of spironolactone for patients with HFpEF between August 10, 2006, and January 31, 2012, the association of baseline β-blocker use with HF hospitalization and CVD mortality was analyzed using unadjusted and adjusted Cox proportional hazards regression models, overall and in strata of patients with an EF of 50% or greater or less than 50%. Participants had symptomatic HF with a left ventricular EF of 45% or greater, with enrollment based on either hospitalization attributed to decompensated HF in the prior year or elevated natriuretic peptide levels. Statistical analysis was performed from January 31 to May 2, 2019. <h3>Exposure</h3> Use of β-blockers. <h3>Main Outcomes and Measures</h3> Incident HF hospitalization and CVD mortality. <h3>Results</h3> Among 1761 participants included in the analysis (879 women and 882 men; mean [SD] age, 71.5 [9.6] years), 1394 (79.2%) reported β-blocker use and 1567 (89.0%) had an EF of 50% or greater. Hospitalizations for HF occurred for 399 participants (22.7%), and CVD mortality occurred for 229 participants (13.0%). Use of β-blockers was associated with a higher risk of HF hospitalization among patients with HFpEF with an EF of 50% or greater (hazard ratio, 1.74 [95% CI, 1.28-2.37];<i>P</i> &lt; .001) but not among patients with an EF between 45% and 49% (hazard ratio, 0.68 [95% CI, 0.28-1.63];<i>P</i> = .39). There was a significant interaction between β-blocker use and EF threshold for incident HF hospitalizations (<i>P</i> = .03). Use of β-blockers was not associated with a change in CVD mortality. <h3>Conclusions and Relevance</h3> For patients with an EF of 50% or greater, β-blocker use was associated with an increased risk of HF hospitalizations but not CVD mortality. For patients with an EF between 45% and 49%, there was no such association.