tbuckley/cabot-search huggingface dataset:
Distinct patterns of intratumoral immune cell infiltrates in patients with HPV-positive versus HPV-negative head and neck squamous cell carcinoma.
Authors: Simona Partlova, Jan Boucek, Ruth Tachezy, Radek Spisek, Anna Fialova
Journal: Journal of Clinical Oncology (2014)

6010 Background: Persistent human papillomavirus (HPV) infection is the most important etiologic agent of the oropharyngeal head and neck squamous cell carcinoma (HNSCC). Patients with HPV-positive HNSCC were reported to have a better clinical outcome than HPV-negative patients. However, little is known about the possible causes of the difference in the clinical outcome. In this study, we analyzed a detailed immune profile of tumor samples from HNSCC patients with respect to their HPV status. Methods: We studied the intratumoral immune cell infiltrates in 51 fresh HNSCC samples collected during the primary surgery. We analyzed the characteristics of immune cell infiltrates, including the frequency and distribution of antigen presenting cells, naïve and effector T cells, Th1/Th2/Th17 lymphocytes, regulatory T cells and cytokine and chemokine levels in the tumor tissue. Results: There was a profound difference in the extent and characteristics of the intratumoral immune cell infiltrates in HNSCC patients depending on their HPV status. In contrast to HPV-negative tumor tissues, HPV-positive tumor samples showed significantly higher levels of infiltrating IFNγ+ CD8+ T lymphocytes, IL-17+ CD8+ T lymphocytes, myeloid dendritic cells and proinflammatory chemokines. Furthermore, HPV positive tumors had significantly lower infiltration by exhausted CD8+ T lymphocytes characterized by high PD-1 and Tim-3 expression. Conclusions: The presence of strong intratumoral immune cell infiltrates might play a crucial role in the significantly better response of HPV-positive patients to standard therapy and their favorable clinical outcome. Additionally, characterization of the HNSCC immune profile may represent a valuable prognostic tool in addition to the HPV status and may help to identify novel targets for therapeutic strategies, including cancer immunotherapy.
Scientists solve mystery of volcano's “natural deaths”
Authors: Xavier Bosch
Journal: BMJ (2001)

Scientists believe they have pieced together the chain of events that can explain some of some of the most bizarre and mysterious deaths in recorded history. When Mount Vesuvius erupted in ad79, thousands of people evacuated areas around the volcano, but about 2000 were killed. Many inhabitants of Pompeii died of suffocation.

However, the skeletons of some victims from nearby Herculaneum who had taken refuge in nearby caves have puzzled scientists since they were …
Abstract P307: A Novel Protective Effect of the Antidiabetic Drug Voglibose via GLP-1 Receptor in the Infarcted Heart
Authors: Masamitsu Iwasa, Yoshihisa Yamada, Shinji Yasuda, Hiroyuki Kobayashi, Hiroaki Ushikoshi, Takuma Aoyama, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara, Shinya Minatoguchi
Journal: Circulation Research (2011)

Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the α-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act via stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits following 30 min of coronary occlusion and 48 h of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9–39), wortmannin, L-NAME or 5-HD, which inhibit GLP-1 receptors, PI3K, NOS and K ATP channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial expression of phospho-Akt, phospho-eNOS, phospho-ERK and HSP27 following myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9–39) and wortmannin, while the upregulation of phospho-ERK and HSP27 was inhibited by wortmannin but not by exendin(9–39). These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of PI3K-Akt-eNOS and ERK pathways, and the opening of mitochondrial K ATP channels. These findings may provide new insight into therapeutic strategies for the treatment of diabetic patients with coronary artery disease.
An update of the WCRF/AICR systematic literature review and meta-analysis on dietary and anthropometric factors and esophageal cancer risk
Authors: S. Vingeliene, D.S.M. Chan, A.R. Vieira, E. Polemiti, C. Stevens, L. Abar, D. Navarro Rosenblatt, D.C. Greenwood, T. Norat
Journal: Annals of Oncology (2017)

In the 2007 World Cancer Research Fund/American Institute for Cancer Research Second Expert Report, the expert panel judged that there was strong evidence that alcoholic drinks and body fatness increased esophageal cancer risk, whereas fruits and vegetables probably decreased its risk. The judgments were mainly based on case-control studies. As part of the Continuous Update Project, we updated the scientific evidence accumulated from cohort studies in this topic.We updated the Continuous Update Project database up to 10 January 2017 by searching in PubMed and conducted dose-response meta-analyses to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) using random effects model.A total of 57 cohort studies were included in 13 meta-analyses. Esophageal adenocarcinoma risk was inversely related to vegetable intake (RR per 100 g/day: 0.89, 95% CI: 0.80-0.99, n = 3) and directly associated with body mass index (RR per 5 kg/m2: 1.47, 95% CI: 1.34-1.61, n = 9). For esophageal squamous cell carcinoma, inverse associations were observed with fruit intake (RR for 100 g/day increment: 0.84, 95% CI: 0.75-0.94, n = 3) and body mass index (RR for 5 kg/m2 increment: 0.64, 95% CI: 0.56-0.73, n = 8), and direct associations with intakes of processed meats (RR for 50 g/day increment: 1.59, 95% CI: 1.11-2.28, n = 3), processed and red meats (RR for 100 g/day increment: 1.37, 95% CI: 1.04-1.82, n = 3) and alcohol (RR for 10 g/day increment: 1.25, 95% CI: 1.12-1.41, n = 6).Evidence from cohort studies suggested a protective role of vegetables and body weight control in esophageal adenocarcinomas development. For squamous cell carcinomas, higher intakes of red and processed meats and alcohol may increase the risk, whereas fruits intake may play a protective role.
Antimicrobial peptide-gold nanoscale therapeutic formulation with high skin regenerative potential
Authors: Michela Comune, Akhilesh Rai, Kiran K. Chereddy, Sandra Pinto, Sezin Aday, André F. Ferreira, Alessandra Zonari, Josephine Blersch, Rodrigo Cunha, Ricardo Rodrigues, Juan Lerma, Pedro N. Simões, Veronique Préat, Lino Ferreira
Journal: Journal of Controlled Release (2017)
Pretreatment features and risk of death from BRAF-positive metastatic melanoma patients treated with vemurafenib.
Authors: Dorota Malgorzata Kwapisz
Journal: Journal of Clinical Oncology (2017)

e21028 Background: Clinicopathologic features of BRAF-positive metastatic melanoma patients were identified. No study to date has examined influence on risk of death features at baseline before starting treatment with vemurafenib. The purpose of the study is to identify demographic, clinical, biochemical, and tumor-related features at baseline before treatment with vemurafenib that are related with increase risk of death in BRAF-positive metastatic melanoma patients. Methods: 323 consecutive patients with metastatic melanoma tested for BRAF mutation were analysed. The presence of BRAF gene V600 mutation was evaluated by the cobas 4800 BRAF V600 Mutation Test. The pretreatment features were collected prospectively after inclusion patients for BRAF inhibitor treatment but before treatment was started. Results: 204 patients had a BRAF mutation. Of these, 115 were treated with vemurafenib. The median time of treatment with vemurafenib was 198 days. Death occurred more frequently among patients with: pretreatment disease symptoms (p = 0.003), ECOG PS ≥1 (p = 0.03), CNS metastases at baseline (p = 0.049) [χ2 test]. The pretreatment elevated serum LDH level (p &lt; 0.0005), leukocytosis (p = 0.042), and hipoalbuminemia (p = 0.002) had an impact on higher incidence of death. AJCC stage 3 was reported more frequently in patients who have died (AJCC 1-2 vs. AJCC 3; p = 0.025, χ2 test). Higher incidence of death in patients with ≥4 localisations of metastases (different organs) was noted (1-3 vs 4-8; p = 0.001, χ 2 test). The maximum metastasis dimension was greater in the group of patients who have died (p = 0.009; Mann-Whitney test). In the analysed population, all patients whose pretreatment metastasis dimension exceeded 56 mm have died. Age, BMI, and sex were not related with higher risk of death. Conclusions: Pretreatment features may identify patients at higher risk of death. Those with features at baseline such as: disease symptoms, poor performance status, elevated LDH, leukocytosis, hipoalbuminemia, increased metastatic tumor burden, especially when brain is one of the metastatic localisation are in higher risk of death among all patients treated with vemurafenib.
Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline <i>BRCA1/2</i> mutations (ABRAZO).
Authors: Nicholas C. Turner, Melinda L. Telli, Hope S. Rugo, Audrey Mailliez, Johannes Ettl, Eva-Maria Grischke, Lida A. Mina, Judith Balmana Gelpi, Peter A. Fasching, Sara A. Hurvitz, Andrew M. Wardley, Colombe Chappey, Wendy Verret, Alison L. Hannah, Mark E. Robson
Journal: Journal of Clinical Oncology (2017)

1007 Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA. This study was designed to assess the activity of TALA in pts with g BRCA1/2mutation previously exposed to platinum or multiple prior cytotoxic regimens. Methods: ABRAZO (NCT02034916) is a 2-cohort, 2-stage phase 2 study of TALA (1 mg/d) following platinum-based therapy (Cohort 1 [C1]) or ≥ 3 platinum-free cytotoxic-based regimens (Cohort 2 [C2]) in pts with locally advanced or metastatic breast cancer (MBC) and g BRCA1/2mutation. Pts had ECOG PS ≤ 1 and measurable disease by RECIST v1.1. Five responses per cohort were required in ≤ 35 pts to progress to stage 2. The primary endpoint was confirmed ORR by independent radiology facility (IRF). Secondary endpoints: clinical benefit rate ≥ 24 weeks (CBR24), DOR, PFS, and OS. Results: From May 2014 to Feb 2016, 84 pts were enrolled (C1, n = 49; C2, n = 35). At data cutoff (1 Sep 2016), 9 pts continued on treatment. Both cohorts proceeded to stage 2 before enrollment closed. Median age was 50 (range, 31–75) years; 58% of pts had an ECOG PS of 0. TNBC/HR+ incidence in C1 and C2 was 59%/41% and 17%/83%, respectively. Median number of prior cytotoxic regimens administered for advanced disease was 2 in C1 and 4 in C2. ORR by IRF for BRCA1/BRCA2 was 24%/34%, and ORR by IRF for TNBC/HR+ was 26%/29%. Common all grade AEs: anemia (52%), fatigue (45%), nausea (42%), diarrhea (33%), thrombocytopenia (33%), and neutropenia (27%). Grade ≥ 3 AEs: anemia (35%), thrombocytopenia (19%), and neutropenia (15%). Nonhematological AEs grade ≥ 3 did not occur. AEs related to TALA led to drug discontinuation in 3 pts (4%); 4 AEs resulted in death, none related to TALA. Conclusions: TALA was well tolerated in MBC pts with a g BRCA1/2 mutation, exhibiting promising antitumor activity in C1 and C2. TALA vs physician’s choice of treatment in g BRCA1/2-mutated MBC is being evaluated in the phase 3 EMBRACA trial (NCT01945775). Clinical trial information: NCT02034916. [Table: see text]
Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension
Authors: Anna E. Dikalova, Hana A. Itani, Rafal R. Nazarewicz, William G. McMaster, Charles R. Flynn, Roman Uzhachenko, Joshua P. Fessel, Jorge L. Gamboa, David G. Harrison, Sergey I. Dikalov
Journal: Circulation Research (2017)

Clinical studies have shown that Sirt3 (Sirtuin 3) expression declines by 40% by 65 years of age paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 because of increased NADH (nicotinamide adenine dinucleotide, reduced form) and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) because of hyperacetylation.In this study, we examined whether the loss of Sirt3 activity increases vascular oxidative stress because of SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension.Hypertension was markedly increased in Sirt3-knockout (Sirt3-/-) and SOD2-depleted (SOD2+/-) mice in response to low dose of angiotensin II (0.3 mg/kg per day) compared with wild-type C57Bl/6J mice. Sirt3 depletion increased SOD2 acetylation, elevated mitochondrial O2· -, and diminished endothelial nitric oxide. Angiotensin II-induced hypertension was associated with Sirt3 S-glutathionylation, acetylation of vascular SOD2, and reduced SOD2 activity. Scavenging of mitochondrial H2O2 in mCAT mice expressing mitochondria-targeted catalase prevented Sirt3 and SOD2 impairment and attenuated hypertension. Treatment of mice after onset of hypertension with a mitochondria-targeted H2O2 scavenger, mitochondria-targeted hydrogen peroxide scavenger ebselen, reduced Sirt3 S-glutathionylation, diminished SOD2 acetylation, and reduced blood pressure in wild-type but not in Sirt3-/- mice, whereas an SOD2 mimetic, (2-[2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino]-2-oxoethyl) triphenylphosphonium (mitoTEMPO), reduced blood pressure and improved vasorelaxation both in Sirt3-/- and wild-type mice. SOD2 acetylation had an inverse correlation with SOD2 activity and a direct correlation with the severity of hypertension. Analysis of human subjects with essential hypertension showed 2.6-fold increase in SOD2 acetylation and 1.4-fold decrease in Sirt3 levels, whereas SOD2 expression was not affected.Our data suggest that diminished Sirt3 expression and redox inactivation of Sirt3 lead to SOD2 inactivation and contributes to the pathogenesis of hypertension.
Pericentral hepatocytes produce insulin‐like growth factor‐2 to promote liver regeneration during selected injuries in mice
Authors: Junlai Liu, Xiao Hu, Jie Chen, Xinqi Li, Lu Wang, Binbin Wang, Wenbo Peng, Cuiwei Yang, Zhijie Li, Yan Chen, Yue J. Wang, Chuanjiang Li, Xiajun Li, Fang Yan, Yunfang Wang, Changzhen Shang, Xin Wang, Tao Chen, Pengyu Huang
Journal: Hepatology (2017)

Liver regeneration (LR) happens after various types of injuries. Unlike the well‐studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin‐like growth factor 2 (IGF‐2) was drastically induced following the liver injuries caused by tyrosinemia or long‐term treatments of CCl 4 . However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl 4 . Remarkably, most IGF‐2‐expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase–deficient mice or in CCl 4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF‐2 overexpression, which could be inhibited by adeno‐associated virus–delivered IGF‐2 short hairpin RNAs or linsitinib, an inhibitor of IGF‐2 signaling. Proliferating hepatocytes in vivo responded to IGF‐2 through both insulin receptor and IGF‐1 receptor. IGF‐2 also significantly promoted DNA synthesis of primary hepatocytes in vitro . More interestingly, the significantly induced IGF‐2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. Conclusion: IGF‐2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post‐PHx. (H epatology 2017;66:2002–2015)
Clinical characteristics of patients with multiple primary lung cancers: Moving beyond the Martini and Melamed criteria.
Authors: Marjorie Glass Zauderer, Alexander Edward Dela Cruz Drilon, Camelia S. Sima, Feiran Lou, David J. Finley, Mark G. Kris
Journal: Journal of Clinical Oncology (2013)

7570 Background: Deciding to operate for lung cancer in patients with a prior lung cancer resection is influenced by the extent of disease at 1st resection and the certainty that the new lesion is a 2nd primary lung cancer. While the Martini and Melamed (M&amp;M) criteria (J Thorac Cardiovasc Surg 1975) guide the decision whether a new lesion represents a 2nd lung cancer, improvements, incorporating detailed clinical and molecular analyses, are needed. Methods: From a prospective database, we identified 130 patients who underwent two curative resections from 1995 to 2009 for non-small cell lung cancers. We examined associations between clinical factors and patterns of recurrence/DFS/OS following 2nd surgery. Results: Patient characteristics: median age 66; 42% men; and 8% never smokers. See Table for stage, histology, and completeness of resection. DFS and OS were not associated with smoking status, surgical procedure, and histology. Stage at 1st resection was not associated with patterns of recurrence (none vs local vs distant, p=0.77), DFS (p=0.61), or OS (p=0.37). Earlier stage at 2nd resection was associated with improved DFS (p&lt;0.001) and OS (p&lt;0.001), as well as a trend toward less distant recurrence (p=0.06). As many surgeries predated routine genotyping, very few patients (5%) had genotyping from both resections. 38% of 2nd resection stage IA lung cancers recurred distantly. 20% had a third lung cancer and 47% had at least one other malignancy. Conclusions: Outcomes after 2nd primary lung cancers are unaffected by the stage of the 1st lung cancer. Pursuit of curative interventions should not be influenced by the stage of the 1st cancer. We need more detailed molecular analysis to help correctly identify new primaries. We also need additional features to help discriminate among those at most risk for another lung cancer vs local recurrence vs distant recurrence. [Table: see text]
Recombinant Factor VIIa (rFVIIa) Mediated Activation of Prothrombin Complex Concentrates (PCCs). Studies on the Comparison of Novoseven with a Biosimilar Product
Authors: Nasir Sadeghi, Daniel Kahn, Debra Hoppensteadt, Reza Eshraghi, Jawed Fareed
Journal: Blood (2014)
More doctors are disclosing payments from drug companies
Authors: Nigel Hawkes
Journal: BMJ (2017)

Nearly two thirds of doctors and other healthcare professionals in the UK have chosen to disclose the payments made to them by drug companies in 2016, a rise of 10 percentage points from 2015.

But some of those doctors who receive the bigger payments have withheld their names, as they are entitled to do. The 65% who chose to disclose accounted for 60% of the total payments, excluding those for conducting trials.

The industry paid a total of £454.5m (€520m; $590m) to work with healthcare professionals and healthcare organisations in the UK in 2016, the latest data released on the Association of the British Pharmaceutical Industry’s disclosure website show (www.disclosureuk.org.uk …
Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps
Authors: Heng Wang, Danh C. Do, Jinxin Liu, Baofeng Wang, Jingjing Qu, Xia Ke, Xiaoyan Luo, Ho Man Tang, Ho Lam Tang, Chengping Hu, Mark E. Anderson, Zheng Liu, Peisong Gao
Journal: Journal of Allergy and Clinical Immunology (2017)
Emergency +: mobile app user guide
Authors: Nash Anderson, Natalie Sharp
Journal: British Journal of Sports Medicine (2017)

Emergency +

Utilities

Android (2.3 and above), iOS (6.0 or later)

Free

It is given that at some point, when working on a sporting sideline, you will have to make a call to emergency services. These scenarios can be unexpected and at times, life threatening.

It is essential that in the event of an emergency, you know the correct phone number to call to receive the appropriate assistance.  

Reasons for calling emergency services may include:



Locations for sporting events can be remote, especially when working with lower level or junior age groups. To speed up the response time of emergency services, it is important to know your exact location, stay calm and focus on …
A systematic comparison of clinically viable nanomedicines targeting HMG-CoA reductase in inflammatory atherosclerosis
Authors: Amr Alaarg, Max L. Senders, Aida Varela-Moreira, Carlos Pérez-Medina, Yiming Zhao, Jun Tang, Francois Fay, Thomas Reiner, Zahi A. Fayad, Wim E. Hennink, Josbert M. Metselaar, Willem J.M. Mulder, Gert Storm
Journal: Journal of Controlled Release (2017)

Atherosclerosis is a leading cause of worldwide morbidity and mortality whose management could benefit from novel targeted therapeutics. Nanoparticles are emerging as targeted drug delivery systems in chronic inflammatory disorders. To optimally exploit nanomedicines, understanding their biological behavior is crucial for further development of clinically relevant and efficacious nanotherapeutics intended to reduce plaque inflammation. Here, three clinically relevant nanomedicines, i.e., high-density lipoprotein ([S]-HDL), polymeric micelles ([S]-PM), and liposomes ([S]-LIP), that are loaded with the HMG-CoA reductase inhibitor simvastatin [S], were evaluated in the apolipoprotein E-deficient (Apoe−/−) mouse model of atherosclerosis. We systematically employed quantitative techniques, including in vivo positron emission tomography imaging, gamma counting, and flow cytometry to evaluate the biodistribution, nanomedicines' uptake by plaque-associated macrophages/monocytes, and their efficacy to reduce macrophage burden in atherosclerotic plaques. The three formulations demonstrated distinct biological behavior in Apoe−/− mice. While [S]-PM and [S]-LIP possessed longer circulation half-lives, the three platforms accumulated to similar levels in atherosclerotic plaques. Moreover, [S]-HDL and [S]-PM showed higher uptake by plaque macrophages in comparison to [S]-LIP, while [S]-PM demonstrated the highest uptake by Ly6Chigh monocytes. Among the three formulations, [S]-PM displayed the highest efficacy in reducing macrophage burden in advanced atherosclerotic plaques. In conclusion, our data demonstrate that [S]-PM is a promising targeted drug delivery system, which can be advanced for the treatment of atherosclerosis and other inflammatory disorders in the clinical settings. Our results also emphasize the importance of a thorough understanding of nanomedicines' biological performance, ranging from the whole body to the target cells, as well drug retention in the nanoparticles. Such systematic investigations would allow rational applications of nanomaterials', beyond cancer, facilitating the expansion of the nanomedicine horizon.
Bortezomib-Induced Apoptosis in Myeloma Cell Via Oxidation of Peroxiredoxin III and Thioredoxin 2
Authors: Yeung-Chul Mun, Jee-Young Ahn, Seung Hye Kang, Eun-Sun Yoo, Kyoung Eun Lee, Eunmi Nam, Soon Nam Lee, Hyun Ae Woo, Sue Goo Rhee, Chu-Myong Seong
Journal: Blood (2016)
Endoscopic treatment vs. esophagectomy for patients with high-risk early esophageal cancer
Authors: Marek Kollar, Jana Krajciova, Jana Maluskova, Eva Honsova, Alexandr Pazdro, Tomáš Haruštiak, Daniela Kodetova, Zuzana Vackova, Julius Spicak, Jan Martinek
Journal: Annals of Oncology (2017)