tbuckley/cabot-search huggingface dataset:
Wee-1 Kinase Inhibition Sensitizes High-Risk HPV+ HNSCC to Apoptosis Accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic Proteins
Authors: Noriaki Tanaka, Ameeta A. Patel, Jiping Wang, Mitchell J. Frederick, Nene N. Kalu, Mei Zhao, Alison L. Fitzgerald, Tong-xin Xie, Natalie L. Silver, Carlos Caulin, Ge Zhou, Heath D. Skinner, Faye M. Johnson, Jeffrey N. Myers, Abdullah A. Osman
Journal: Clinical Cancer Research (2015)

Although the majority of patients with HPV(+) oropharyngeal cancers have a favorable prognosis, there are some patients with tumors that are resistant to aggressive chemoradiotherapy with unusual patterns of locoregional and systemic recurrences. Therefore, more effective therapies are needed. In this study, we investigated the chemosensitizing efficacy of the selective Wee-1 kinase inhibitor, AZD-1775, in HPV(+) head and neck squamous cell carcinoma (HNSCC).Clonogenic survival assays and an orthotopic mouse model of HPV(+) oral cancer were used to examine the in vitro and in vivo sensitivity of HPV(+) HNSCC cell lines to AZD-1775 in combination with cisplatin, respectively. Cell-cycle analysis, DNA damage (γH2AX), homologous recombination (HR), and apoptosis were examined to dissect molecular mechanisms.We found that AZD-1775 displays single-agent activity and enhances the response of HPV(+) HNSCC cells to cisplatin both in vitro and in vivo. The sensitivity of the HPV(+) HNSCC cells to AZD-1775 alone or in combination with cisplatin was associated with G2 checkpoint abrogation, persistent DNA damage, and apoptosis induction. This finding of AZD-1775 increasing the sensitivity of HPV(+) HNSCC cells to cisplatin through apoptosis was not seen previously in the HPV(-) HNSCC cancer cells and is accompanied by a decreased expression of the antiapoptotic proteins, MCl-1and XIAP, which appear to be cleaved following AZD-1775 treatment.AZD-1775 selectively sensitizes HPV(+) HNSCC cells and orthotopic oral xenografts to cisplatin through apoptosis and support the clinical investigation of AZD-1775 in combination with cisplatin particularly in patients with advanced and recurrent metastatic HPV(+) HNSCC tumors.
Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction
Authors: Eric J. Velazquez, Kerry L. Lee, Marek A. Deja, Anil Jain, George Sopko, Andrey Marchenko, Imtiaz S. Ali, Gerald Pohost, Sinisa Gradinac, William T. Abraham, Michael Yii, Dorairaj Prabhakaran, Hanna Szwed, Paolo Ferrazzi, Mark C. Petrie, Christopher M. O'Connor, Pradit Panchavinnin, Lilin She, Robert O. Bonow, Gena Roush Rankin, Robert H. Jones, Jean-Lucien Rouleau
Journal: New England Journal of Medicine (2011)

The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established.
Assessment of Tumor Necrosis Factor Alpha Blockade As an Intervention to Improve Tolerability of Dose-Intensive Chemotherapy in Cancer Patients
Authors: J. Paul Monk, Gary Phillips, Ross Waite, John Kuhn, Larry J. Schaaf, Gregory A. Otterson, Denis Guttridge, Chris Rhoades, Manisha Shah, Tamara Criswell, Michael A. Caligiuri, Miguel A. Villalona-Calero
Journal: Journal of Clinical Oncology (2006)

Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue. Tumor necrosis factor (TNF) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies. We used etanercept (TNF-decoy receptor) to maintain dose-intensity of weekly docetaxel.Initially, 12 patients with advanced malignancies were randomly assigned to either docetaxel 43 mg/m2 weekly alone (cohort A) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly (cohort B). Subsequently, higher doses of docetaxel in combination with etanercept were evaluated. Pharmacokinetics (PKs), nuclear factor-kappa B (NF-kappaB) activation, and intracellular cytokines levels were measured. Patients completed weekly questionnaires quantifying asthenia/fatigue.Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A, and 35 of 36 doses were delivered in cohort B (P = .055). Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity, whereas no patients from cohort A received additional cycles. Escalation to docetaxel 52 mg/m2 weekly with etanercept resulted in neutropenia, not fatigue, as the limiting adverse effect, and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients. Patients randomly selected to receive etanercept/docetaxel self-reported less fatigue (P < .001), and docetaxel PKs show no relevant influence of etanercept. NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose. Antitumor activity was noticed exclusively in patients receiving etanercept.The addition of etanercept is safe and had no impact on docetaxel concentrations. The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies.
Rare diseases bullet 6: Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis
Authors: P. L Shah
Journal: Thorax (2000)

Pulmonary alveolar proteinosis was first described by Rosen et al in 1958. 1 It is an unusual diVuse lung disease characterised by the accumulation of large amounts of a phospholipoproteinaceous material in the alveoli.It has a variable clinical presentation and course.Most cases are primary but occasionally the condition is secondary to other conditions or inhalation of chemicals.Whole lung lavage remains the most eVective treatment and the overall prognosis is good.Surfactant homeostasis is abnormal and animal experiments suggest that this may relate, in some instances at least, to defects in GM-CSF signalling.There are at least two congenital forms of the disease and several diVerent animal models suggesting that pulmonary alveolar proteinosis is unlikely to be a single disease entity and more likely to represent a clinical syndrome. EpidemiologyPulmonary alveolar proteinosis is a rare lung disease and accurate estimates of incidence are not available.Current estimates suggest an incidence of one in two million people.2][3][4][5][6][7][8][9] However, there are reports of the disease occurring in neonates, 12 children, [13][14][15] and the elderly. 11
Tissue factor induction by aggregated LDL depends on LDL receptor-related protein expression (LRP1) and Rho A translocation in human vascular smooth muscle cells
Authors: S CAMINOLOPEZ, V LLORENTECORTES, J SENDRA, L BADIMON
Journal: Cardiovascular Research (2006)

Objective: Low density lipoprotein (LDL) internalized in the vascular wall and modified by binding to extracellular matrix-proteoglycans (ECM) becomes aggregated (agLDL). AgLDL induces tissue factor (TF) expression and activity in human vascular smooth muscle cells (VSMC). TF expression in vascular cells promotes the prothrombotic transformation of the vascular wall. However, the mechanisms by which agLDL induces TF are not known. The aim of this study was to investigate the mechanisms involved in TF activation by extracellular matrix-modified LDL in human VSMC.
American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation Universal Definition of Myocardial Infarction Classification System and the Risk of Cardiovascular Death
Authors: Marc P. Bonaca, Stephen D. Wiviott, Eugene Braunwald, Sabina A. Murphy, Christian T. Ruff, Elliott M. Antman, David A. Morrow
Journal: Circulation (2011)

The availability of more sensitive biomarkers of myonecrosis and a new classification system from the universal definition of myocardial infarction (MI) have led to evolution of the classification of MI. The prognostic implications of MI defined in the current era have not been well described.We investigated the association between new or recurrent MI by subtype according to the European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation Task Force for the Redefinition of MI Classification System and the risk of cardiovascular death among 13 608 patients with acute coronary syndrome in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). The adjusted risk of cardiovascular death was evaluated by landmark analysis starting at the time of the MI through 180 days after the event. Patients who experienced an MI during follow-up had a higher risk of cardiovascular death at 6 months than patients without an MI (6.5% versus 1.3%, P<0.001). This higher risk was present across all subtypes of MI, including type 4a (peri-percutaneous coronary intervention, 3.2%; P<0.001) and type 4b (stent thrombosis, 15.4%; P<0.001). After adjustment for important clinical covariates, the occurrence of any MI was associated with a 5-fold higher risk of death at 6 months (95% confidence interval 3.8-7.1), with similarly increased risk across subtypes.MI is associated with a significantly increased risk of cardiovascular death, with a consistent relationship across all types as defined by the universal classification system. These findings underscore the clinical relevance of these events and the importance of therapies aimed at preventing MI.
Sniff nasal inspiratory pressure in children with muscular, chest wall or lung disease
Authors: B. Fauroux, G. Aubertin, E. Cohen, A. Clément, F. Lofaso
Journal: European Respiratory Journal (2008)

Sniff nasal inspiratory pressure is proposed as a noninvasive test of inspiratory muscle strength. During this manoeuvre, the nasal pressure is supposed to reflect oesophageal pressure. The aim of the present study was to compare the nasal pressure with the oesophageal pressure during a maximal sniff in children with neuromuscular disease (NM, n = 78), thoracic scoliosis (n = 12) and cystic fibrosis (CF, n = 23). A significant correlation was observed between the sniff nasal and oesophageal pressure. The ratio of the sniff nasal/oesophageal pressure was lower in patients with CF (0.72±0.13) than in NM patients (0.83±0.17) or patients with thoracic scoliosis (0.86±0.10). In patients with CF and NM disease, this ratio was not correlated to age or spirometric data. The difference between the sniff oesophageal and nasal pressure exceeded 15 cmH 2 O in 17, 33 and 87% of the NM, thoracic scoliosis and CF patients, respectively. Sniff nasal pressure often underestimates the strength of inspiratory muscles in cystic fibrosis. Such an underestimation occurs more rarely in neuromuscular disease disorders and thoracic scoliosis. A normal value excludes inspiratory muscle weakness but a low value requires the measurement of the oesophageal pressure.
Abstract 581: Development of RNA interference-based therapeutics for bladder cancer and hepatocellular carcinoma
Authors: Kathy L. Fosnaugh, Shaguna Seth, Yoshiyuki Matsui, Roger Adami, Narendra Vaish, Yan Chen, Yan Liu, Pierrot Harvie, Rachel Johns, Gregory Severson, Susan Bell, Brian Granger, Tianying Zhu, Pat Charmley, Alan So, Michael V. Templin, Barry Polisky
Journal: Cancer Research (2010)

Abstract Bladder cancer and hepatocellular carcinoma are two of many cancers refractory to current treatments. Small interfering RNAs (siRNAs) are a new therapeutic modality able to specifically silence expression of targets not accessible via current small molecule and antibody options. MDRNA is developing UsiRNAs, a novel siRNA construct containing unlocked nucleobase analogs, with improved specificity for RNA interference (RNAi). Delivery of UsiRNAs to target tissues is achieved using proprietary Di-alkylated Amino Acid (DiLA2)-based liposomes. Survivin, overexpressed in many cancers, is involved in cell division and inhibition of apoptosis. In orthotopic and xenograft models of liver cancer, systemic administration of survivin UsiRNA-DiLA2 liposomes resulted in approximately 60% and 70% reductions in survivin mRNA, respectively, and &amp;gt; 50% decreases in tumor weight. Local intravesical administration in an orthotopic bladder cancer model resulted in 90% inhibition of mRNA expression and substantial tumor growth inhibition. Polo-like kinase 1 (PLK-1), also elevated in many tumors, regulates cell cycle progression and mitosis. Treatment of bladder cancer and liver cancer cell lines with PLK-1 UsiRNA/DiLA2 liposomes leads to significant caspase activation and corresponding apoptotic cell death. In vivo studies with PLK-1 UsiRNA are in progress. These UsiRNAs and UsiRNAs directed against additional targets are being evaluated in vitro and in orthotopic and xenograft models of cancer as single agents, in combinations of target-specific UsiRNAs, and with existing small molecule and antibody therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 581.
Childhood IQ and Adult Mental Disorders: A Test of the Cognitive Reserve Hypothesis
Authors: Karestan C. Koenen, Terrie E. Moffitt, Andrea L. Roberts, Laurie T. Martin, Laura Kubzansky, HonaLee Harrington, Richie Poulton, Avshalom Caspi
Journal: American Journal of Psychiatry (2008)

Cognitive reserve has been proposed as important in the etiology of neuropsychiatric disorders. However, tests of the association between premorbid IQ and adult mental disorders other than schizophrenia have been limited and inconclusive. The authors tested the hypothesis that low childhood IQ is associated with increased risk and severity of adult mental disorders.Participants were members of a representative 1972-1973 birth cohort of 1,037 males and females in Dunedin, New Zealand, who were followed up to age 32 with 96% retention. WISC-R IQ was assessed at ages 7, 9, and 11. Research diagnoses of DSM mental disorders were made at ages 18, 21, 26, and 32.Lower childhood IQ was associated with increased risk of developing schizophrenia spectrum disorder, adult depression, and adult anxiety. Lower childhood IQ was also associated with greater comorbidity and with persistence of depression; the association with persistence of generalized anxiety disorder was nearly significant. Higher childhood IQ predicted increased risk of adult mania.Lower cognitive reserve, as reflected by childhood IQ, is an antecedent of several common psychiatric disorders and also predicts persistence and comorbidity. Thus, many patients who seek mental health treatment may have lower cognitive ability; this should be considered in prevention and treatment planning.
The Accuracy of Clinical Assessment of Dehydration During Diabetic Ketoacidosis in Childhood
Authors: Ildiko H. Koves, Jocelyn Neutze, Susan Donath, Warren Lee, George A. Werther, Peter Barnett, Fergus J. Cameron
Journal: Diabetes Care (2004)

The objective of this study was to examine the accuracy of the assessment of clinical dehydration in children with type 1 diabetes and diabetic ketoacidosis (DKA). DKA remains the single most common cause of diabetes-related death in childhood (1). Accurate assessment and management of dehydration is the cornerstone of DKA treatment (1,2). The assessment of the degree of dehydration has traditionally been according to clinical criteria including peripheral tissue perfusion and indicators of hemodynamic status (3). The clinical assessment of dehydration in children in common nonacidotic states (e.g., gastroenteritis) has been previously shown (4) to overestimate the degree of dehydration by ∼3.2%. There have been no comparable studies in either DKA or any other form of metabolic acidosis.

We studied a random convenience sample of 37 children with type 1 diabetes, newly or previously diagnosed, who presented to the Royal Children’s Hospital, Melbourne, with DKA. The patients were all <18 years of age and presented to the emergency department at Royal Children’s Hospital between 1996 and 2000. The study entry criteria were pH <7.30 (capillary, venous, or arterial) and/or bicarbonate <15 mmol/l and ketones in the urine on dipstick testing. The following information was recorded by the primary assessing doctor: newly diagnosed or established diabetes, age, sex, date and time seen, heart rate, respiratory rate, blood pressure, pale and/or cool hands and feet, peripheral capillary refill time, reduced skin …
Epitope-dependent Selection of Highly Restricted or Diverse T Cell Receptor Repertoires in Response to Persistent Infection by Epstein-Barr Virus
Authors: Pedro-Otavio de Campos-Lima, Victor Levitsky, Martha P. Imreh, Riccardo Gavioli, Maria G. Masucci
Journal: The Journal of Experimental Medicine (1997)

The T cell receptor (TCR) repertoires of cytotoxic responses to the immunodominant and subdominant HLA A11–restricted epitopes in the Epstein-Barr virus (EBV) nuclear antigen-4 were investigated in four healthy virus carriers. The response to the subdominant epitope (EBNA4 399-408, designated AVF) was highly restricted with conserved Vβ usage and identical length and amino acid motifs in the third complementarity-determining regions (CDR3), while a broad repertoire using different combinations of TCR-α/β V and J segments and CDR3 regions was selected by the immunodominant epitope (EBNA4 416-424, designated IVT). Distinct patterns of interaction with the A11–peptide complex were revealed for each AVF- or IVT-specific TCR clonotype by alanine scanning mutagenesis analysis. Blocking of cytotoxic function by antibodies specific for the CD8 coreceptor indicated that, while AVF-specific TCRs are of high affinity, the oligoclonal response to the IVT epitope includes both low- and high-affinity TCRs. Thus, comparison of the memory response to two epitopes derived from the same viral antigen and presented through the same MHC class I allele suggests that immunodominance may correlate with the capacity to maintain a broad TCR repertoire.
Increased Carotid Intima-Media Thickness and Stiffness in Obese Children
Authors: Arcangelo Iannuzzi, Maria Rosaria Licenziati, Ciro Acampora, Vittorio Salvatore, Lucia Auriemma, Maria Luigia Romano, Salvatore Panico, Paolo Rubba, Maurizio Trevisan
Journal: Diabetes Care (2004)

HOMA, homeostasis model
Splenectomy and the increasing risk of secondary acute leukemia in Hodgkin's disease.
Authors: S Tura, M Fiacchini, P L Zinzani, E Brusamolino, P G Gobbi
Journal: Journal of Clinical Oncology (1993)

PURPOSE Following irradiation alone, secondary acute nonlymphocytic leukemia (ANLL) is uncommon; following chemotherapy alone, the risk is increased, but not as much as when combined modality treatments are used. Because ANLL seems more likely to occur in splenectomized patients, attention is focused on an unexpected association between splenectomy and the risk of secondary leukemia. PATIENTS AND METHODS The risk of ANLL was assessed in 503 patients with Hodgkin's disease (HD) homogeneously treated with combined modality therapy (mechlorethamine, vincristine, procarbazine, and prednisone [MOPP] plus radiotherapy). These patients were diagnosed from 1970 through 1984 and monitored until June 1991. RESULTS ANLL was observed in one of 145 (0.69%) patients not splenectomized and in 21 of 358 (5.86%) splenectomized patients, demonstrating a significantly higher frequency of ANLL in the group of patients who underwent splenectomy. The group of patients who developed ANLL received a statistically greater number of MOPP courses than did the group not developing ANLL. ANLL was statistically more frequent in those patients who received more than four cycles of MOPP. Sex, symptoms, extent of radiotherapy, splenectomy, age, and number of MOPP courses were assessed for their impact on ANLL incidence by multivariate analysis. CONCLUSION Cox's proportional hazards regression showed that splenectomy and, as previously described by others, the number of courses of MOPP are prognostic factors that increase the risk of secondary ANLL in HD patients treated with combined modality therapy. These data raise interesting questions regarding the possible role of the spleen in leukemia development.
Expression of ΔNp73 Predicts Poor Prognosis in Lung Cancer
Authors: Hidetaka Uramoto, Kenji Sugio, Tsunehiro Oyama, Shoji Nakata, Kenji Ono, Masaru Morita, Keiko Funa, Kosei Yasumoto
Journal: Clinical Cancer Research (2004)

Abstract Purpose: ΔNp73 is an isoform of the p53 homologue p73, which lacks an NH2-terminal transactivation domain and antagonizes the induction of gene expression by p53/p73. The aim of this study was to detect ΔNp73 expression in lung cancer and to evaluate the relationship between the ΔNp73 expression level and the prognosis of patients with resected lung cancer. Experimental Design: We used immunohistochemistry to analyze the protein expression of ΔNp73 in paraffin-embedded tumor samples from 132 well-characterized lung cancer patients and compared the expression level of ΔNp73, clinical variables, and survival outcome. Results: Positive expression of ΔNp73 was detected mainly in the cytoplasm of tumor cells in 77 of 132 patients (58.3%) with lung cancer. The incidence of positive expression of ΔNp73 was 52.2, 50.0, and 70.2% in patients with stage I, II, and III, respectively (P = 0.04). Positive expression of ΔNp73 was associated with gender but not associated with age, histologic type, pathological stage, pathological T status, and pathological N status. Lung cancer patients with positive ΔNp73 expression had a poorer prognosis than those with negative ΔNp73 expression. In addition, multivariate analysis of the clinicopathological characteristics of lung cancer indicated that positive expression of ΔNp73 was a significant independent factor for predicting poor prognosis (P &amp;lt; 0.0001, risk ratio = 3.39). Conclusions: Expression of ΔNp73 may be a useful marker for predicting poor prognosis of patients who underwent resection of lung cancer.
Child poverty and malnutrition rise in Spain as austerity measures bite
Authors: A. Garcia Rada
Journal: BMJ (2013)

The austerity measures the European Union has demanded that the Spanish government impose because of the economic crisis are having a deepening impact on the most vulnerable. 

A recent report on child malnutrition in the autonomous community of Catalonia (7.5 million inhabitants)1 said that 50 000 children were now suffering food deprivation. As of 30 June this year, there were 751 cases of malnutrition and other poverty related diagnoses, affecting 0.06% of the child population and mostly among foreigners (56%).

In 2011, the prevalence of Catalan households that could not …