tbuckley/cabot-search huggingface dataset:
Selective interleukin-1 receptor–associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy
Authors: Priscilla N. Kelly, Donna L. Romero, Yibin Yang, Arthur L. Shaffer, Divya Chaudhary, Shaughnessy Robinson, Wenyan Miao, Lixin Rui, William F. Westlin, Rosana Kapeller, Louis M. Staudt
Journal: The Journal of Experimental Medicine (2015)

Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling.
2-Deoxy-d-Glucose Ameliorates PKD Progression
Authors: Marco Chiaravalli, Isaline Rowe, Valeria Mannella, Giacomo Quilici, Tamara Canu, Veronica Bianchi, Antonia Gurgone, Sofia Antunes, Patrizia D’Adamo, Antonio Esposito, Giovanna Musco, Alessandra Boletta
Journal: Journal of the American Society of Nephrology (2015)

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy- d -glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25–28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of 13 C-glucose and conversion to 13 C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP–activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45–positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.
Leydig cell function in boys following treatment for testicular relapse of acute lymphoblastic leukemia.
Authors: J Blatt, R J Sherins, D Niebrugge, W A Bleyer, D G Poplack
Journal: Journal of Clinical Oncology (1985)

Current practice for achieving local control of testicular relapse in males with acute lymphoblastic leukemia (ALL) includes the use of 2,400-rad testicular radiation. Although this therapy is known to cause germ cell depletion, it has been assumed that it does not alter testicular secretion of testosterone. To test this assumption, we measured gonadotropin and testosterone levels in seven boys with ALL who had been treated with radiation for clinically apparent testicular relapse. In four of seven boys, testicular relapse was bilateral with overt involvement of one testicle and microscopic involvement of the other. Three of these four boys demonstrated delayed sexual maturation, and in addition to elevated follicle-stimulating hormone (FSH) concentrations, testosterone levels were low and luteinizing hormone levels were elevated compared with controls. These data indicate that boys with overt testicular leukemia who are treated with 2,400-rad testicular radiation are at risk for Leydig cell dysfunction. However, the relative contributions of radiation, prior chemotherapy, and leukemic infiltration to this dysfunction remain to be clarified.
Preoperative chemotherapy and radiation therapy for patients with cancer of the esophagus: a potentially curative approach.
Authors: L Leichman, Z Steiger, H G Seydel, A Dindogru, J Kinzie, S Toben, G MacKenzie, J Shell
Journal: Journal of Clinical Oncology (1984)

Twenty-one patients with squamous cell cancer of the esophagus were entered into a pilot clinical trial using preoperative chemotherapy (5-fluorouracil and cis-platinum) and radiation with the intent of improving cure rate and survival. After the preoperative treatment was complete, 15 patients (71%) were resected for cure. Seven (47%) of 15 had no histologic evidence of cancer in the resected esophagus, but two of these had microscopic cancer in resected lymph nodes. The median survival for all patients entered in the trial was 18 months, whereas for those with no cancer in the resected esophagus the median survival was 24 months. The six patients who either refused surgery (two patients) or were unresectable at surgery (four patients) died within nine months. Our conclusion in this trial is that survival and potential cure are clearly linked to successfully clearing the esophagus and nodes of histologic evidence of tumor through preoperative treatment.
Variations in genes regulating tumor-associated macrophages (TAMs) to predict outcome of bevacizumab (bev)-based treatment in patients with metastatic colorectal cancer (mCRC): Results from TRIBE and FIRE3 trials.
Authors: Yu Sunakawa, Sebastian Stintzing, Volker Heinemann, Chiara Cremolini, Alfredo Falcone, Shu Cao, Dongyun Yang, Wu Zhang, Shinichi Yamauchi, Yan Ning, Stefan Stremitzer, Satoshi Matsusaka, Anish Parekh, Shannon Graver, Angela Mendez, Satoshi Okazaki, Rita Elkhoueiry, Stefan J. Scherer, Fotios Loupakis, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2015)

3552 Background: TAMs with the M2-like phenotype are regulated by NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors and tumor promoting cytokines, such as VEGF-A and CCL18. These factors drive tumor angiogenesis, migration and immunosuppression. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), PIGF and VEGF play a critical role in the polarization of M1 and M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We hypothesized that genes involved in regulating TAMs may predict outcome of bev-based therapy in patients (pts) with mCRC. Methods: We analyzed genomic DNA extracted from blood or tumor samples of pts receiving bev plus FOLFIRI in 2 prospective trials, using PCR-based direct sequencing. Eleven functional polymorphisms in 7 genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1 and CCL18) were tested for associations with clinical outcome in a discovery cohort of 228 pts (male 61%, median age 60, follow-up time 27 months [m]) enrolled in TRIBE (T) trial (NCT00719797), then validated in 244 KRAS exon 2 (KRAS) wild-type (wt) pts (male 69%, median age 64, follow-up time 39 m) enrolled in FIRE3 (F) trial (NCT00433927). 246 pts receiving cetuximab plus FOLFIRI in F served as negative control. Results: TBK1 rs7486100 (A > T) was associated with response rate (RR) and overall survival (OS) in KRAS wt pts of T cohort (n= 95, any T vs A/A: 58 % vs 82 %, p= 0.046; 25.1 m vs 49.1 m, adjusted HR 2.39, p= 0.046, respectively). In F cohort, the association was observed for progression-free survival (any T vs A/A: 10.1 m vs 12.3 m, adjusted HR 1.42, p= 0.047) although there was no statistically association with RR and OS (23.7 m vs 28.6 m, p= 0.15). No polymorphism was established between KRAS mutant of T cohort and F cohort. No association was seen in control. Conclusions: TBK1 rs7486100 is associated with outcome of bev-based chemotherapy in mCRC pts, suggesting that NF-kB signaling may play a critical role in tumor angiogenesis as an independent pathway. Our results also suggest that TBK1 may be a potential biomarker to identify pts benefitting from bev-based treatment.
Annual malaria deaths have halved since 2000
Authors: Anne Gulland
Journal: BMJ (2015)

Health experts are warning against complacency after the publication of a report showing that the worldwide number of deaths each year from malaria has halved in the past 15 years.

A joint World Health Organization and United Nations Children’s Fund (Unicef) report shows that the number of deaths from malaria has fallen from 839 000 in 2000 to an estimated 438 000 in 2015.1 The number of cases of malaria has also fallen but not by such a large amount, largely because there are many more cases than deaths. In 2000 there were 262 million cases of malaria, while in 2015 the estimated number is 214 million. Most cases (89%) and deaths (91%) occur in sub-Saharan Africa.

The report hails the cut in mortality as an impressive achievement in light of the …
TCT-8 First results of the EXPLORE trial, a Global, Randomized, Prospective, Multicenter Trial Investigating the Impact of Recanalization of a Chronic Total Occlusion on Left Ventricular Function in Patients after Primary Percutaneous Coronary Intervention for Acute ST-Elevation Myocardial Infarction
Authors: Jose P. Henriques, Loes Hoebers, Truls Råmunddal, Peep Laanmets, Erlend Eriksen, Matthijs Bax, Dan Ioanes, Maarten J. Suttorp, Bradley Strauss, Emanuele Barbato, Robin Nijveldt, Albert C. van Rossum, Koen Marques, Jan G. Tijssen, Rene J. van der Schaaf
Journal: Journal of the American College of Cardiology (2015)
Analysis of Linked Human ɛ and γ Transgenes: Effect of Locus Control Region Hypersensitive Sites 2 and 3 or a Distal YY1 Mutation on Stage-Specific Expression Patterns
Authors: Wei Zhu, Catherine TomHon, Marsha Mason, Thomas Campbell, Eric Shelden, Neil Richards, Morris Goodman, Deborah L. Gumucio
Journal: Blood (1999)
THE PHYSICIAN AND THE NOSTRUM.
Authors: EDWARD BOK
Journal: JAMA (1907)

During the four years that we have been engaged in the work of arousing public interest in the evil of "patent medicines" it has been my pleasure, in common with others, to have received hundreds of approving letters from physicians all over the country and scores of complimentary resolutions from medical bodies. And it is my sincere hope that the few words I shall say to you this evening, in my first appearance before a medical body, may not be accepted as being in any way unappreciative of those marks of approval. I appreciate and value them. But I feel that the time has come, if we are to succeed in the fight in which we are engaged, to be perfectly frank as regards the relation of the medical profession to proprietary medicines. I am going to try to point out to you that in two distinct ways the medical
Response to Comment on Rasmussen et al. A Randomized Controlled Trial Comparing Telemedical and Standard Outpatient Monitoring of Diabetic Foot Ulcers. Diabetes Care 2015;38:1723–1729
Authors: Knud Bonnet Yderstraede, Johnny Froekjaer, Benjamin Schnack Brandt Rasmussen
Journal: Diabetes Care (2015)

We appreciate the comments made by Muller et al. (1) to our recent article in Diabetes Care (2). Their findings corroborate those of ours, including the logistics for dissemination of technology, the lack of ownership among the number of stakeholders in a complex setup, the need for patient stratification to define particular subgroups that might or might not benefit from telemedical monitoring, and other aspects.

The lack of difference in mortality in the research data from the Medico-economical Assessment of Telemedicine During Chronic Diabetes-related Foot Wound Management (AIRPEDIA) can, as mentioned in the …
Standardization of allergen products: 2. Detailed characterization of GMP-produced recombinant Phl p 5.0109 as European Pharmacopoeia reference standard
Authors: M. Himly, A. Nandy, H. Kahlert, M. Thilker, M. Steiner, P. Briza, A. Neubauer, S. Klysner, R. van Ree, K.-H. Buchheit, S. Vieths, F. Ferreira
Journal: Allergy (2015)

The Biological Standardization Programme of the European Directorate for Quality of Medicines and Healthcare (EDQM) aims at the establishment of well-characterized reference standards based on recombinant allergens and validated assays for the quantification of major allergen content. The objective of this study was to examine the detailed physicochemical and immunological characterization of recombinant Phl p 5.0109, the second available allergen reference standard.Recombinant Phl p 5.0109 PP5ar06007 was produced under GMP conditions and analyzed by an array of physicochemical and immunological methods for identity, quantity, homogeneity, and folding stability in bulk solution, as well as thermal denaturation, aggregation state, and biological activity when formulated for long-time storage.PP5ar06007 revealed as a highly homogeneous, monomeric, well-folded preparation of rPhl p 5.0109, as documented by mass spectrometry, SDS-PAGE, isoelectric focusing, size-exclusion chromatography with light scattering, circular dichroism, and infrared spectroscopy. Upon storage at +4°C, PP5ar06007 retained the monomeric state for at least 2 months. A protein quantity of 1.56 ± 0.03 mg/ml was determined by amino acid analysis in PP5ar06007, and its biological activity was shown to be comparable to natural Phl p 5 in terms of basophil activation and T-cell reactivity.Recombinant Phl p 5.0109 PP5ar06007 was characterized extensively at the physicochemical and immunological level. It revealed to be a highly stable, monomeric, and immunologically equivalent of its natural counterpart. PP5ar06007 is now available as European Pharmacopoeia allergen reference standard for grass pollen products.
Benjamin Hobson
Journal: BMJ (1873)

This study investigates the life of Benjamin Hobson(合信, 1816.1.2-1873.2.13) -the writer of five books of western medicine which influenced the establish of 「ShinGiCheonHeom(身機踐驗)」-in order to expand our base to study 「ShinGiCheonHeom」. Findings and results of the investigation are as follows.   1. Treatise on Physiology(『全體新論』) excited a deeper interest among the Chinese literati and was so eagerly sought after that a reprint of it was made for sale. The income of works of Hobson's probably excited a deeper interest among the Korean literati also.   2. We found Hobson had written many works. Among those we must pay attention to A Medical Vocabulary in English and Chinese; (『醫學英華字釋』)Through this book we can reach agreeable translation of 『ShinGiCheonHeom』.   3. Evangelism and philanthropism promoted activities of Hobson as a doctor and as a an introducer of western medicine. But ignorance of oriental medicine-Hobson thought medical science in China was at a low level-lied in these activities and passion to do it. Nowadays we must wipe out thought of this way through the scientific way.
Pleiotropic Effects of Transforming Growth Factor-β1 on Pericardial Interstitial Cells
Authors: Xiaohong Liu, Chenguang Bai, Dejun Gong, Yang Yuan, Lin Han, Fanglin Lu, Qinqi Han, Hao Tang, Shengdong Huang, Zhiyun Xu
Journal: Journal of the American College of Cardiology (2011)
Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer
Authors: Huang-Chiao Huang, Srivalleesha Mallidi, Joyce Liu, Chun-Te Chiang, Zhiming Mai, Ruth Goldschmidt, Neema Ebrahim-Zadeh, Imran Rizvi, Tayyaba Hasan
Journal: Cancer Research (2016)

Abstract The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment. Cancer Res; 76(5); 1066–77. ©2015 AACR.
Abstract P009: Dietary Exposure to Polychlorinated Biphenyls and Incidence of Myocardial Infarction in Men - A Population-Based Prospective Cohort Study
Authors: Agneta Åkesson, Charlotte Bergkvist, Marika Bergkvist, Anders Glynn, Bettina Julin, Alicja Wolk
Journal: Circulation (2015)

Introduction: Fish consumption may promote cardiovascular health. The role of major food contaminants present in fish, such as polychlorinated biphenyls (PCBs) is, however, largely unexplored. Experimental studies indicate that PCBs cause endothelial cell dysfunction, hyperlipidemia and hypertension and cross-sectional associations have been observed between PCB-biomarkers and several intermediate risk factors for cardiovascular disease. PCBs accumulate and magnify in the food chain and fatty fish is a dominating source of exposure in populations with a relatively high fish intake. We assessed the hypothesis that dietary PCB exposure is associated with increased risk of myocardial infarction (MI) and that the exposure may mask a protective association with marine omega-3 fish fatty acids intake. Methods: Validated food frequency questionnaire-based estimates of dietary PCB exposure was obtained at baseline (1997) in 36,759 men from the population-based Cohort of Swedish Men, free of cancer, cardiovascular disease and diabetes. The estimated dietary PCB exposure was based on the food concentrations of PCB congener 153 at the time of baseline. PCB-153 is the most abundant congener in food and an excellent indicator for total PCB in food and in blood. The long-term dietary PCB exposure assessments showed acceptable validity against six PCB congeners in serum (correlation coefficients 0.30 to 0.58). Cases of MI were ascertained via register-linkage through 2010. Relative risks (RR) and 95% confidence intervals (CI) were adjusted for known cardiovascular risk factors. : Results During 12 years of follow-up (433,243 person-years), we ascertained 3,005 incident cases of MI. The major dietary sources of PCB exposure was fish, dairy products and meat. Compared with the lowest quintile of dietary PCB exposure (median 113 ng/day), men in the highest quintile (median 436 ng/day) had multivariable-adjusted RR of 1.22 (95% CI, 1.05-1.41) for MI, without adjusting for the intake of marine omega-3 fish fatty acids. In a separate model, we observed no association between the intake of marine omega-3 fish fatty acids and MI (RR, 1.07; 95% CI, 0.93-1.24). In mutually-adjusted models, dietary PCB exposure was associated with RR 1.72 (95% CI 1.28-2.30), and the intake of marine omega-3 fish fatty acids with RR, 0.67 (95% CI, 0.50-0.90), comparing highest quintiles with lowest. Conclusions: Exposure to an integrated measure of total PCBs from food was associated with increased risk of MI in men. The results may provide important information regarding the risk-benefit analysis of fish consumption. To increase the net benefits of fish consumption, PCB contamination should be reduced to a minimum: Future studies are needed to clarify the concentrations of PCBs that may offset the beneficial effects of fish consumption.
Hemoptysis and Progressive Dyspnea in a 67-Year-Old Woman with History of Renal Transplantation
Authors: Filippo Lococo, Gloria Montanari, Maria Cecilia Mengoli, Filippo Ferrari, Paolo Spagnolo, Giulio Rossi
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Hemoptysis and Progressive Dyspnea in a 67-Year-Old Woman with History of Renal Transplantation Filippo Lococo, Gloria Montanari, Maria Cecilia Mengoli, Filippo Ferrari, Paolo Spagnolo, and Giulio Rossi Unit of Thoracic Surgery, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Respiratory Disease Clinic, Pathologic Anatomy, and Laboratory of Microbiology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy; and Medical University Clinic, Canton Hospital Baselland, and University of Basel, Liestal, Switzerland
Abstract 19263: Vasodilator Use and Wave Intensity Patterns in Hypertension
Authors: Julio A Chirinos, Payman Zamani, Deepa Rawath, Rushik Bhuva, Prithvi Shiva kumar, Shivapriya Peddireddy, Priyanka Bhattacharya, Victor Ferrari, Patrick Segers
Journal: Circulation (2014)

Background: Blood pressure is the result of interactions between the heart and the arteries. Although the effects of vasoactive blood pressure-lowering drugs on arteries has been widely investigated, their in vivo effects on ventricular-arterial interactions are not well understood. Hypothesis: We aimed to assess the relationship between antihypertensive drug use and ventricular arterial interactions assessed via wave intensity analysis (WIA), which quantifies the energy contained in waves generated by the heart and/or reflected from the periphery (figure). Methods: We studied 152 subjects with treated hypertension. We measured central pressure using carotid arterial tonometry. Ascending aortic flow was quantified with through-plane phase-contrast MRI. We performed WIA and assessed the relationship between specific classes of blood pressure lowering drug use and WIA patterns. Results: In models that adjusted for age, gender, body size, race, presence of diabetes and glomerular filtration rate, angiotensin receptor blocker (ARB) use was associated with a greater likelihood of a mid-systolic expansion (i.e., suction) wave (Hazard Ratio=31.1; P=0.005), whereas beta-blocker use was associated with a lower likelihood of such wave (HR=0.16; P=0.02). ARB use was also independently associated with a lower energy in the late systolic forward suction wave (Beta=-0.18; standardized beta=-0.24; P=0.007). This association persisted after adjustment for the forward compression wave (beta=-0.13; standardized beta=-0.16; P=0.008). No associations between WIA patterns and calcium channel blocker use, diuretic use, ACE inhibitor use or long-anting nitrate use were found. Conclusions: Wave intensity analysis is a useful tool to assess the effects of vasodilators on ventricular-arterial interactions. ARB use is selectively associated with systolic suction waves (from blood inertia), which may in turn unload the heart in mid and late systole.