tbuckley/cabot-search huggingface dataset:
Pharmacogenetic Profiling and Clinical Outcome of Patients With Advanced Gastric Cancer Treated With Palliative Chemotherapy
Authors: Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Emanuele Canestrari, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Enrica Testa, Rosarita Silva, Bruno Vincenzi, Paolo Giordani, Stefano Cascinu, Lucio Giustini, Giuseppe Tonini, Mauro Magnani
Journal: Journal of Clinical Oncology (2006)

To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC).Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival.The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis.Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.
Dysregulated expression of the T cell cytokine Eta-1 in CD4-8- lymphocytes during the development of murine autoimmune disease.
Authors: R Patarca, F Y Wei, P Singh, M I Morasso, H Cantor
Journal: The Journal of Experimental Medicine (1990)

The development of autoimmune disease in the MRL/MpJ-lpr inbred mouse strain depends upon the maturation of a subset of T lymphocytes that may cause sustained activation of immunological effector cells such as B cells and macrophages. We tested the hypothesis that abnormal effector cell activation reflects constitutive overexpression of a T cell cytokine. We found that a newly defined T cell cytokine, Eta-1, is expressed at very high levels in T cells from MRL/l mice but not normal mouse strains and in a CD4-8- 45R+ T cell clone. The Eta-1 gene encodes a secreted protein that binds specifically to macrophages, possibly via a cell adhesion receptor, resulting in alterations in the mobility and activation state of this cell type (Patarca, R., G. J. Freeman, R. P. Singh, et al. 1989. J. Exp. Med. 170:145; Singh, R. P., R. Patarca, J. Schwartz, P. Singh, and H. Cantor. 1990. J. Exp. Med. 171:1931). In addition, recent studies have indicated that Eta-1 can enhance secretion of IgM and IgG by mixtures of macrophages and B cells (Patarca, R., M. A. Lampe, M. V. Iregai, and H. Cantor, manuscript in preparation). Dysregulation of Eta-1 expression begins at the onset of autoimmune disease and continues throughout the course of this disorder. Maximal levels of Eta-1 expression and the development of severe autoimmune disease reflect the combined contribution of the lpr gene and MRL background genes.
Conjunctival ulcers in behçet’s disease
Authors: Ehud Zamir, Bahram Bodaghi, Ilknur Tugal-Tutkun, Robert F See, Frederic Charlotte, Robert C Wang, Bertrand Wechsler, Phuc LeHoang, Irene Anteby, Narsing A Rao
Journal: Ophthalmology (2003)
The association of bullous pemphigoid and malignant disease: a case control study
Authors: V.A. VENNING, F. WOJNAROWSKA
Journal: British Journal of Dermatology (2006)

In a case control study, the incidence of malignant disease in 84 patients with bullous pemphigoid (BP) was compared with 168 controls. The rate of malignant disease (past, concurrent or during follow‐up) in BP patients was 17.9% compared to 5.3% in the controls. A number of the malignancies occurring in the BP group may be of doubtful significance, being either temporally very remote or partially attributable to treatment. The rate of concurrent BP and malignancy (within 8 weeks) was 6.0% suggesting that there is probably a slight excess of malignancy in BP, but insufficient to warrant extensive investigation in pursuit of cancer. Comparison of the BP patients with and without cancer identified no clinical or immunopathological subgroups in whom investigations would be indicated. Three patients with both BP and malignancy were HLA‐DR 13 positive, which may point to an immunogenetic predisposition to both diseases.
Perinatal development influences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently
Authors: P.J Boels, J Deutsch, B Gao, S.G Haworth
Journal: Cardiovascular Research (2001)

Objective: As bradykinin (BYK) relaxes conduit (EPA) and resistance (RPA) pulmonary arteries from both perinatal and adult lungs, we investigated whether this vasodilator's relaxation-mechanisms were altered during perinatal development, differed between EPA and RPA and differed with other endothelium-dependent vasodilators, acetyicholine (ACH) and substance P (SP). Methods: Arteries from mature foetal (5 days), neonatal (≈5 min), newborn (60–84 h) and adult pigs (≥6 months) were isolated, mounted for in vitro isometric force recording, activated with PGF2α (30 μmol/l) and relaxed with BYK (10 pmol/l–1 μmol/l), SP (10 pmol/l–0.1 μmol/l) or ACH (1 nmol/l–1 mmol/l). Results: (i) BYK: l-NAME (100 μmol/l) attenuated relaxations in foetal EPA (≈55%) but nearly abolished them in the adult (≈80%). In RPA, l-NAME nearly abolished (≈90%) relaxations in the foetus and this effect diminished progressively with age to ≈20% in the adult. Indomethacin (IND, μmol/l) attenuated relaxations in neonatal (≈25%), new-born and adult EPA (both ≈45%). Together, l-NAME and IND abolished relaxations in all EPA and in neonatal RPA but not in older RPA. SKF525a (100 μmol/l) attenuated relaxations in foetal RPA (≈4%), diminishing in the adult RPA to ≈10%. Together, SKF52Sa and l-NAME largely abolished relaxations in postnatal RPA (≈80%). Activation with K+=125 mmol/l attenuated relaxations in adult EPA (≈80%), foetal RPA (≈45%) and neonatal RPA (≈75%) and abolished relaxations in RPA from older ages. (ii) ACH: l-NAME abolished relaxations in new-born EPA and RPA. In adult EPA, combined l-NAME and IND moderately attenuated relaxations. (iii) SP: Combined application of l-NAME and IND attenuated relaxations to a similar degree in new-born and adult EPA and RPA. Conclusions: In postnatal EPA, BYK-relaxations depend completely on prostaglandin- and NO-synthesis whereas those to SP (at all ages) and ACH (in the adult) do not. In RPA, BYK-relaxations develop from being completely dependant on the sole release of NO (foetus) to being almost completely independent of it (adult), a situation mimicked partially by SP but not by ACH, which, in new-born RPA is completely dependent on NO. BYK-relaxations in postnatal RPA depend on the release of a hyperpolarising factor generated through an SKF525a-sensitive pathway in conjunction with NO. The mechanisms of endothelium-dependent BYK-relaxations in the pulmonary vascular bed undergo diverging alterations, depending on the stage of development and arterial size/function. These changes are specific for BYK as they differ from those obtained from ACH or SP.
Ethical Issues in Informed Consent
Authors: D. Mark Mahler
Journal: JAMA (1982)

The decision to contain medical costs, which is a political and social decision, entails restriction of medical services. To guide public policy, research on the impact of such restriction must be carried out, but this type of research differs significantly from most other medical research. Difficult issues concerning informed consent arise, with potential conflicts among principles of maximization of good and minimization of harm to the patient, the patient's right to self-determination, and the utilitarian goal of maximization of collective welfare. We have discussed these principles in the context of relationships between patient and physician and between subject and investigator. Approaches considered include emphasis on retrospective studies, use of statistical techniques to formulate clinical decision-making rules on the basis of available data, three-celled randomization designs, and the role of the primary-care physician in maximizing patient autonomy and minimizing the potentially threatening aspects of informed consent for such studies. (<i>JAMA</i>1982;247:481-485)
Acoustic analysis of snoring before and after palatal surgery
Authors: T. M. Jones, A. C. Swift, P. M. A. Calverley, M. S. Ho, J. E. Earis
Journal: European Respiratory Journal (2005)

To investigate the effectiveness of palatal surgery for nonapnoeic snoring, 35 patients were block randomised to undergo one of two different palatoplasty procedures. Patients were admitted pre-operatively for audio recording of snoring sound and video recording of sleeping position, and between 1.0 and 4.1 months (mean 2.5) and between 5.9 and 17.5 months (mean 9.7) post-operatively. Sound files, comprising the inspiratory sound of the first 100 snores whilst sleeping in a supine position, were analysed using specifically designed software. Snore duration (s), loudness (dBA), periodicity (%) and energy ratios for the frequency bands 0–200 Hz, 0–250 Hz and 0–400 Hz were calculated. Subjective outcomes were noted. Operation type, body mass index, age, peak nasal inspiratory flow rate, Epworth sleep score and alcohol intake were considered as confounding variables. No patient was cured from snoring. Paired t-test analysis demonstrated statistically significant changes between pre- and early post-operative recordings for snore periodicity and energy ratios in the frequency ranges 0–200 Hz, 0–250 Hz and 0–400 Hz. In conclusion, only the 0–250-Hz energy ratio measurements maintained a statistically significant improvement at the time of the late post-operative recording, despite an obvious drift back to pre-operative levels. No confounding variables were identified. The subjective and objective results correlated poorly. Post-operative changes in the acoustic parameters of snoring sound, following palatal surgery, are demonstrable but short-lived.
Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer
Authors: Isaac Garcia-Murillas, Gaia Schiavon, Britta Weigelt, Charlotte Ng, Sarah Hrebien, Rosalind J. Cutts, Maggie Cheang, Peter Osin, Ashutosh Nerurkar, Iwanka Kozarewa, Javier Armisen Garrido, Mitch Dowsett, Jorge S. Reis-Filho, Ian E. Smith, Nicholas C. Turner
Journal: Science Translational Medicine (2015)

The identification of early-stage breast cancer patients at high risk of relapse would allow tailoring of adjuvant therapy approaches. We assessed whether analysis of circulating tumor DNA (ctDNA) in plasma can be used to monitor for minimal residual disease (MRD) in breast cancer. In a prospective cohort of 55 early breast cancer patients receiving neoadjuvant chemotherapy, detection of ctDNA in plasma after completion of apparently curative treatment-either at a single postsurgical time point or with serial follow-up plasma samples-predicted metastatic relapse with high accuracy [hazard ratio, 25.1 (confidence interval, 4.08 to 130.5; log-rank P < 0.0001) or 12.0 (confidence interval, 3.36 to 43.07; log-rank P < 0.0001), respectively]. Mutation tracking in serial samples increased sensitivity for the prediction of relapse, with a median lead time of 7.9 months over clinical relapse. We further demonstrated that targeted capture sequencing analysis of ctDNA could define the genetic events of MRD, and that MRD sequencing predicted the genetic events of the subsequent metastatic relapse more accurately than sequencing of the primary cancer. Mutation tracking can therefore identify early breast cancer patients at high risk of relapse. Subsequent adjuvant therapeutic interventions could be tailored to the genetic events present in the MRD, a therapeutic approach that could in part combat the challenge posed by intratumor genetic heterogeneity.
Stuck between Health and Immigration Reform — Care for Undocumented Immigrants
Authors: Benjamin D. Sommers
Journal: New England Journal of Medicine (2013)

Interview with Dr. Benjamin Sommers and Prof. Wendy Parmet on the limited health care and insurance options for both legal and undocumented U.S. immigrants. (22:02)Download Despite a flurry of political activity, health care for the approximately 11 million to 12 million undocumented immigrants in the United States remains a patchwork with gaping holes, and that reality is unlikely to change much over the coming decade.
It is time for patients to undergo bronchoscopy without discomfort
Authors: S. Gasparini
Journal: European Respiratory Journal (2011)

Thirty years ago, when I started performing bronchoscopy, sedation for flexible bronchoscopy was not a very common practice. At that time, some authors suggested that routine sedation could do little for patients undergoing the procedure and that bronchoscopy could be carried out without pre-medication [1–3]. However, over the last few decades, several things have changed. Patients’ need for comfort, and the desire to avoid anxiety and distress in patients undergoing medical procedures has increased generally. Furthermore, the advent and routine use of new bronchoscopic techniques and technologies have made diagnostic bronchoscopy a more complex procedure that requires prolonged time, the absence of cough, and patient cooperation and comfort. In this new scenario, the problem of sedation during bronchoscopy requires careful re-evaluation in order to definitively assess its indication and also to define the best sedative drugs to be used.

The British Thoracic Society guidelines on diagnostic flexible bronchoscopy recommend that sedation should be offered to patients when there is no contraindication [4], and in surveys conducted in the USA and in the UK in 1999 and in 2002, respectively, only 4 and 10% of physicians performed bronchoscopy without sedation [5, 6]. The old argument that up to half of the major complications of bronchoscopy are sedation related [7] is not confirmed by several more recent studies. In fact, even after comparing different sedative drugs versus placebo, no difference in the complication rate between sedated and nonsedated patients has been found [8–14], except for a slight but manageable increase in hypoxaemia risk with the use of midazolam and alfentanil [14] and a prolonged hospital stay after the procedure [10]. In fact, the use of sedation, when compared with placebo, resulted in improved …
Tumours of the Lung and the Carcinoid Syndrome
Authors: E. D. Williams, J. G. Azzopardi
Journal: Thorax (1960)

The majority of bronchial adenomas show a histological structure usually described as carcinoid in type.Until recently the term " carcinoid " used in this way was meant to be descriptive only, on the understanding that this tumour bore no relationship to the better-known carcinoids of the alimentary tract.This sharp distinction has been challenged histologically by Feyrter (1959a) and on functional grounds by Stanford, Davis, Gunter, and Hobart (1958) and by other workers who have described cases with metastasizing bronchial adenomas and the clinical and biochemical features of the carcinoid syndrome.The charac- teristics of the carcinoid syndrome in association with malignant argentaffinomas of the small bowel have been well described by Thorson, Biorck, Bjorkman, and Waldenstrom (1954) and many other writers.A case of bronchial adenoma previously published by Kincaid-Smith and Brossy (1956) has since shown features similar to those of the American workers.The new data on this case are presented here, together with some observations that cast light on the possible relationship between the carcinoid type of bronchial adenomas and carcinoids of the bowel.In addition, a case of oat-cell carcinoma of the bronchus with an associated " carcinoid " syn- drome is reported.The small group of bronchial and tracheal tumours of the adenoid cystic type ("cylindromas") are quite distinct from the carcinoid type, and are not discussed further.The clinico- pathological differences between the two types have been summarized by Feyrter (1959a and b).CASE REPORTS CASE 1.*-Mrs.W.A., aged 58, was first seen in Mr. Cleland's clinic in February, 1948, complaining of a cough and blood-streaked sputum.There was radiological evidence of collapse of the middle lobe of the right lung.A right middle and lower * An account of this case up to March, 1955, has been published by Kincaid-Smith and Brossy (1956).lobectomy was performed after biopsy.A bronchial adenoma, 11 mm. in diameter and 35 mm.long, occupied the medial branch of the middle lobe bronchus and extended into the lung parenchyma.Microscopically, it was a carcinoid type of bronchial adenoma (Fig. 1) with invasion of lymphatics.The patient was well until April, 1954, when she developed intermittent watery diarrhoea with no blood or mucus in the stools; this was accompanied by flatulence, colic, and abdominal rumblings.About this time she also complained of episodes of facial flushing.In September, 1954, a rounded tumour was felt in FIG.1.-Bronchial adenoma from Case I showing intraand extra- luminal growth (haematoxylin and eosin x 95).
Narrative Review: Furosemide for Hypercalcemia: An Unproven yet Common Practice
Authors: Susan B. LeGrand, Dona Leskuski, Ivan Zama
Journal: Annals of Internal Medicine (2008)

Although primary hyperparathyroidism is the most common cause of hypercalcemia, cancer is the most common cause requiring inpatient intervention. An estimated 10% to 20% of all patients with cancer have hypercalcemia at some point in their disease trajectory, particularly in advanced disease. Aggressive saline hydration and varying doses of furosemide continue to be the standard of care for emergency management. However, a review of the evidence for the use of furosemide in the medical management of hypercalcemia yields only case reports published before the introduction of bisphosphonates, in contrast to multiple randomized, controlled trials supporting the use of bisphosphonates. The use of furosemide in the management of hypercalcemia should no longer be recommended.
Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin
Authors: Hakan Alakus, Michele L Babicky, Pradipta Ghosh, Shawn Yost, Kristen Jepsen, Yang Dai, Angelo Arias, Michael L Samuels, Evangeline S Mose, Richard B Schwab, Michael R Peterson, Andrew M Lowy, Kelly A Frazer, Olivier Harismendy
Journal: Genome Medicine (2014)

Mucinous neoplasms of the appendix (MNA) are rare tumors which may progress from benign to malignant disease with an aggressive biological behavior. MNA is often diagnosed after metastasis to the peritoneal surfaces resulting in mucinous carcinomatosis peritonei (MCP). Genetic alterations in MNA are poorly characterized due to its low incidence, the hypo-cellularity of MCPs, and a lack of relevant pre-clinical models. As such, application of targeted therapies to this disease is limited to those developed for colorectal cancer and not based on molecular rationale.We sequenced the whole exomes of 10 MCPs of appendiceal origin to identify genome-wide somatic mutations and copy number aberrations and validated significant findings in 19 additional cases.Our study demonstrates that MNA has a different molecular makeup than colorectal cancer. Most tumors have co-existing oncogenic mutations in KRAS (26/29) and GNAS (20/29) and are characterized by downstream PKA activation. High-grade tumors are GNAS wild-type (5/6), suggesting they do not progress from low-grade tumors. MNAs do share some genetic alterations with colorectal cancer including gain of 1q (5/10), Wnt, and TGFβ pathway alterations. In contrast, mutations in TP53 (1/10) and APC (0/10), common in colorectal cancer, are rare in MNA. Concurrent activation of the KRAS and GNAS mediated signaling pathways appears to be shared with pancreatic intraductal papillary mucinous neoplasm.MNA genome-wide mutational analysis reveals genetic alterations distinct from colorectal cancer, in support of its unique pathophysiology and suggests new targeted therapeutic opportunities.
Expression of leptin and leptin receptor isoforms in the human stomach
Authors: H Mix, A Widjaja, O Jandl, M Cornberg, A Kaul, M Göke, W Beil, M Kuske, G Brabant, M P Manns, S Wagner
Journal: Gut (2000)

<h3>BACKGROUND</h3> Leptin is an important regulator of food intake and energy expenditure. Initially it was thought to be expressed exclusively in and secreted by adipocytes. Recently, leptin expression was also noted in other tissues, including rat gastric mucosa. Information on leptin and leptin receptor expression in the human stomach is lacking. <h3>AIM</h3> To investigate expression of leptin and its corresponding receptors in human gastric epithelial cells. <h3>METHODS</h3> Fundic and antral gastric mucosal biopsies, primary cultures of human gastric epithelial cells, and the human gastric cancer cell line AGS were screened for expression of leptin and different leptin receptor isoform mRNA by reverse transcriptase-polymerase chain reaction. Immunohistochemistry was performed for localisation of leptin and leptin receptor proteins in gastric mucosa. <h3>RESULTS</h3> mRNA of leptin and its four receptor isoforms (huOB-R, long receptor isoform; huB219.1–3, short receptor isoforms) was detected in gastric mucosal biopsies, cultured human gastric epithelial cells, and gastric cancer cells. Immunohistochemistry demonstrated that chief as well as parietal cells were reactive to leptin and leptin receptors. <h3>CONCLUSIONS</h3> Leptin and leptin receptors are expressed in human gastric mucosa. These findings suggest a paracrine and/or autocrine effect of leptin on gastric epithelial cell function.