tbuckley/cabot-search huggingface dataset:
<i>PIK3CA</i> Mutations in Head and Neck Squamous Cell Carcinoma
Authors: Wanglong Qiu, Frank Schönleben, Xiaojun Li, Daniel J. Ho, Lanny G. Close, Spiros Manolidis, Boyce P. Bennett, Gloria H. Su
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic α (PIK3CA) gene in several human solid tumors. Although gene amplifications of PIK3CA have been reported in head and neck squamous cell carcinoma (HNSCC), small mutation of the gene has not been evaluated in HNSCC previously. In this study, we examined the mutation frequency of PIK3CA in HNSCC. Experimental Design: More than 75% of the somatic mutations of PIK3CA are clustered in the helical (exon 9) and kinase domains (exon 20). To investigate the possible role of PIK3CA in HNSCC tumorigenesis, exons 1, 4, 5, 6, 7, 9, and 20 of the gene were analyzed by direct genomic DNA sequencing in 38 HNSCC specimens. Results: We identified four missense mutations in the seven exons of PIK3CA from 38 HNSCC specimens (11%). Three of the four mutations (i.e., H1047R, E542K, and E545K) have been previously reported as hotspot mutations. The remaining novel mutation, Y343C, is identified at exon 4 nucleotide 1028 A → G. Three of the four mutations were shown to be somatic, whereas the fourth mutation (H1047R) was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples. Conclusions: These data provide evidence that oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers, especially in pharyngeal cancer. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer in particular.
A series of Infections due to Capnocytophaga spp. in immunosuppressed and immunocompetent patients
Authors: H. Bonatti, D. W Rossboth, D. Nachbaur, M. Fille, C. AspöUck, I. Hend, K. Hourmont, L. White, H. Malnick, F.J. Allerberger
Journal: Clinical Microbiology and Infection (2003)
Chronic non-specific ulcerative duodenojejunoileitis: report of four cases.
Authors: R Modigliani, P Poitras, A Galian, B Messing, P Guyet-Rousset, M Libeskind, J L Piel-Desruisseaux, J C Rambaud
Journal: Gut (1979)

Four patients with chronic non-specific ulcerative duodenojejunoileitis (CNSUDJI) are reported. The clinical picture included abdominal pain, fever, and a malabsorption syndrome. Main rediological findings were diffuse narrowing of the jejunal loops with total effacement of the mucosal folds. Multiple peroral biopsies of the small intestine showed various degrees of mucosal abnormalities from total villous atrophy to normal villi, but ulcerations were diagnosed only by operative full thickness biopsies or resection of the small bowel. The ulcerative process was associated with well-documented coeliac disease in two patients: in one of them it occurred as a fatal complication involving also the colon, three years after the start of a gluten free diet, while the disease was in full clinical and histological remission. In the other case, coeliac disease was revealed by obstructive symptoms due to stenosing ulcerations; five months after surgical resection of the stenosis, institution of a gluten free diet induced a dramatic improvement. In the two other patients ulcerations were not associated with coeliac disease: one of them had a patchy villous atrophy and resisted a gluten free diet and total parenteral nutrition; she was improved by and dependent upon steroids but finally died. The last patient had normal villous height; ulcerations were located exclusively along the mesenteric border of the small bowel; he had a low-grade protracted evolution resisting any form of therapy and developed a peripheral neuropathy of unknown aetiology. On the basis of our cases and of a review of the literature the discussion focuses on the difficulty in diagnosing CNSUDJI, its relationship with coeliac disease, and its management and prognosis.
Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells
Authors: Rachel Sarig, Noa Rivlin, Ran Brosh, Chamutal Bornstein, Iris Kamer, Osnat Ezra, Alina Molchadsky, Naomi Goldfinger, Ori Brenner, Varda Rotter
Journal: The Journal of Experimental Medicine (2010)

p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, we studied the influence of mutant p53 (mut-p53) on somatic cell reprogramming. Our data indicate a novel gain of function (GOF) property for mut-p53, which markedly enhanced the efficiency of the reprogramming process compared with p53 deficiency. Importantly, this novel activity of mut-p53 induced alterations in the characteristics of the reprogrammed cells. Although p53 knockout (KO) cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability and gave rise to malignant tumors. This novel GOF of mut-p53 is not attributed to its effect on proliferation, as both p53 KO and mut-p53 cells displayed similar proliferation rates. In addition, we demonstrate an oncogenic activity of Klf4, as its overexpression in either p53 KO or mut-p53 cells induced aggressive tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells, such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.
Impaired gastric accommodation and its role in dyspepsia
Authors: S Kindt, J Tack
Journal: Gut (2006)

The accommodation reflex is an important mechanism of normal gastric physiology. In functional dyspepsia, impairment of accommodation has been found in 40% of cases, but it has been described in several other upper gastrointestinal disorders, such as diabetic gastropathy and postfundoplication syndrome. This review focuses on the pathways involved in the normal accommodation reflex, the relevance of impaired gastric accommodation as a cause of morbidity and the methods used to assess gastric accommodation in humans. The available medical and therapeutic strategies based on the actual knowledge of the physiology and pharmacology of the accommodation reflex are outlined, with a focus on the role of nitrergic neurones and serotonergic receptors.
Hypoxia Enhances Metastatic Efficiency in HT1080 Fibrosarcoma Cells by Increasing Cell Survival in Lungs, Not Cell Adhesion and Invasion
Authors: Li Zhang, Richard P. Hill
Journal: Cancer Research (2007)

Abstract This study examined possible mechanisms for hypoxia-increased metastasis in a green fluorescent protein–labeled human fibrosarcoma cell line (HT1080). The efficiency of the lung arrest of tumor cells, which can be dependent on the adhesive potential of the tumor cells, was assessed by measuring the level of integrin α3β1 protein and by adhesion assays, whereas the extravasation potential was examined by an invasion assay. These properties were not changed by exposure to hypoxia, indicating that lung arrest and extravasation are unlikely to play a major role in the effect of hypoxia on metastasis in this model. The main effect of hypoxic exposure was found to be increased survival after lung arrest as determined by clonogenic assay of tumor cells recovered from mouse lungs after i.v. injection. Concomitantly, apoptosis was identified as responsible for the death of lung-arrested cells, suggesting the involvement of an altered apoptotic response following hypoxic exposure of these cells. Consistent with this finding, we found that the effect of hypoxia on both increased metastasis and survival of arrested cells was inhibited by treatment with farnesylthiosalicylic acid. However, this effect was not due to down-regulation of hypoxia-inducible factor-1α, a mechanism of action of this drug reported by previous studies. Further detailed studies of the mechanisms of action of the drug are needed. [Cancer Res 2007;67(16):7789–97]
Amplification and Overexpression of the <i>KIT</i> Gene Is Associated with Progression in the Seminoma Subtype of Testicular Germ Cell Tumors of Adolescents and Adults
Authors: Alan McIntyre, Brenda Summersgill, Beata Grygalewicz, Ad J.M. Gillis, J. Stoop, Ruud J.H.L.M. van Gurp, Nening Dennis, Cyril Fisher, Robert Huddart, Colin Cooper, Jeremy Clark, J. Wolter Oosterhuis, Leendert H.J. Looijenga, Janet Shipley
Journal: Cancer Research (2005)

Abstract We have previously identified amplification at 4q12 in testicular germ cell tumors of adolescents and adults centered around the KIT gene encoding a tyrosine kinase transmembrane receptor. Analysis of primary testicular germ cell tumors totaling 190 cases revealed 21% of the seminoma subtype with an increased copy number of KIT whereas this change was rarely found in the nonseminomas. In most cases, gain of KIT did not include the immediately flanking noncoding DNA or the flanking genes KDR and PDGFRA. Increased copy number of KIT was not found in the putative precursor lesion, carcinoma in situ (CIS), adjacent to tumor with this change. KIT overexpression was found independent of gain and KIT immunostaining was stronger in selected cases with gain of KIT compared to those without. Taken together with activating mutations of KIT in exon 17 identified in 13% of seminomas, this suggests that the KIT gene product plays a role in the progression of CIS towards seminoma, the further understanding of which may lead to novel less toxic therapeutic approaches.
Primary mFOLFOX6 Plus Bevacizumab Without Resection of the Primary Tumor for Patients Presenting With Surgically Unresectable Metastatic Colon Cancer and an Intact Asymptomatic Colon Cancer: Definitive Analysis of NSABP Trial C-10
Authors: Laurence E. McCahill, Greg Yothers, Saima Sharif, Nicholas J. Petrelli, Lily Lau Lai, Naftali Bechar, Jeffrey K. Giguere, Shaker R. Dakhil, Louis Fehrenbacher, Samia H. Lopa, Lawrence D. Wagman, Michael J. O'Connell, Norman Wolmark
Journal: Journal of Clinical Oncology (2012)

Purpose Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial. Patients and Methods Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention. Results Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months). Conclusion This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT.
MTDH Activation by 8q22 Genomic Gain Promotes Chemoresistance and Metastasis of Poor-Prognosis Breast Cancer
Authors: Guohong Hu, Robert A. Chong, Qifeng Yang, Yong Wei, Mario A. Blanco, Feng Li, Michael Reiss, Jessie L.-S. Au, Bruce G. Haffty, Yibin Kang
Journal: Cancer Cell (2009)
Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration
Authors: Paolo Grumati, Luisa Coletto, Patrizia Sabatelli, Matilde Cescon, Alessia Angelin, Enrico Bertaggia, Bert Blaauw, Anna Urciuolo, Tania Tiepolo, Luciano Merlini, Nadir M Maraldi, Paolo Bernardi, Marco Sandri, Paolo Bonaldo
Journal: Nature Medicine (2010)
Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons
Authors: Luigi F. Agnati, Sergi Ferré, Carme Lluis, Rafael Franco, Kjell Fuxe
Journal: Pharmacological Reviews (2003)

The molecular basis for the known intramembrane receptor/receptor interactions among G protein-coupled receptors was postulated to be heteromerization based on receptor subtype-specific interactions between different types of receptor homomers. The discovery of GABA<sub>B</sub> heterodimers started this field rapidly followed by the discovery of heteromerization among isoreceptors of several G protein-coupled receptors such as δ/κ opioid receptors. Heteromerization was also discovered among distinct types of G protein-coupled receptors with the initial demonstration of somatostatin SSTR<sub>5</sub>/dopamine D<sub>2</sub> and adenosine A<sub>1</sub>/dopamine D<sub>1</sub> heteromeric receptor complexes. The functional meaning of these heteromeric complexes is to achieve direct or indirect (via adapter proteins) intramembrane receptor/receptor interactions in the complex. G protein-coupled receptors also form heteromeric complexes involving direct interactions with ion channel receptors, the best example being the GABA<sub>A</sub>/dopamine D<sub>5</sub> receptor heteromerization, as well as with receptor tyrosine kinases and with receptor activity modulating proteins. As an example, adenosine, dopamine, and glutamate metabotropic receptor/receptor interactions in the striatopallidal GABA neurons are discussed as well as their relevance for Parkinson9s disease, schizophrenia, and drug dependence. The heterodimer is only one type of heteromeric complex, and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist. These complexes may assist in the process of linking G protein-coupled receptors and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for some forms of learning and memory.
Bronchoalveolar lavage immunodiagnosis for tuberculosis suspects in Europe and Africa
Authors: C. Lange, A. Bossink, R. Eberhardt, D. Goletti, C. Jafari, I. Latorre, D. Kirsten, M. Losi, G. B. Migliori, G. Sotgiu
Journal: Thorax (2010)

We read with interest the article by Dheda et al 1 who followed our approach for a rapid diagnosis of smear-negative tuberculosis by bronchoalveolar lavage (BAL) enzyme-linked immunospot (ELISpot)2 in a country of high tuberculosis incidence, including individuals with HIV-1 infection.

The authors report a sensitivity of 88.9% and specificity of 94.7% of the BAL ELISpot (T-SPOT.TB test) for the diagnosis of tuberculosis in suspects with scarce or negative acid-fast bacilli (AFB) sputum smears. This observation is important, as it confirms the findings of other …
Asthma, airway inflammation and epithelial damage in elite athletes
Authors: K-H. Carlsen
Journal: European Respiratory Journal (2009)

In recent years there has been special focus on the increased occurrence of asthma and bronchial responsiveness among top athletes within endurance sports. As early as 1989, an increase in nonspecific bronchial responsiveness after heavy endurance training was found in young competitive swimmers 1. Later, reports were made concerning increased prevalence of asthma and bronchial hyperresponsiveness to metacholine among top cross-country skiers 2, 3. Reports came from Trondheim (Norway) regarding inflammatory changes in bronchial biopsies appearing during a winter season in young competitive cross-country skiers 4, 5. These studies confirmed that both bronchial responsiveness and airway inflammation increased through heavy endurance training 1–5.

In the Olympic arena, such reports were confirmed by Voy 6, who reported a prevalence of exercise-induced asthma of 11% among the American summer Olympic athletes of 1984; this increased to >20% among the American participants in the 1996 summer Olympic Games, and was especially high among cyclists and mountain bikers 7. K. Fitch (who supplied some of the data presented in 8) reported that the use of asthma drugs and, in particular, inhaled β2-agonists, was highest in cross-country skiing and speed-skating followed by cycling, Nordic combined (both cross-country skiing and ski jumping) …
Systemic inflammation in patients with chronic obstructive pulmonary disease
Authors: Nataliia Sanina, Tetyana Pertseva, Svitlana Panina
Journal: European Respiratory Journal (2013)

COPD is considered a systemic disease with chronic inflammation, predominantly in distal respiratory tract with the development of bronchial remodeling and reduction of pulmonary function. One of lipid mediators with important role in resolution of inflammation is lipoxin A4 - an eicosanoid derived from arachidonic acid.  In order to study the severity of systemic inflammation, we assessed level of lipoxin A4 in blood plasma. Were examined 64 patients with COPD stage II-III without exacerbation, mean age 54,2 ± 1,3 yrs, 91.7% male, disease duration 12,4 ± 1,0 yrs, mean FEV1 64,2 ± 4,5%, smoking index - 15,8 ± 2,7 yrs, dyspnea by mMRC 2,1 ± 0,1 pts, CAT score - 23,2 ± 0,7 pts.  In COPD patients lipoxin A4 level was 1,62 ± 0,09 ng/ml, whereas in healthy individuals it was 0,38 ± 0,75 ng/ml, p   The correlation analysis showed a direct relationship of lipoxin A4 level and leukocytes (r=0,66), granulocytes in the peripheral blood (r=0,34), total cholesterol (r=0,40) and HDL cholesterol (r=0, 39), level of total protein (r=0,34), and its inverse relationship with 6MWT distance (r=-0, 41). All correlations were significant with p   Thus we have shown the presence of active and intense persistent systemic inflammatory process in the patients with COPD, as evidenced by the level of lipoxin A4. Determination of lipoxin A4 in blood plasma of COPD patients may be one of the markers of systemic inflammation activity, and its normalization can be a promising area of rehabilitation of COPD patients.
Amiloride reduces portal hypertension in rat liver cirrhosis
Authors: C. J. Steib, M. Hennenberg, F. Beitinger, A. C. Hartmann, M. Bystron, E. N. De Toni, A. L. Gerbes
Journal: Gut (2010)

This study aimed to investigate the effect of amiloride on portal hypertension. Amiloride is known to inhibit Na(+)/H(+) exchangers on activated hepatic stellate cells.Liver cirrhosis in rats was induced by bile duct ligation (BDL) or thioacetamide (TAA) administration. The effects of zymosan for Kupffer cell (KC) activation or a thromboxane (TX) analogue (U46619) were tested in isolated perfused livers of cirrhotic rats and in vivo. Downstream mechanisms were investigated using Rho kinase inhibitor (Y-27632) or amiloride. Acute and chronic effects of amiloride and canrenoate on portal pressure were compared in perfused livers and in vivo. TXB(2) efflux was measured by ELISA. The phosphorylation state of moesin (p-moesin) as an indicator of Rho kinase activity and expression of the thromboxane synthase were assessed by western blot analyses. The activity of hepatic stellate cells was analysed by western blot and staining for alpha-smooth muscle actin (alpha-SMA).In BDL rats, KC activation via zymosan increased portal pressure. This was attenuated by the Rho kinase inhibitor Y-27632. Increased thromboxane efflux following zymosan infusion remained unaltered by Y-27632. The infusion of amiloride attenuated zymosan- and U46619-induced increases in portal perfusion pressure. In vivo, direct administration of amiloride, but not of canrenoate, lowered portal pressure. In TAA and BDL rats, treatment with amiloride for 3 days reduced basal portal pressure and KC-induced increases in portal pressure whereas canrenoate had no effect. In livers of amiloride-treated animals, the phosphorylation state of moesin and the number of alpha-SMA positive cells were reduced.Amiloride lowers portal pressure in rat liver cirrhosis by inhibition of intrahepatic vasocontraction. Therefore, patients with cirrhosis and portal hypertension may benefit from amiloride therapy.
Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate.
Authors: G A Curt, J Jolivet, D N Carney, B D Bailey, J C Drake, N J Clendeninn, B A Chabner
Journal: Journal of Clinical Investigation (1985)

We have characterized the determinants of methotrexate (MTX) responsiveness in eight patient-derived cell lines of small-cell lung cancer (SCLC). Clonogenic survival was correlated with factors known to affect sensitivity to drug. NCI-H209 and NCI-H128 were most drug sensitive, with drug concentrations required to inhibit clonogenic survival by 50% with less than 0.1 microM MTX. Six cell lines (NCI-H187, NCI-H345, NCI-H60, NCI-H524, NCI-H146, and NCI-N417D) were relatively drug resistant. In all cell lines studied, higher molecular weight MTX-polyglutamates (MTX-PGs) with 3-5 glutamyl moieties (MTX-Glu3 through MTX-Glu5) were selectively retained. Relative resistance to low (1.0 microM) drug concentrations appeared to be largely due to decreased intracellular metabolism of MTX. Five of the six resistant lines were able to synthesize polyglutamates at higher (10 microM) drug concentrations, although one resistant cell line (NCI-N417D) did not synthesize higher molecular weight MTX-PGs, even after exposure to 10 microM drug. Two cell lines with resistance to 10 microM MTX (NCI-H146 and NCI-H524) synthesized and retained higher molecular weight MTX-PGs in excess of binding capacity after exposure to 10 microM drug. However, the specific activity of thymidylate synthase in these cell lines was low. MTX sensitivity in patient-derived cell lines of SCLC requires the ability of cells to accumulate and retain intracellular drug in the form of polyglutamate metabolites in excess of dihydrofolate reductase, as well as a high basal level of consumption of reduced folates in the synthesis of thymidylate.
Dual Functional Activity of Semaphorin 3B Is Required for Positioning the Anterior Commissure
Authors: Julien Falk, Ahmad Bechara, Roberto Fiore, Homaira Nawabi, Heather Zhou, Carolina Hoyo-Becerra, Muriel Bozon, Geneviève Rougon, Martin Grumet, Andreas W. Püschel, Joshua R. Sanes, Valérie Castellani
Journal: Neuron (2005)
Stenting after cutting balloon versus plain old balloon angioplasty: Interim results of the REDUCE III trial
Authors: Tetsu Yamaguchi, Takahiko Suzuki, Michihiko Kitayama, Hideo Nishikawa, Teruo Inoue, Masami Sakurada, Kazuhiro Hara, Fumihiko Usuba, Kojiro Awano, Tetsuo Matsubara, Osamu Kato, Shinichi Momomura, Tatsuya Yasukawa, Yukio Ozaki
Journal: Journal of the American College of Cardiology (2003)