tbuckley/cabot-search huggingface dataset:
Lung cancer: New biological insights and recent therapeutic advances
Authors: Suresh S. Ramalingam, Taofeek K. Owonikoko, Fadlo R. Khuri
Journal: CA A Cancer Journal for Clinicians (2011)

Approximately 1.6 million new cases of lung cancer are diagnosed each year throughout the world. In many countries, the mortality related to lung cancer continues to rise. The outcomes for patients with all stages of lung cancer have improved in recent years. The use of systemic therapy in conjunction with local therapy has led to improved cure rates in both resectable and unresectable patient groups. For patients with advanced stage disease, modest but real improvements in overall survival and quality of life have been achieved with systemic chemotherapy. A major focus of research has been the development of molecularly targeted agents and the identification of biomarkers for patient selection. Patients with non-small cell lung cancer with mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain achieve response rates of greater than 70% and superior progression-free survival when treated with an EGFR tyrosine kinase inhibitor compared with standard chemotherapy. This has now emerged as the preferred therapeutic approach for the subset of patients with a mutation in exons 19 or 21 of the EGFR. Another promising targeted approach involves the use of an anaplastic lymphoma kinase (ALK) inhibitor in patients with a translocation involving the echinoderm microtubule-associated protein-like 4 (EML4) and -ALK genes. Finally, a paradigm shift in favor of maintenance therapy for patients with advanced stage disease has gained strength from recent data. All of these advances have been made possible by developing a greater understanding of the biology, the discovery of novel anticancer agents, and improved supportive care measures. This article reviews the major strides made in the treatment of lung cancer in the recent past. CA Cancer J Clin 2011. © 2011 American Cancer Society, Inc.
Plasma Copeptin and Renal Outcomes in Patients With Type 2 Diabetes and Albuminuria
Authors: Gilberto Velho, Nadine Bouby, Samy Hadjadj, Nadia Matallah, Kamel Mohammedi, Frédéric Fumeron, Louis Potier, Naïma Bellili-Munoz, Christopher Taveau, François Alhenc-Gelas, Lise Bankir, Michel Marre, Ronan Roussel
Journal: Diabetes Care (2013)

Plasma copeptin, a surrogate for vasopressin, was associated with albuminuria in population-based studies. These associations are consistent with the effect of vasopressin on albuminuria observed in humans and rodents. The objective of this study was to determine whether plasma copeptin is an independent marker of risk of renal events in people with type 2 diabetes and albuminuria.We studied 3,101 participants of the DIABHYCAR trial (6-year follow-up) with type 2 diabetes and albuminuria. A renal event was defined as doubling of serum creatinine or development of end-stage renal disease.During follow-up, 86 renal events occurred in 76 subjects (2.45%). Incidences by tertiles of baseline plasma copeptin were 1.06% (T1), 1.45% (T2), and 4.84% (T3). They were 2.43% (T1), 5.11% (T2), and 11.81% (T3) for the subset of subjects with macroalbuminuria at baseline (n = 729). Hazard ratio for plasma copeptin tertiles as a risk for renal events was 4.79 (95% CI, 2.48-9.24; P < 0.0001; for T3 vs. T1). In a stepwise regression analysis, urinary albumin excretion and plasma copeptin remained positively associated and HDL cholesterol and estimated glomerular filtration rate were inversely associated with the incidence of renal events. These independent predictors explained ∼18% of the variance of the outcome. The yearly variations of estimated glomerular filtration rate by copeptin tertiles were -1.43 ± 0.51 (T1), -2.29 ± 0.49 (T2), and -3.52 ± 0.44 mL/min/1.73 m2 per year (T3) (P = 0.005) in subjects with macroalbuminuria.Plasma copeptin may help to identify subjects with diabetic chronic kidney disease who are at high risk for renal function decline.
Homozygous Deletion of <i>MTAP</i> Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors
Authors: Hsuan-Ying Huang, Shau-Hsuan Li, Shih-Chen Yu, Fong-Fu Chou, Ching-Cherng Tzeng, Tsung-Hui Hu, Yih-Huei Uen, Yu-Fang Tian, Yu-Hui Wang, Fu-Min Fang, Wen-Wei Huang, Yu-Ching Wei, Jing-Mei Wu, Chien-Feng Li
Journal: Clinical Cancer Research (2009)

Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs.To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation.Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11%) and seven high-risk (70%) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P < 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P < 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P < 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P < 0.0001), Ki-67 index >5% (P = 0.0106), and nongastric location (P = 0.0416).MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17% of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression.
ΔNp63 Overexpression, Alone and in Combination with Other Biomarkers, Predicts the Development of Oral Cancer in Patients with Leukoplakia
Authors: Pierre Saintigny, Adel K. El-Naggar, Vali Papadimitrakopoulou, Hening Ren, You-Hong Fan, Lei Feng, J. Jack Lee, Edward S. Kim, Waun Ki Hong, Scott M. Lippman, Li Mao
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. ΔNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess ΔNp63 expression in OPL and its role as a marker of oral cancer risk. Experimental Design: ΔNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus β-carotene with low-dose 13-cis-retinoic acid. The associations between ΔNp63 expression as well as ΔNp63 expression with other potential risk factors for oral cancer development were analyzed. Results: ΔNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were ΔNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive ΔNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive ΔNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P &amp;lt; 0.0001). Conclusion: ΔNp63 overepression in OPL is associated with increased oral cancer risk. Together, ΔNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk. (Clin Cancer Res 2009;15(19):6284–91)
Inhibition of Constitutive and Inducible Nitric Oxide Synthase: Potential Selective Inhibition
Authors: J M Fukuto, G Chaudhuri
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Nitric oxide (NO) is a molecule that has been shown to be involved in a diverse array of physiological events. A variety of disease states and disorders are, in fact, due to either an over- or an underproduction of NO. As a result of the ubiquity and diversity of NO-mediated phenomenon, pharmacological manipulation is difficult. NO biosynthesis is the result of an oxidation of a terminal nitrogen on the amino acid arginine by a class of enzymes generally referred to as the nitric oxide synthases (NOSs). Since the various isoforms of NOS are distributed in cells and tissues according to their function, there is the possibility that manipulation of NO levels can be accomplished by designing specific pharmacological agents targeted at a single NOS isoform. Thus, this review discusses general inhibition of the NOSs by a variety of agents and then focuses on the possibility of developing agents for specific isoform inhibition.
Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors
Authors: Sheri L. Spunt, Burgess B. Freeman, Catherine A. Billups, Valerie McPherson, Raja B. Khan, Charles B. Pratt, Clinton F. Stewart
Journal: Journal of Clinical Oncology (2007)

Purpose To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity. Patients and Methods Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m 2 , 130 mg/m 2 , or 160 mg/m 2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]). Results Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m 2 . The MTD was 130 mg/m 2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m 2 (range, 6.5 to 15.5 L/h/m 2 ). Addition of carbamazepine permitted dose escalation to 160 mg/m 2 without DLT. DLT was not observed with a fixed dose of 85 mg/m 2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed. Conclusion The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.
Eruptive angiomatous lesions associated with graft-versus-host disease
Authors: H. Adamski, F. Le Gall, L. Cartron, C. Dauriac, G. Lancien, J. Wechsler, I. Ollivier, S. Lachgar, C. Dosquet, M.C. Coudert, J. Chevrant-Breton
Journal: British Journal of Dermatology (2003)

Sir, Graft‐versus‐host disease (GVHD) is a complication of bone marrow transplantation.1 The skin is one of the most frequently affected organs. Different cutaneous manifestations have been observed in the acute and chronic phases of the disease. Acute GVHD often includes a maculopapular or scarlatiniform rash. In contrast, the chronic form is characterized by lichenoid or sclerodermatous lesions.1 We describe a patient who developed eruptive angiomatous lesions in the course of chronic GVHD. A 43‐year‐old‐man was diagnosed as having B‐cell chronic lymphocytic leukaemia in 1994. After failure of chemotherapy, he underwent allogeneic bone marrow transplantation in January 1999. One month later, he presented with acute GVHD: disseminated erythema with pruritus, diarrhoea and hepatic involvement. He had received oral prednisone and ciclosporin on alternative days with success for 2 years. However, his dermatological status had progressed to generalized sclerosis. Histopathology revealed vacuolization of the epidermal basal cell layer with satellite necrotic keratinocytes and lymphocytic infiltration with collagen fibrosis of the dermis. These findings were consistent with chronic GVHD. In October 2000, numerous red and necrotic nodules erupted on the back and limbs (Fig. 1a). Skin biopsies showed dermal vascular proliferation with cavities containing papillary endothelial hyperplasia (Fig. 1b). The stroma was oedematous with enlarged macrophages. Warthin–Starry stain was negative. Electron microscopy did not reveal the rod‐like profile of bartonellosis. Mycological and mycobacterial cultures of nodules were negative. Polymerase chain reaction was negative for human herpesvirus 8 nucleotide sequences in skin lesions. Various therapeutic procedures such as shave biopsy and cryotherapy failed. In February 2002, evaluation of angiogenic factors revealed high levels of urinary basic fibroblast growth factor (bFGF; 6214 pg g−1 creatinine; normal < 465) and serum vascular endothelial growth factor (VEGF; 559 pg mL−1; normal < 143). Thalidomide 100–300 mg daily was initiated. One month later, the patient suffered from neurological deterioration and died.
Hepatocellular adenomatosis presenting as prurigo
Authors: I. Loze, M.H. Tessier, O. Jumbou, B. Dreno
Journal: British Journal of Dermatology (2000)

Journal Article Hepatocellular adenomatosis presenting as prurigo Get access I. Loze, I. Loze Clinique Dermatologique, C.H.U., Hôtel‐Dieu, Place A.Ricordeau, 44093 Nantes cedex 1, France E‐mail: bdreno@chu‐nantes.fr Search for other works by this author on: Oxford Academic Google Scholar M.H. Tessier, M.H. Tessier Clinique Dermatologique, C.H.U., Hôtel‐Dieu, Place A.Ricordeau, 44093 Nantes cedex 1, France E‐mail: bdreno@chu‐nantes.fr Search for other works by this author on: Oxford Academic Google Scholar O. Jumbou, O. Jumbou Clinique Dermatologique, C.H.U., Hôtel‐Dieu, Place A.Ricordeau, 44093 Nantes cedex 1, France E‐mail: bdreno@chu‐nantes.fr Search for other works by this author on: Oxford Academic Google Scholar B. Dreno B. Dreno Clinique Dermatologique, C.H.U., Hôtel‐Dieu, Place A.Ricordeau, 44093 Nantes cedex 1, France E‐mail: bdreno@chu‐nantes.fr Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 2, 1 February 2000, Pages 384–386, https://doi.org/10.1046/j.1365-2133.2000.03321.x Published: 01 February 2000
Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus
Authors: Z. Z R Hamady, N. Scott, M. D Farrar, J P. A Lodge, K. T Holland, T. Whitehead, S. R Carding
Journal: Gut (2009)

<h3>Abstract</h3> The most promising way to prevent the explosive spread of COVID-19 infection is to achieve herd immunity through vaccination. It is therefore important to motivate those who are less willing to be vaccinated. To address this issue, we conducted an online survey of 6232 Japanese people to investigate age- and gender-dependent differences in attitudes towards COVID-19 vaccination and the underlying psychological processes. We asked participants to read one of nine different messages about COVID-19 vaccination and rate their willingness to be vaccinated. We also collected their 17 social personality trait scores and demographic information. We found that males 10-20 years old showed the minimum willingness to be vaccinated. We also found that prosocial traits are the driving force for young people, but the motivation in older people also depends on risk aversion and self-interest. Furthermore, an analysis of 9 different messages demonstrated that for young people (particularly males), the message emphasizing the majority's intention to vaccinate and scientific evidence for the safety of the vaccination had the strongest positive effect on the willingness to be vaccinated, suggesting that the herding effect arising from the "majority + scientific evidence" message nudges young people to show their prosocial nature in action.
Activated Protein C Induces Endothelial Cell Proliferation by Mitogen-Activated Protein Kinase Activation In Vitro and Angiogenesis In Vivo
Authors: Mitsuhiro Uchiba, Kenji Okajima, Yuichi Oike, Yasuhiro Ito, Kenji Fukudome, Hirotaka Isobe, Toshio Suda
Journal: Circulation Research (2004)

Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase (MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor (EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinase-dependent phosphorylation, followed by activation of protein kinase G, suggesting that APC bound to EPCR might activate the endothelial MAPK pathway by a mechanism similar to that of VEGF. APC induced morphogenetic changes resembling tube-like structures of endothelial cells, whereas DIP-APC did not. When applied topically to the mouse cornea, APC clearly induced angiogenesis in wild-type mice, but not in eNOS knockout mice. These in vitro events induced by APC might at least partly explain the angiogenic activity in vivo. This angiogenic activity of APC might contribute to maintain proper microcirculation in addition to its antithrombotic activity.
Arterial hypoxaemia in morbid obesity
Authors: Ebymar Arismendi, Eva Rivas, Yolanda Torralba, Concepcion Gistau, Felip Burgos, Josep Roca, Roberto Rodriguez-Roisin
Journal: European Respiratory Journal (2012)

Introduction: Morbid obesity (MO) can be associated with arterial hypoxaemia, mostly due to a highly prevalent obstructive sleep apnoea (OSA).  Objective: To determine the prevalence of hypoxaemia in patients with MO before and one year after bariatric surgery (BS) and its correlation with OSA.  Methods: We included 230 patients (44±[SD]12 yrs; 165 females; BMI, 46±7 kg/m2; and, waist-to-hip-ratio, 0.96±0.08). OSA was defined as an apnoea/hypopnoea index (AHI) ≥10.  Results: Before BS, all patients (ERV, 33±22%) had spirometry and DLCO within reference values, with normal PaO2 (83±12 mmHg) and PaCO2 (36±3 mmHg) values. One hundred and fifty four (70%) patients had OSA (48%, severe OSA [AHI ≥30]), 66 (43%) with hypoxaemia (PaO2, 70±7 mmHg). Patients with OSA had lower PaO2 and higher PaCO2 than those without OSA (p   Conclusions: Hypoxaemia continues to be a common finding in MO, mostly in patients with OSA. However, hypoxaemia can also be present without OSA, possibly related to central obesity.  Supported by FIS PI080311, CIBERES, Almirall and Esteve.
Clinical Course of Polyoma Virus Nephropathy in 67 Renal Transplant Patients
Authors: Emilio Ramos, Cinthia B. Drachenberg, John C. Papadimitriou, Omar Hamze, Jeffrey C. Fink, David K. Klassen, Rene C. Drachenberg, Anne Wiland, Ravinder Wali, Charles B. Cangro, Eugene Schweitzer, Stephen T. Bartlett, Matthew R. Weir
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 ± 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 ± 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus–negative control group, the PVN patients were older (P = .0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P = .0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.
Decision analysis in the surgical treatment of patients with familial adenomatous polyposis: a Dutch-Scandinavian collaborative study including 659 patients
Authors: H F A Vasen, P van Duijvendijk, E Buskens, C Bülow, J Björk, H J Järvinen, S Bülow
Journal: Gut (2001)

BACKGROUND AND AIMS The choice of colorectal surgery in patients with familial adenomatous polyposis lies between the morbidity of proctocolectomy and ileum-pouch-anal anastomosis (IPAA) and the mortality from rectal cancer after total colectomy and ileorectal anastomosis (IRA). The aims of the present study were: (1) to assess the risk of dying from rectal cancer after IRA, (2) to compare the life expectancy between patients with an IRA and those with an IPAA, and (3) to investigate whether regular endoscopic examination of the rectum leads to detection of cancer at an earlier stage. METHODS Clinical and pathological data on 659 patients who underwent colectomy and ileorectal anastomosis were collected from four national polyposis registries—that is, in Denmark, Finland, Sweden, and the Netherlands. Data were analysed using survival analysis methods. Decision analysis was used to compare the life expectancy between patients with an IRA and those with an IPAA. RESULTS A total of 47 patients developed rectal cancer after IRA. The risk of dying from rectal cancer was 12.5% (95% confidence interval 7.1–17.9%) by age 65. Compared with IRA, IPAA would lead to an increase in life expectancy of 1.8 years. Seventy five per cent of patients with rectal cancer had a negative rectoscopy within 12 months before the diagnosis. CONCLUSION IRA is associated with substantial mortality due to rectal cancer. Follow up examinations of the rectum does not have sufficient preventive effect on morbidity and mortality of rectal cancer.