tbuckley/cabot-search huggingface dataset:
Abstract P2-16-13: Phase I dose escalation clinical trial of the PI3K inhibitor BKM120 and capecitabine (C) in metastatic breast cancer (MBC)
Authors: EC Dees, PK Marcom, A Snavely, J Noe, CK Anders, K Blackwell, G Kimmick, K Reeder-Hayes, D Rosenstein, CM Perou, LA Carey
Journal: Cancer Research (2013)

Abstract Background: PIK3CA is one of the most frequently mutated genes in human breast cancer, and the high expression of a PIK3CA-pathway signature is associated with the poor prognosis Luminal B and Basal-like expression subtypes. BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which has shown activity in preclinical and early clinical testing, and synergy with both endocrine and chemotherapy. In this trial we sought to evaluate the safety and estimate the maximum tolerated dose (MTD) of the combination of BKM120 and C in patients (pts) with MBC. Methods: In a 3+3 dose escalation design, we evaluated four cohorts of BKM 120 daily plus C BID x 14 days in 21 day cycles. Standard definitions for DLT and MTD were used and evaluated on the first cycle. Toxicity was graded by CTCAE version 4. Response was evaluated after 2 cycles by RECIST criteria. Pts with MBC appropriate for treatment with C who had &amp;lt;4 prior chemotherapy regimens and normal organ, bone marrow and cardiac parameters were eligible. Results: 21 pts (11 hormone receptor (HR)+, 3 HER2+, 9 HR/HER2-negative) were enrolled and treated. All were evaluable for toxicity and 14 for response to date. Median age was 54 (range 35-65). Median prior chemotherapy regimens for MBC was 2 (range 1-4). The following dose levels (DL) were evaluated: BKM120 50 mg/d + C 1000 mg/m2/BID x 14(DL 1-4 pts), BKM120 80 mg/d + C 1000 mg/m2/BID x 14 (DL2-3 pts), BKM120 100 mg/d + C 1000 mg/m2/BID x 14 (DL3-9 pts), BKM120 100 mg/d + C 1250 mg/m2/BID x 14 (DL4-5 pts). Most frequent adverse events (all grades) included: Nausea (12), mood disorders (11), PPE (9), diarrhea (8), fatigue (7), vomiting (5) mucositis (4), rash (4), photosensitivity (3), hyperglycemia (3). Grade 3 or higher AEs in any cycle were transaminitis (3) diarrhea (2) mood disorder (2), hyperglycemia, fatigue, photosensitivity, PPE (1 pt each). DLTs: grade 3 hyperglycemia (1/6 pts at DL3), and grade 3 mood disorder in 1/5 pts DL 4. Additionally 4 of 5 patients at DL 4 required dose reduction or delay prior to C3D1. Thus DL 4 exceeded the MTD and DL 3 was expanded for further safety evaluation. Antitumor activity was seen with best responses of 1 CR (at DL 3), 3 PR (DL1 and 4) and 7 SD. PK analysis, assessment of tumor PIK3CA mutation status and intrinsic subtype by PAM50 is ongoing. Conclusions: The combination of BKM120 100 mg po q day and C 1000 mg/m2 / BID x 14 d in 21 day cycles is tolerable and appears active. PK and biomarker analysis are ongoing. A phase II trial is planned. Acknowledgements: This study was funded by Novartis Pharmaceuticals and by a grant from Susan G. Komen for the Cure (SAC 110044). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-13.
β<sub>2</sub>-Adrenergic Receptor Arg16/Arg16 Genotype Is Associated with Reduced Lung Function, but Not with Asthma, in the Hutterites
Authors: ELEANOR SUMMERHILL, STEPHANIE A. LEAVITT, HEIDI GIDLEY, RODNEY PARRY, JULIAN SOLWAY, CAROLE OBER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In a genome-wide screen for asthma loci in the Hutterites, a marker locus on chromosome 5q23–31 showed evidence of linkage to asthma (C. Ober and colleagues, Hum. Molec. Genet. 1998;7:1393). To determine whether the β2-adrenergic receptor ( β2AR) gene is the 5q-linked asthma locus in the Hutterites, we genotyped this sample for polymorphisms in the β2AR gene. Neither the Arg16Gly nor Gln27Glu polymorphisms showed evidence of linkage to qualitative measures of asthma and bronchial hyperresponsiveness (BHR) (p > 0.10) or to quantitative measures of serum IgE and airway reactivity (p > 0.10). In contrast, FEV1 percentage of predicted and FVC percentage of predicted were significantly lower among individuals homozygous for the Arg16 allele (FEV1 %: 98.3 ± 13.2% versus 103.8 ± 14.9%, p = 0.003; FVC %: 104.2 ± 12.3% versus 108.3 ± 13.2%, p = 0.02 by t test). These findings held true for adolescents and adults, but not for children ⩽ 12 yr of age. This study demonstrates that the observed linkage to asthma in the 5q23–31 region is unrelated to variation in the β2AR gene. However, it is the first study to suggest that the β2AR Arg16Gly polymorphism influences either lung growth or the rate of decline of lung function with age.
Loving opioids in the brain
Authors: Jaak Panksepp, Joseph R. Moskal
Journal: Behavioral and Brain Sciences (2005)

brain opioids regulate social emotions in several distinct ways. the abundance of neuroscientific detail in the target article helps familiarize the uninitiated with the true and humbling complexities of mammalian brains, but little of it translates to research strategies, with robust predictions, at the human level. only global neurochemical affective state variables derived from animal research have clear implications for human research.
Reconstructive Coronary Artery Surgery: Postoperative Assessment
Authors: WILLIAM C. SHELDON, F. MASON SONES, EARL K. SHIREY, DAVID J. G. FERGUSSON, RENE G. FAVALORO, DONALD B. EFFLER
Journal: Circulation (1969)

Results of 288 direct coronary artery reconstructive operations in 281 patients have been reported. Selected patients with segmental obstructive lesions in their coronary arteries can be helped with direct reconstructive surgery. Best results have been achieved in patients with isolated segmental obstructions in the predominant right coronary artery. With the saphenous vein graft technique, surgical mortality has been reduced to 5.1%, and angiographic evidence of improvement has been achieved in three of four of the survivors. The direct surgical reconstruction of segmental occlusive disease offers the advantage of immediate improvement of myocardial perfusion, attendant protection against myocardial infarction, and immediate improvement if not complete remission of symptoms of myocardial ischemia. Excellent long-term results have been obtained in many patients who underwent patch-graft reconstruction; early experience indicates that saphenous vein graft reconstruction can be accomplished for patients with a greater variety of obstructive lesions, with better reliability, and lower risk. Its ultimate role in the surgical treatment of coronary atherosclerosis, however, will require a longer period of observation.
Germline Brca2 Heterozygosity Promotes KrasG12D -Driven Carcinogenesis in a Murine Model of Familial Pancreatic Cancer
Authors: Ferdinandos Skoulidis, Liam D. Cassidy, Venkat Pisupati, Jon G. Jonasson, Hordur Bjarnason, Jorunn E. Eyfjord, Florian A. Karreth, Michael Lim, Lorraine M. Barber, Susan A. Clatworthy, Susan E. Davies, Kenneth P. Olive, David A. Tuveson, Ashok R. Venkitaraman
Journal: Cancer Cell (2010)
Leadership in Community Mental Health
Authors: Dana L. Farnsworth, Howard Rome
Journal: JAMA (1964)

NO GREATER MEDICAL problem exists than that of devising improved methods of treating the mentally ill and at the same time formulating effective ways of preventing such illness whenever and wherever possible. The impetus to improve the care of the mentally ill and develop better programs for raising the level of mental health in the nation is probably greater than most physicians realize. The medical profession will either have to assume strong leadership in this rapidly changing field or run the risk of having this role taken over by other disciplines. In view of the central importance of medicine in the diagnosis and treatment of mental illness, it would be most unfortunate if professions with more peripheral interests were to assume the primary positions of leadership, but this is what they may do if medicine does not discharge the responsibilities that so clearly belong to it. <h3>Congress on Mental Health</h3>
Intravenous Administration of Metoprolol Is More Effective Than Oral Administration in the Prevention of Atrial Fibrillation After Cardiac Surgery
Authors: Jari Halonen, Tapio Hakala, Tommi Auvinen, Jari Karjalainen, Anu Turpeinen, Ari Uusaro, Pirjo Halonen, Juha Hartikainen, Mikko Hippeläinen
Journal: Circulation (2006)

Background— Atrial fibrillation (AF) is the most common arrhythmia to occur after cardiac surgery, with an incidence of 20% to 40%. AF is associated with postoperative complications, including increased risk of stroke and need of additional treatment, as well as prolonged hospital stay and increased costs. It has been shown that prophylactic oral administration of β-blocker therapy reduces the incidence of postoperative AF after cardiac surgery. However, it is possible that absorption of drugs is impaired after cardiopulmonary perfusion associated with cardiac surgery. The purpose of this prospective, controlled, randomized trial was to study compare intravenous and per oral metoprolol administration in the prevention of AF after cardiac surgery. Methods and Results— 240 consecutive patients who were scheduled to undergo their first on-pump coronary artery bypass graft (CABG), aortic valve replacement, or combined aortic valve replacement and CABG were randomized to receive 48-hour infusion of metoprolol or oral metoprolol starting on the first postoperative morning. Patients were excluded if they had contraindications for β-blocker or had to stay &gt;1 day in the intensive care unit. Dosage of metoprolol was adjusted according to heart rate. The dosage was 1 to 3 mg/h in the intravenous group and from 25 mg twice per day to 50 mg 3 times per day in the oral group. The incidence of postoperative AF was significantly lower in the intravenous group than in the oral group (16.8% versus 28.1%, P =0.036). No serious adverse effects were associated with intravenous metoprolol therapy. Conclusions— Our study suggests that intravenous metoprolol is well-tolerated and more effective than oral metoprolol in the prevention of AF after cardiac surgery.
CD62L Is Required on Effector Cells for Local Interactions in the CNS to Cause Myelin Damage in Experimental Allergic Encephalomyelitis
Authors: Iqbal S. Grewal, Harald G. Foellmer, Kate D. Grewal, Hua Wang, Wyne P. Lee, Daniel Tumas, Charles A. Janeway, Richard A. Flavell
Journal: Immunity (2001)
Effects on Quality of Life of Combined Trastuzumab and Chemotherapy in Women With Metastatic Breast Cancer
Authors: David Osoba, Dennis J. Slamon, Michael Burchmore, Maureen Murphy
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The study was designed to compare the effects of treatment with a combination of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and chemotherapy versus chemotherapy alone on health-related quality of life (HRQL) in patients with HER-2/neu overexpressing, metastatic breast cancer. PATIENTS AND METHODS: A sample of 400 patients, not previously treated for metastatic disease and randomized to receive either trastuzumab plus chemotherapy (208 patients) or chemotherapy alone (192 patients), completed the European Organization for Research and Treatment Care Quality of Life Questionnaire at baseline and on at least one subsequent occasion at 8, 20, 32, 44, and 56 weeks. HRQL improvement or worsening was defined as a ≥ 10-point change (range, 0 to 100 points) in the scores of six preselected domains (global quality of life [QOL], physical, role, social, and emotional functioning, and fatigue). Stable HRQL was defined as a change of less than 10. A Bonferroni correction was applied for multiple testing. RESULTS: After completion of chemotherapy, patients treated with trastuzumab and chemotherapy reported significant improvement in fatigue (P &lt; .05) as compared with their baseline scores. Higher proportions of patients receiving the combined therapy achieved improvement in global QOL (P &lt; .05) than did patients treated with chemotherapy alone. Higher proportions of the combined therapy group also achieved improvement in physical and role functioning and in fatigue as compared with the chemotherapy group, but the differences were not statistically significant. There were no differences in the proportions of patients in the two groups that reported worsening. CONCLUSION: Statistically significantly higher proportions of patients treated with a combination of trastuzumab and chemotherapy reported improved global QOL than did patients treated by chemotherapy alone.
Imbalance of prostacyclin and thromboxane synthesis in Crohn's disease.
Authors: C J Hawkey, F Karmeli, D Rachmilewitz
Journal: Gut (1983)

Synthesis of prostanoids in Crohn's disease was investigated using rectal biopsy specimens maintained in organ culture. As with ulcerative colitis increased synthesis of prostaglandin (PG)E2 was observed when the mucosa was inflamed, compared with uninflamed mucosa in Crohn's disease, and with control biopsy specimens. In contrast with ulcerative colitis differences from control specimens were observed even in the absence of inflammation. There was a raised synthesis of thromboxane (Tx)B2 (stable breakdown product of TxA2); concentrations of 6-keto PGF1 alpha (stable breakdown product of prostacyclin) were unchanged and hence the ratio of 6-keto PGF1 alpha/TxB2 was reduced. These changes might lead to an altered cytoprotective capacity or reduced suppressor cell activity, such as has previously been reported in intestinal lymphocytes in Crohn's disease.
22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis
Authors: Michinori Hirata, Kyoko Katsumata, Toshimi Masaki, Nobuo Koike, Koichi Endo, Kunihiko Tsunemi, Hiroyuki Ohkawa, Kiyoshi Kurokawa, Masafumi Fukagawa
Journal: Kidney International (1999)
TCTAP C-022 A Case with STEMI Due to Acute Occlusion of Left Internal Mammary Artery Graft in Postoperative Remote Period
Authors: Shingo Yamamoto, Kei Yamamoto, Kohki Ishida, Shin-Ichi Momomura, Takeshi Ishida, Tomohiro Nakamura, Yusuke Adachi
Journal: Journal of the American College of Cardiology (2014)
Rapid, severe repigmentation of congenital melanocytic naevi after curettage and dermabrasion: histological features
Authors: K. Kishi, N. Matsuda, Y. Kubota, K.-I. Katsube, N. Imanishi, T. Nakajima
Journal: British Journal of Dermatology (2007)

Curettage and dermabrasion are effective in treating giant congenital melanocytic naevi (GCMN). We report two patients with rapid, severe postoperative repigmentation. To the best of our knowledge this is the first report on the histological features of such patients.We wish to call attention to histological features that may cause rapid, severe repigmentation after curettage and dermabrasion of medium to giant CMN.From 1998 to 2002, we treated 23 patients with medium to giant CMN with curettage and dermabrasion. Patients being treated ranged in age from 1 month to 19 years. Histological samples were taken from the centre of naevi in all patients during surgery. Histological types were 12 intradermal and 11 compound. Follow-up after curettage lasted at least 3 years.Among our 23 patients only two showed repigmentation soon after surgery. Histological sections from these two patients indicated naevoid cells in the deep dermis along hair follicles or sebaceous glands. However, no such pigmented naevoid cells along hair follicles were observed in samples from patients successfully treated with curettage and dermabrasion with less repigmentation.Although we saw only two cases of repigmentation soon after curettage and dermabrasion, we suspect a correlation between pigmented naevoid cells around hair follicles and repigmentation. If histological sections of skin biopsies show pigmented cells along hair follicles in the deep dermis, other treatments such as total skin resection followed by skin grafting or tissue expansion may be better choices than curettage or dermabrasion.
Familial Sinus Bradycardia Associated with a Mutation in the Cardiac Pacemaker Channel
Authors: Raffaella Milanesi, Mirko Baruscotti, Tomaso Gnecchi-Ruscone, Dario DiFrancesco
Journal: New England Journal of Medicine (2006)

We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic AMP (cAMP)-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis found that mutant channels respond normally to cAMP but are activated at more negative voltages than are wild-type channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia.
Micrometastases in bone marrow in patients with breast cancer.
Authors: R W Blamey, J F Robertson, A P Locker
Journal: BMJ (1987)

Self injury and mental handicap SIR,-Like suicide, self injury is a form of self mutilation and is not always a form of attention seeking due to boredom, as Dr Brian Kirman assumes (31 October, p 1086).Suicide and self mutilation are often forms of aggression turned inwards and associated with aggression to others.This is particularly true ofthe mentally retarded.Control ofaggression is difficult but notoriously so in those severely retarded.'From 1969 onwards there have been several reports on the usefulness of lithium in patients exhibiting aggression.The patients included groups of delinquents, psychotics, and the ment- ally handicapped.The larger studies indicate a positive response in some 70-75% of cases.2These figures were confirmed in the first published multicentre double blind trial of lithium in mentally handicapped patients, published last May.3Until the survey quoted by Dr Kirma. is published it is not possible to say whether the authors were aware of this but it seems unlikely.Lithium is not necessarily a cure and is usually given only when all other methods have failed, although a plea for its earlier use in these patients was made recently.5It seems helpful in relieving aggression, including self mutilation, in these patients, which distresses them, their relatives, and staff.The grave shortages of staff trained in behavioural techniques may to some extent be relieved if this element is used with effect.The patient may become more receptive to this type of treatment.
Effects of chronic myocardial infarction on responsiveness to isoprenaline and the state of myocardial beta adrenoceptors in rats
Authors: J.-P. CLOZEL, M. HOLCK, W. OSTERRIEDER, W. BURKARD, M. D. PRADA
Journal: Cardiovascular Research (1987)

Responsiveness to catecholamines and alterations in myocardial beta adrenoceptors were determined in rats with chronic myocardial infarction. Myocardial infarction was produced by ligating the left main coronary artery. Three weeks after myocardial infarction, when left ventricular function was impaired, catecholamine responsiveness was determined by measuring the effects of isoprenaline in the conscious animal, the isolated perfused heart, the isolated right atria, and the right papillary muscles. The catecholamine content and the density and affinity of beta adrenergic receptors [( 3H]dihydroalprenolol binding) were determined in non-ischaemic myocardium (ventricular septum). In conscious rats isoprenaline induced the same tachycardia in the sham operated as in the rats with infarction, but it induced only a slight increase of myocardial contractility because of a high basal sympathetic tone. In isolated perfused hearts, right atria, and right papillary muscles isoprenaline increased contractile force and heart rate with the same EC50 in both groups. However, in the infarcted group the maximal increase of contractile force induced by isoprenaline was smaller because of mechanical limitation due to the infarction. The catecholamine content was decreased in non-ischaemic myocardium and beta adrenergic density was increased by 30% (p less than 0.02) without any change of affinity. Thus in rats chronic myocardial infarction does not change the responsiveness of the non-ischaemic myocardium to isoprenaline and is not associated with a downregulation of the beta adrenoceptors.
The Changing Pool of International Medical Graduates Seeking Certification Training in US Graduate Medical Education Programs
Authors: Gerald P. Whelan
Journal: JAMA (2002)

International medical graduates (IMGs) consistently represent approximately one fourth of both the physician workforce and the graduate medical education (GME) population of the United States. To enter into accredited US GME programs, IMGs must be certified by the Educational Commission for Foreign Medical Graduates (ECFMG). Changes in the number and characteristics of those seeking certification directly affect the GME population and the future physician workforce in the United States. In July 1998, in response to concerns that IMGs might be lacking in basic clinical skills (eg, history taking, physical examinations, communicating with patients in spoken English), the ECFMG initiated a requirement that IMGs pass a clinical skills assessment (CSA) to achieve ECFMG certification. In this study we examined the pool of IMGs seeking certification, using databases reporting on all individuals beginning the certification process from 1995 through 2001. For this period, we found that the number of IMG candidates taking the Step 1 examination decreased by 45.5% (36,983 vs 16,828), and the number of IMGs registered to take Step 2 decreased by 38.1% (31 751 vs 12 122). The number of ECFMG certificates issued annually decreased, from a range of 9000 to 12,000 (1995-1998) to fewer than 6000 (1999-2001). Although the number of IMGs annually seeking and receiving certification has decreased, the quality of the applicants appears to have improved and the number of IMGs certified annually continues to adequately fill GME positions not taken by US medical graduates.
Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump
Authors: Renxue Wang, Huey-Ling Chen, Lin Liu, Jonathan A. Sheps, James M. Phillips, Victor Ling
Journal: Hepatology (2009)

Bile salt export pump (BSEP; ATP-binding cassette, subfamily B, member 11) mutations in humans result in progressive familial intrahepatic cholestasis type 2, a fatal liver disease with greatly reduced bile flow. However in mice, Bsep knockout leads only to mild cholestasis with substantial bile flow and up-regulated P-glycoprotein genes (multidrug resistance protein 1a [Mdr1a] and Mdr1b). To determine whether P-glycoprotein is responsible for the relatively mild phenotype observed in Bsep knockout mice, we have crossed mouse strains knocked out for Bsep and the two P-glycoprotein genes and generated a triple knockout mouse. We found that a knockout of the three genes leads to a significantly more severe phenotype with impaired bile formation, jaundice, flaccid gallbladder, and increased mortality. The triple knockout mouse is the most severe genetic model of intrahepatic cholestasis yet developed.P-glycoprotein functions as a critical compensatory mechanism, which reduces the severity of cholestasis in Bsep knockout mice.