tbuckley/cabot-search huggingface dataset:
Abstract P6-12-05: Ways To Understand Mechanism of Action for Targeted Drugs? Gene Expression Analyses from Paired Biopsies in Patients with Advanced Breast Cancer in a Substudy from the Randomized Study Docetaxel +/− Sunitinib A6181064
Authors: LS Lindstrom, C Giorgetti, J Smeds, A-L Borg, A-L Liljegren, L Skoog, KA Kern, J. Bergh
Journal: Cancer Research (2010)

Abstract Background: The randomized SUN 1064 study, docetaxel +/− sunitinib included 593 patients with advanced breast cancer. The response rate was statistically significantly (p-value=0.001) higher in the combined arm, but no difference in progression free survival or overall survival was found, median 24.8months in combined arm and median 25.5 months in docetaxel arm (HR 1.21: 95% confidence interval 0.91-1.60). This substudy aimed at unraveling gene expression patterns together with differentially expressed genes, contrasting gene expression before and after docetaxel +/− sunitinib treatment. The study also aimed at testing if sunitinib altered the gene expression of previously proposed sunitinib receptor tyrosine kinase targets. Material and methods: In a substudy at Karolinska we aimed to have cytological biopsies taken; before start of therapy and repeated in both arms after 14 (+/−1 day) days of therapy, randomly consisting of either docetaxel at 100 mg/m2 q 3 w, or docetaxel 75 mg/m2 q 3w + sunitinib 37.5 mg orally day 2-15. Eighteen of 21 patients accepted participation. From 14 (7 per arm) individuals we had sufficient material to make paired comparisons. We used the HG-U133plus2 Affymetrix chip containing 54 675 probe sets in the 14 paired pre-treatment and post-treatment patient samples. Results: Unsupervised hierarchical clustering revealed differential gene expression patterns for the combined arm (Figure A) compared with docetaxel alone (Figure B). The sunitinib proposed target receptor tyrosine kinases, showed no clustering patterns associated with the combined sunitinib and docetaxel treatment. The top 100 differentially expressed genes did not include the proposed sunitinib target genes. However interestingly, genes involved in the VEGF signaling pathway and apoptosis were significantly more frequently upregulated and those involved in the cell cycle were more frequently down-regulated in patients after treatment of sunitinib and docetaxel in combination, in contrast to the pre-therapy situation. Conclusions: Unsupervised hierarchical clustering revealed differential gene expression patterns corresponding to before and after combined sunitinib and docetaxel treatment, clearly clustering patients into the two groups. Interestingly, genes involved in the VEGF signaling pathway, apoptosis and cell cycle were modulated significantly more frequently by combined therapy treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-05.
Cerebrovascular Disease: Trial of Long-term Anticoagulant Therapy
Authors: A. B. Hill, J. Marshall, D. A. Shaw
Journal: BMJ (1962)

A trial of long-term anticoagulant therapy in patients with cerebrovascular disease was started in October, 1957, and progress during the first 20 months to June, 1959, was reported by Hill, Marshall, and Shaw in 1960.At that stage there was no evidence that anticoagulants were reducing either the mortality or the recurrence rate of cerebrovascular accidents; indeed, the data suggested an adverse effect, particularly in hypertensive patients.The trial was therefore modified by withdrawing those who were hypertensive, and we report here the further progress of the trial in its modified form to its conclusion in October, 1961.The design of the trial, the selection of patients, and the methods of treatment and control were described in detail in the original report (Hill, Marshall, and Shaw, 1960).All the patients included were under 70 years of age and had suffered one or more disturbances of neural function lasting more than 24 hours and attributed to non-haemorrhagic cerebral, carotid, or vertebral arterial disease.Admission to the trial was permissible any time after 14 days had elapsed since the last acute episode.The usual contraindications to anticoagulant therapy were observed and patients were included in the trial only if it seemed likely that their personal, occupational, and geographical situations would permit regular attendance and adequate co-opera- tion.Patients admitted to the trial were differentiated by sex and allotted by pairs to high-dosage (treatment) or low-dosage (control) groups by a random method.The former group received tablets containing 50 mg.phenindione (" dindevan ") in a dosage aimed at maintaining the prothrombin time, estimated by the Quick one-stage test (human brain thromboplastin), at a level of two to two and a half times the control value.The low-dosage control group received apparently identical tablets containfing 1 mg.phenindione, and their manage- ment otherwise did not differ from that of the highdosage group.All patients were seen and had blood taken for prothrombin estimation at least once every four weeks.Many of the criteria adopted for selection and control were based on the plan of the Medical Research Council (1959) trial of anticoagulant therapy in coronary thrombosis, to which access was kindly granted.By the end of 20 months-that is, at the time of the last report-142 patients had been adniitted to the trial,
Brucellosis with mesangial IgA nephropathy: successful treatment with doxycycline and rifampicin.
Authors: T O Nunan, S J Eykyn, N F Jones
Journal: BMJ (1984)

mortality strongly.Nevertheless, our findings are reassuring to the extent that the possible absolute risk carried by passive smoking is probably small.This study was supported by a grant from the Netherlands Heart Founda- tion.Help from the
TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling
Authors: Koichiro Kuwahara, Yanggan Wang, John McAnally, James A. Richardson, Rhonda Bassel-Duby, Joseph A. Hill, Eric N. Olson
Journal: Journal of Clinical Investigation (2006)

The heart responds to injury and chronic pressure overload by pathologic growth and remodeling, which frequently result in heart failure and sudden death. Calcium-dependent signaling pathways promote cardiac growth and associated changes in gene expression in response to stress. The calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear factor of activated T cells (NFAT) transcription factors, serves as a transducer of calcium signals and is sufficient and necessary for pathologic cardiac hypertrophy and remodeling. Transient receptor potential (TRP) proteins regulate cation entry into cells in response to a variety of signals, and in skeletal muscle, expression of TRP cation channel, subfamily C, member 3 (TRPC3) is increased in response to neurostimulation and calcineurin signaling. Here we show that TRPC6 was upregulated in mouse hearts in response to activated calcineurin and pressure overload, as well as in failing human hearts. Two conserved NFAT consensus sites in the promoter of the TRPC6 gene conferred responsiveness to cardiac stress. Cardiac-specific overexpression of TRPC6 in transgenic mice resulted in heightened sensitivity to stress, a propensity for lethal cardiac growth and heart failure, and an increase in NFAT-dependent expression of beta-myosin heavy chain, a sensitive marker for pathologic hypertrophy. These findings implicate TRPC6 as a positive regulator of calcineurin-NFAT signaling and a key component of a calcium-dependent regulatory loop that drives pathologic cardiac remodeling.
THE VALUE OF GYNÆCOLOGICAL TREATMENT IN HYSTERIA AND ALLIED AFFECTIONS.
Authors: PHILIP ZENNER
Journal: JAMA (1883)

[Read in the Section of obstetrics and Diseases of Women, June, 1883, and referred for publication] That lesions of the female genitalia are sometimes times productive of hysteria or allied affections; that the removal of the local lesion sometimes alleviates or cures the nervous disease is proven by past experience. Happy results thus obtained in the management of cases usually so intractable naturally inspire the hope that a like cause for these diseases will always be found and tempt one to the institution of like measures in their treatment. And in practice we actually see that it has become only too fashionable to institute gynæcological examination or treatment on account of the presence of some nervous affection. These efforts might be deemed laudable were it not that they have also their shadow side, that such measures may injure as well as benefit. That gynæcological cal examination or treatment may be
Legal Rights and Mental-Health Care
Authors: Thomas G. Gutheil
Journal: JAMA (1984)

Although written somewhat as an advocate manifesto, this book apparently is designed to inform clinicians about what advocacy is all about— specifically, as chapter 2 expresses it, to demystify advocacy. The advocacy espoused here is the "mouthpiece" model that mandates the advocate to adopt only the client's explicitly stated views as the advocate's "job description." The strengths of this book are in its plea for collaboration between clinicians and mental health professionals on the one hand, and advocates on the other. The book laudably takes the position that attention to patient rights is totally consistent with good clinical care and that areas of noncooptive collaboration are, indeed, possible and highly beneficial to the patients. Despite a legal focus (only occasionally verging on the legalistic), the book seems quite attuned to actual clinical needs of patients. Highlights of the book include an excellent chapter on antidiscrimination laws; a valuable review of
Protein-Sulfhydryl Groups in Cancer and Gene Control
Authors: Frances E. Knock
Journal: JAMA (1966)

<h3>To the Editor:—</h3> Cell division fails if sulfhydryl (SH) compounds are blocked. From their work with the natural cell regulator<i>retine</i>, Nobel Laureate Szent-Gyorgyi and co-workers found that SH inhibitors can inhibit cell division of lower forms preferentially, with apparently greater effect on cancer than normal. Egyud and Szent-Gyorgyi note that sensitivity of SH to most agents known to initiate or retard cancer also "pleads for some intimate relation between cancer and SH," and predicted that use of proper SH inhibitors may open the way to a specific cancer therapy (<i>Proc Nat Acad Sci</i><b>55</b>:388, 1966). On hundreds of human cancers, sensitivity tests have shown greater attack by proper SH inhibitors on cancer than normal (<i>Arch Surg</i><b>86</b>:489, 1963). The sensitivity tests showed promise for the SH inhibitor pyruvaldehyde, now believed by Szent-Gyorgyi to be an active component of retine. Histochemically, pyruvaldehyde and other active SH inhibitors are
Driving and dementia
Authors: David A Breen, David P Breen, John W Moore, Patricia A Breen, Desmond O'Neill
Journal: BMJ (2007)

#### Summary points

Dementia is important in relation to driving. As the disease progresses the ability to drive safely is eventually lost and at that point current regulations demand that driving stops. Many patients continue to drive after dementia has been diagnosed,1 2 3 4 5w10 however, and withdrawal of their licence should not be undertaken lightly. A study highlighted the negative consequences of stopping people with dementia from driving.w11 Stopping driving can limit access to family, friends, and services and is an independent risk factor for entry to a nursing home.w12

Traffic medicine has evolved significantly since the 1990s, with more emphasis on preserving mobility. As populations age and increasing numbers of older people drivew1 general practitioners are key players in ensuring that older people are not constrained by an unfair attribution of risk. Health professionals, however, practise in a society where the perception of older drivers is negative.w2 This may stem from misconceptions about the impact of age related disease on driving: these misunderstandings also apply to medical journals, which commonly reproduce statements on the apparent increase …
Comparative study of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) level and ratio measurements and their relationship with an index of clinical activity in the management of patients with acromegaly
Authors: Concepción Páramo, M.Amalia Andrade O, Enrique Fluiters, Reyes Luna, Javier de la Fuente, Ricardo V. García-Mayor
Journal: Metabolism (1997)
A Telephone-Delivered Intervention for Patients With NIDDM: Effect on coronary risk factors
Authors: M Sue Kirkman, Morris Weinberger, Pamela B Landsman, Gregory P Samsa, E Anne Shortliffe, David L Simel, John R Feussner
Journal: Diabetes Care (1994)

OBJECTIVE To examine whether a telephone-delivered intervention (TDI), designed to improve glycemie control in patients with non-insulin-dependent diabetes mellitus (N1DDM), improved coronary risk factors in high-risk patients. RESEARCH DESIGN AND METHODS This randomized controlled trial involved 275 veterans with N1DDM followed in a general medical clinic. Intervention (TDI) patients were telephoned at least monthly by a nurse. Calls emphasized compliance with the medical regimen (diet, medications, and exercise), encouraged behavioral changes, and facilitated referrals to a dietitian or smoking cessation clinic. Control patients received no such calls. Baseline and 12-month follow-up measurements included fasting lipid profiles, weight, smoking status (self-reported; cessation verified by measurement of exhaled CO), adherence to diet and exercise (self-reported), appointments, and medications (hospital computerized data base). RESULTS After 12 months, equal numbers of obese patients in the two groups reported adhering to a diabetic diet and exercising, although more obese TDI patients had seen a dietitian (30 vs. 7%, P = 0.003). Weight loss was not seen in either group (—0.9 ± 5.3 vs. —0.1 ± 3.6 kg, P = 0.202). Hyperlipidemic TDI patients were more likely to see a dietitian (31 vs. 6%, P = 0.003) and receive lipid-lowering medications (22 vs. 9%, P = 0.096), but serum cholesterol reduction was similar between groups (–11.7 ± 33.4 vs. –4.3 ± 32.7 mg/dl, P = 0.270); comparable results were seen for high-density lipoprotein, low-density lipoprotein, and triglyceride levels. More TDI group smokers reported quitting (26 vs. 0%, P = 0.033), but the difference was not significant for CO-verified abstention (10 vs. 0%, P = 0.231). CONCLUSIONS The TDI improved self-reported adherence to regimens that might reduce coronary risk, but had little effect on objective measures of risk.
Treatment of intermittent claudication
Authors: G Karthikeyan, J. W Eikelboom
Journal: BMJ (2009)

Should start with interventions that improve both symptoms and cardiovascular risk

Peripheral artery disease of the lower extremities affects more than one in 10 people aged over 55 years.1 2 Half of those affected present with leg symptoms that limit physical activity and impair quality of life.1 The most feared complication is loss of limbs, but only 1-3% of those presenting with intermittent claudication progress to amputation over five years.3 Myocardial infarction and stroke resulting from progressive atherogenesis in other vascular beds are far more common—15% to 30% of people presenting with peripheral artery disease die within five years, mainly from cardiovascular causes.4

In the linked meta-analysis (doi:10.1136/bmj.b603), De Backer and colleagues assess the effects of the orally active vasodilator naftidrofuryl on pain-free walking distance in patients with intermittent claudication.5 

The most important goal of medical treatment in patients with peripheral artery disease of the lower extremities is the prevention of systemic cardiovascular complications.6 Many treatments that prevent myocardial infarction and stroke also improve leg symptoms (table⇓), but specific treatments for intermittent claudication have been …
Tumor Necrosis Factor-α-Induced Matrix Proteolytic Enzyme Production and Basement Membrane Remodeling by Human Ovarian Surface Epithelial Cells
Authors: Wan-Lin Yang, Andrew K. Godwin, Xiang-Xi Xu
Journal: Cancer Research (2004)

Abstract The majority of cancer is of surface/cyst epithelial origin. The ovarian surface epithelial cells are organized by a sheet of basement membrane composed mainly of collagen IV and laminin, and it is believed that the basement membrane greatly influences the physiological properties of ovarian surface epithelial cells. Previous studies in our laboratories indicated that loss of the basement membrane, an obligated step in ovulation, is also a critical step during the morphological transformation and tumor initiation of the ovarian surface epithelium. It is speculated that the loss of basement membrane in ovarian surface epithelial transformation may have similar biological mechanism to the loss of surface epithelial basement membrane in ovulation. However, the mechanisms involved in the ovarian surface epithelial basement membrane removal during ovulation are still not completely understood. In the current study, cultured human ovarian surface epithelial (HOSE) cells were examined for their abilities to produce matrix hydrolyzing enzymes and degrade basement membrane in response to a number of potential local mediators in ovulation. Among the candidate-stimulating factors tested, tumor necrosis factor (TNF)-α and IL-1β (to a lesser extent) were found to drastically increase urokinase type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 activities secreted from HOSE cells. MMP-2, the other major HOSE cell-secreted gelatinase, is constitutively produced but not regulated. As demonstrated by immunofluorenscence staining and Western blot analysis, TNF-α treatment caused the degradation and structural reorganization of collagen IV and laminin secreted and deposited by HOSE cells in culture. Amiloride, an uPA inhibitor, not only inhibited the activity of uPA but was also able to suppress TNF-α-stimulated MMP-9 activity and prevented the TNF-α-stimulated remodeling of the basement membrane extracellular matrix, suggesting the contribution of uPA-mediated proteolytic cascade in this process. This study implicates the potential roles of TNF-α, uPA, and MMP-9 in ovarian surface epithelial basement membrane degradation and remodeling, which are processes during ovulation and may contribute to epithelial transformation. The findings may underscore the importance of TNF-α, uPA, and MMP-9 in ovarian surface epithelial basement membrane remodeling and may provide a molecular mechanism linking ovulation and ovarian cancer risk.
Scientists Warn NIH Funding Squeeze Hampering Biomedical Research
Authors: Mike Mitka
Journal: JAMA (2007)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Effects of Helicobacter pylori Treatment on Gastric Cancer Incidence and Mortality in Subgroups
Authors: Wen-Qing Li, Jun-Ling Ma, Lian Zhang, Linda M. Brown, Ji-You Li, Lin Shen, Kai-Feng Pan, Wei-Dong Liu, Yuanreng Hu, Zhong-Xiang Han, Susan Crystal-Mansour, David Pee, William J. Blot, Joseph F. Fraumeni, Wei-Cheng You, Mitchell H. Gail
Journal: JNCI Journal of the National Cancer Institute (2014)

Among 2258 Helicobacter pylori-seropositive subjects randomly assigned to receive one-time H. pylori treatment with amoxicillin-omeprazole or its placebo, we evaluated the 15-year effect of treatment on gastric cancer incidence and mortality in subgroups defined by age, baseline gastric histopathology, and post-treatment infection status. We used conditional logistic and Cox regressions for covariable adjustments in incidence and mortality analyses, respectively. Treatment was associated with a statistically significant decrease in gastric cancer incidence (odds ratio = 0.36; 95% confidence interval [CI] = 0.17 to 0.79) and mortality (hazard ratio = 0.26; 95% CI = 0.09 to 0.79) at ages 55 years and older and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline (odds ratio = 0.56; 95% CI = 0.34 to 0.91). Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar. Thus H. pylori treatment can benefit older members and those with advanced baseline histopathology, and benefits are present even with post-treatment infection, suggesting treatment can benefit an entire population, not just the young or those with mild histopathology.
Escape from tolerance in the human X-linked autoimmunity–allergic disregulation syndrome and the Scurfy mouse
Authors: Dhavalkumar D. Patel
Journal: Journal of Clinical Investigation (2001)

T cells that respond to self antigens exist in normal tissues but are, of necessity, stringently controlled in healthy individuals. Autoreactive T cells may be specifically deleted as they develop in the thymus; those that survive and reach the peripheral tissues are kept mitotically quiescent and otherwise unresponsive by stimuli from other immune cells. Together, these two mechanisms, termed central and peripheral tolerance, hold autoreactive T cells in check. Autoimmune disease arises when clones of these cells overcome the usual safeguards, expand, and become activated.

The mechanism behind such an escape from tolerance is uncertain, and defects in both central and peripheral tolerance have been proposed to underlie various disorders. Now, two independent sets of reports establish that both of these mechanisms participate in the pathogenesis of an unusual form of immune disregulation observed in humans and mice. The human disorder, X-linked autoimmunity–allergic disregulation syndrome (XLAAD), presents with a collection of symptoms that are also seen in the Scurfy mouse. With the report by Chatila et al. (1) in a recent issue of the JCI and independent analyses by Brunkow et al. (2), it is now clear that the genes affected are orthologues and encode a transcription factor termed Foxp3, JM2, or scurfin. This parallel offers the prospect of insights into the molecular regulation of human autoimmune diseases. The current findings also suggest that certain allergic diseases arise because of intrinsic defects in CD4+ T cells, leading to Th2-skewing and hyperreactivity to antigens.
Implementing Health Care Reform — Why Medicare Matters
Authors: Robert A. Berenson
Journal: New England Journal of Medicine (2010)

Despite the major achievements of the Patient Protection and Affordable Care Act in providing health insurance for more than 30 million Americans and regulating objectionable insurance-company practices, its opponents alleged throughout the health care reform debate that it would negatively affect Medicare beneficiaries. Although nothing in the law (now being referred to simply as the Affordable Care Act, or ACA) grants government the authority to ration care for these patients — to “pull the plug on Granny,” as Senator Charles Grassley (R-IA) put it — Medicare is in fact central to the legislation. Indeed, more than half of the $938 . . .