tbuckley/cabot-search huggingface dataset:
Prognostic significance of p53 overexpression in luminal HER2-negative type breast cancer.
Authors: Shoichi Kikuchi
Journal: Journal of Clinical Oncology (2013)

35 Background: In this study, we evaluated the prognostic significance of p53 overexpression, because it was reported that there was a significant correlation between p53 and resistance to endocrine therapy, and prognosis. Methods: A retrospective analysis was performed using 2,332 primary breast cancer patients who underwent surgery between 2001 and 2010. There were 1,899 cases with luminal subtypes (905 cases: HER2-negative and Ki67 low type; 808 cases: HER2-negative and Ki67 high type; and, 186 cases: HER2-positive type), 155 cases with HER2-enriched subtypes, and 278 cases with triple-negative subtypes. Luminal type was defined as ER-positive cell rates ≥ 1%, regardless of PgR status. The cut-off value of the Ki67 index was 20%. Moreover, tumor size, nodal status and nuclear grade were studied in relation to disease free (DFS) and overall survival (OS) using the Cox proportional hazard model. Results: We found that p53 overexpression was present in 10% of the patients and significantly correlated with larger tumors, younger age, positive nodes, a higher grade, negative ER/PgR, a higher Ki67, and positive HER2. The patients with p53 overexpression had significantly unfavorable prognosis, especially in the patients who only received endocrine therapy. There were 26 cases in the luminal HER2 negative and Ki67 low type group that had p53 overexpression and showed a significantly shorter DFS. In the univariate analysis for DFS, p53, Ki67, tumor size, nuclear grade and nodal status were significant factors in luminal HER2 negative type. In the subsequent multivariate analysis for DFS, the p53 status was one of the most significant factors. Conclusions: The p53 overexpression was a significant prognostic factor in luminal type breast cancer. Therefore, the prognostic evaluation of luminal HER2 negative type breast cancer might be improved using an immunopanel, which includes Ki67 and p53. Moreover, it might isolate the patients who are resistant to endocrine therapy.
Myocardial Contrast Echocardiography for the Detection of Coronary Artery Stenosis
Authors: Paramjit Jeetley, Michael Hickman, Otto Kamp, Roberto M. Lang, James D. Thomas, Mani A. Vannan, Jean Louis Vanoverschelde, Poll A. van der Wouw, Roxy Senior
Journal: Journal of the American College of Cardiology (2005)
Evidence based management of hypertension: What are the elements of good treatment for hypertension?
Authors: C. D Mulrow
Journal: BMJ (2001)

Shank-associated RH domain-interacting protein (SHARPIN, alias SIPL1) is a cytosolic protein that plays a key role in activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and regulation of inflammation. Furthermore, SHARPIN controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice. Arginyl-glycyl-aspartic acid (RGD), a cell adhesion tripeptide motif, is an integrin recognition sequence that facilitates positron emission tomography (PET) imaging of integrin upregulation during tumor angiogenesis. We hypothesized that increased integrin activity due to loss of SHARPIN protein would affect the uptake of αvβ3 selective cyclic, dimeric RGDfK peptide <sup>68</sup>Ga-DOTA-E[c(RGDfK)]<sub>2</sub>, both in several tissue types and in the tumor microenvironment. To test this hypothesis, we used RGD-based in vivo PET imaging to evaluate wild-type (wt) and SHARPIN-deficient (Sharpincpdm) mice with and without melanoma tumor allografts. <b>Methods:</b> Sharpincpdm mice with spontaneous null mutation in the Sharpin gene and their wt littermates with or without B16-F10-luc melanoma tumors were studied by in vivo imaging and ex vivo measurements with αvβ3 integrin specific cyclic-RGD peptide <sup>68</sup>Ga-DOTA-E[c(RGDfK)]<sub>2</sub>. After the last <sup>68</sup>Ga-DOTA-E[c(RGDfK)]<sub>2</sub> peptide PET/computed tomography (CT), tumors were cut into cryosections for autoradiography, histology and immunohistochemistry. <b>Results:</b> The ex vivo uptake of <sup>68</sup>Ga-DOTA-E[c(RGDfK)]<sub>2</sub> in the mouse skin and tumor was significantly higher in Sharpincpdm mice than in wt mice. B16-F10-luc tumors were detected 4 days post-inoculation, without differences in volume or blood flow between the mouse strains. PET imaging with <sup>68</sup>Ga-DOTA-E[c(RGDfK)]<sub>2</sub> peptide at day 10 post-inoculation revealed significantly higher uptake in the tumors transplanted into Sharpincpdm mice compared with wt mice. Furthermore, tumor vascularization was increased in the Sharpincpdm mice. <b>Conclusion:</b> Sharpincpdm mice demonstrated increased integrin activity and vascularization in B16-F10-luc melanoma tumors, as demonstrated by RGD-based in vivo PET imaging. These data indicate that SHARPIN, a protein previously associated with increased cancer growth and metastasis, may also have important regulatory roles in controlling the tumor microenvironment.
Determining disability due to mental impairment: APA's evaluation of Social Security Administration guidelines
Authors: H A Pincus, C Kennedy, S J Simmens, H H Goldman, P Sirovatka, S S Sharfstein
Journal: American Journal of Psychiatry (1991)

APA evaluated the Social Security Administration's (SSA's) medical standards and guidelines for determining disability due to mental impairment to determine how well the standards and guidelines operationalize the statutory definition of disability in a manner consistent with current psychiatric practice.Seventy-two psychiatrists were trained in one of two procedures: those in the sequential evaluation condition were trained in the process and forms used by the SSA's reviewing medical consultants, and those in the statutory definition condition were trained in the statutory definition of disability and application of clinical judgment according to this standard. Decisions regarding claimant's ability or inability to work were recorded on an instrument designed for the study. Each condition consisted of 12 panels of three members. They reviewed 732 actual claims for disability benefits. The panelists reviewed claims independently, then rendered panel judgments. Each claim was reviewed by one panel in each condition.The proportion of agreement between conditions for panel decisions (0.77) was higher than chance agreement (kappa = 0.46). The high level of agreement on claims judged to have good medical evidence and on which confident decisions were made (proportion of agreement = 0.96, kappa = 0.78) suggests that disagreements largely reflected ambiguities in application of the standards and guidelines to more complex cases or those with inadequate information.The SSA's revised medical standards and guidelines reflect clinical decisions about ability to work based on the statute and, with procedural modifications, should be retained. The SSA should be involved in further systematic studies to develop a field of scientific inquiry into disability and psychiatric disorders.
Crosstalk between Estrogen Receptor and Growth Factor Receptor Pathways as a Cause for Endocrine Therapy Resistance in Breast Cancer
Authors: C. Kent Osborne, Jiang Shou, Suleiman Massarweh, Rachel Schiff
Journal: Clinical Cancer Research (2005)

Abstract Data suggest that breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signaling pathways. In tumors with active growth factor receptor signaling (e.g., HER2 amplification), tamoxifen may lose its estrogen antagonist activity and may acquire more agonist-like activity, resulting in tumor growth stimulation. Because treatments designed to deprive the ER of its ligand estrogen will reduce signaling from both nuclear and membrane ER, aromatase inhibitors might be expected to be superior to tamoxifen in tumors with high growth factor receptor content, such as those overexpressing HER2. Recent clinical studies suggest that this is the case in humans, as trials of aromatase inhibitors show superior results compared with tamoxifen, especially in tumors overexpressing HER2. Although estrogen deprivation therapy is often effective in ER-positive breast cancer, de novo and acquired resistance are still problematic. Experimental models suggest that in one form of resistance to estrogen deprivation therapy, the tumor becomes supersensitive to low residual estrogen concentrations perhaps because of activation of mitogen-activated protein kinase. Such tumors respond to additional treatment with fulvestrant or even tamoxifen. On the other hand, in tumors overexpressing HER2, acquired resistance to estrogen deprivation therapy involves the loss of ER and ER-regulated genes and further up-regulation of growth factor signaling rendering the tumor hormonal therapy resistant. This process can be delayed or reversed by simultaneous treatment with growth factor pathway inhibitors. This strategy is now being tested in clinical trials.
From Chaos to Coercion: Detention and the Control of Tuberculosis
Authors: David Wilkinson
Journal: BMJ (2000)

Richard J Coker 

St Martin's Press, £19, pp 304 ISBN: 0312222505

Rating: ![Graphic][1] ![Graphic][2] ![Graphic][3] 

Our enduring inability to control tuberculosis shames us all. More people die from the disease now than ever before, despite the availability of effective treatment. Poverty, inequity, and ineffective control programmes are our collective fault. The story of tuberculosis control in New York City—abject failure rapidly followed by extraordinary success at a cost of $1bn—has, in the past 10-15 years, developed almost mythical status.

In 1994 I was privileged to be at …

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BODY BUILD IN INFANTS
Authors: Harry Bakwin, Ruth Morris Bakwin
Journal: Journal of Clinical Investigation (1931)

Measurements of the external dimensions of sick infants were made and compared with the values obtained in healthy infants (1).The technique employed for making the measurements has been described in a previous paper (2). DESCRIPTION OF MATERIALOnly sick infants observed at Bellevue Hospital are reported here and hence, comparisons are made only with the healthy infants admitted to Bellevue Hospital.a. Acute intestinal intoxkation.Acute intestinal intoxication is here used to designate a type of reaction in infants characterized by som- nolence alternating with periods of hyper-irritability and at times convulsions, cyanosis, hyperpnea, oliguria or anuria, and evidence of dehydration.There is usually fever and an associated infection.Diarrhea and vomiting may or may not be present.There are no characteristic gross anatomical changes except, perhaps, in the liver.Most of the infants here reported were ill during the winter months.There were 133 infants in this group of whom 64 were males and 69 females.Forty-four (33 per cent) were admitted to the hospital and measured before the onset of illness.Forty infants (30 per cent) were foundlings.There were 78 deaths (59 per cent).b. Tetany.By tetany in infants is meant a metabolic disorder resulting from deprivation of vitamin D or sunlight, characterized by a tendency to convulsions and spasms of various kinds.The calcium concentration in the serum is regularly diminished and there is a change in the reaction to galvanic stimulation.It may be cured by the administration of vitamin D or ultraviolet radiant energy.
<i>Ornithine decarboxylase</i> (<i>Odc</i>)-1 gene polymorphism effects on baseline tissue polyamine levels and adenoma recurrence in a randomized phase III adenoma prevention trial of DFMO + sulindac versus placebo
Authors: J. A. Zell, C. E. McLaren, E. W. Gerner, F. L. Meyskens
Journal: Journal of Clinical Oncology (2008)

1502 Background: The Odc G315A single nucleotide polymorphism (SNP) affects Odc transcription and favorably modifies aspirin's effect on colorectal adenoma risk. Treatment with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) and sulindac has been shown to markedly decrease adenoma recurrence compared to placebo. Here we investigate modifying effects of the Odc G315A SNP on baseline tissue polyamine content and polyp recurrence after treatment with DFMO + sulindac or placebo. Methods: Data from the randomized phase III DFMO (500mg daily) + sulindac (150mg daily) colorectal adenoma prevention trial were analyzed. Odc genotyping was performed on patient-derived genomic DNA samples using allele-specific TaqMan probes. Baseline rectal tissue polyamine content was determined via HPLC. Clinicopathologic data were compared after stratification by genotype. Fisher's exact test or χ2 tests for independence were used for comparisons of categorical variables. Two-tailed t-tests or Kruskal-Wallis nonparametric analysis of variance were used for numerical comparisons between groups. Results: Data were available for 122 of 375 study patients. Odc genotype distribution was 54% GG, 5% AA, 41% GA. Patients with any Odc A- allele (AA/GA) were similar in age, gender, race, and prior aspirin use across treatment arms, as were Odc GG patients. Odc GG vs AA/GA patients had significantly higher median baseline rectal tissue putrescine (0.52 vs 0.31 nmol/mg protein, P=0.046) and spermidine (2.10 vs 1.65 nmol/mg protein, P=0.011) content. Among Odc AA/GA patients, 7/26 patients (27%) had recurrent adenoma in the DFMO + sulindac arm vs 14/30 patients (47%) in the placebo arm (P=0.13, absolute risk difference=20%). Among Odc GG patients, 6/39 patients (15%) had recurrent adenoma in the DFMO + sulindac arm compared with 14/27 (52%) placebo patients (P=0.002, absolute risk difference=37%). Conclusions: DFMO + sulindac treatment lowers the incidence of recurrent adenomata among adenoma patients, with pronounced effects observed among Odc homozygous GG patients. This may be related to baseline tissue polyamine differences across these genetically-defined groups. No significant financial relationships to disclose.
Pancreatic carcinoma and Trousseau's syndrome: experience at a large cancer center.
Authors: R Pinzon, B Drewinko, J M Trujillo, V Guinee, G Giacco
Journal: Journal of Clinical Oncology (1986)

It is common belief that carcinoma of the pancreas has an inherent and unique ability to induce a hypercoagulable diathesis that leads to clinically significant thrombosis. We evaluated 130 consecutive patients with adenocarcinoma of the pancreas to document the incidence and the predisposing factors related to the postulated increased association of thromboembolic disorder (TED) and pancreatic carcinoma. Only nine such patients (6.9%) demonstrated TED complications of the classical Trousseau syndrome. In these instances, the location of the tumor and its mucin-producing potential were significant predisposing factors. In our series, TED was usually associated with tumors of the body and tail, which had a greater likelihood to be mucinogenic as compared with those localized to the head of the pancreas. Routine tests for hemostasis were not helpful in predicting the development of TED except, perhaps, for decreased platelet counts. Therefore, we believe that the relationship between cancer of the pancreas and TED should be de-emphasized since it is neither unique nor especially common to pancreatic carcinoma and since it may be frequently encountered in other varieties of visceral malignancies of the cancer patient population.
Optimal sequencing of docetaxel and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Benjamin Louis Maughan, Daniel L. Suzman, Rosa Nadal, Sunakshi Bassi, Michael Thomas Schweizer, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2015)

252 Background: Currently there are multiple agents approved for the treatment of mCRPC based on prolongation of life. However, it is unclear what the optimal sequencing of these therapies is to maximize clinical benefit and survival. Here, we aimed to compare clinical outcomes among men with mCRPC who received docetaxel first followed immediately by abiraterone (doce-to-abi) or the opposite sequence (abi-to-doce). Only men that were treated with sequential therapy using these two agents (i.e. without intervening treatments) were included. Methods: A retrospective review of consecutive mCRPC patients treated at Johns Hopkins was conducted. A combined PFS (PFS = PFS1 + PFS2) was the primary endpoint, measured from the start of the first therapy (i.e. doce or abi) until the time of clinical/radiographic progression on the subsequent therapy (i.e. abi or doce). Overall survival (OS) from the start of the first therapy until death was the main secondary endpoint. Multivariable regressions were performed to determine whether one sequence was better than the other (doce-to-abi versus abi-to-doce) after adjusting for a number of baseline patient and treatment characteristics. Results: In total, 86 patients were identified that met our study criteria: 53 men received doce-to-abi and 33 men received abi-to-doce. PFS was longer in the doce-to-abi cohort: median 19.1 (95% CI 13.0–27.4) mo versus 10.4 (95% CI 9.1–11.5) mo (HR 2.6, 95% CI 1.5 – 4.5). OS was also superior in the doce-to-abi cohort: median 30.3 (95% CI 25.4–44.3) mo compared to 18.2 (95% CI 14.1–21.1) mo (HR 2.3, 95% CI 1.2 – 4.1). In multivariable analyses, superior outcomes were still observed in the doce-to-abi group with respect to PFS (HR 2.77, 95% CI 1.5–5.0, P=0.0008) and OS (HR 2.8, 95% CI 1.5–5.3, P=0.0016) after adjusting for Gleason score, baseline PSA and ECOG status at study initiation. Conclusions: This hypothesis-generating study seems to suggest superior PFS and OS in men with mCRPC receiving doce followed by abi (rather than the opposite sequence). These findings are in alignment with the results of the CHAARTED trial supporting earlier docetaxel use, but require prospective validation.
Animal research
Authors: P. Hawkins
Journal: BMJ (2001)

Editor—The RSPCA (Royal Society for the Protection of Cruelty to Animals) believes that the use of laboratory animals presents an ethical dilemma that affects everyone. Animals are used for a broad range of purposes, and thus it is not possible or constructive to make sweeping statements about scientific validity, justification, or suffering. Issues subject to such polarised debate are inevitably difficult to resolve. In this case, sentient animals capable of suffering are involved.

The human race has a moral imperative to reduce the pain, suffering, and distress that it inflicts on other animals to an absolute minimum. In the case of animal experiments, the principle of the three Rs—replacement, reduction, refinement1—is an excellent practical starting point, and the RSPCA is committed to promoting and supporting it. Greater consideration is now given to implementing this concept, but it is not universally applied (or understood), and much is still to be achieved. One likely reason for this is that the three Rs are often seen as a separate issue and not part of mainstream life sciences.

One way to raise the profile of the three Rs, and push for them to pervade the whole of the life sciences, would be for journal editors to insist that published papers include comprehensive information about the lifetime experiences of the animals involved. This could include their source, transport, husbandry and care, group sizes and structure, enrichment, what was actually done to the animals, protocol refinements, welfare problems (and what was done about them), and the animals' eventual fate (and why).

Journal space is at a premium, but it is possible to convey this information in surprisingly few words.2,3 Such detail would provide guidance for other researchers wishing to improve animal welfare and reduce suffering, as well as giving other interested parties an insight into what laboratory animals actually experience and why. This would help to depolarise the debate and enable people with an interest to contribute to it in an informed and constructive way.

Although the BMJ rarely publishes animal research, perhaps it would consider this kind of comprehensive editorial policy to help steer the debate towards the middle ground so that it can go further, faster.
No Evidence of Disease Activity in Multiple Sclerosis
Authors: Jacob A. Sloane, Caterina Mainero, R. Philip Kinkel
Journal: JAMA Neurology (2015)

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Clinical and neuropsychological characteristics of patients with late- onset schizophrenia
Authors: D V Jeste, M J Harris, A Krull, J Kuck, L A McAdams, R Heaton
Journal: American Journal of Psychiatry (1995)

The goal was to compare clinical and neuropsychological characteristics of patients with late-onset schizophrenia, a poorly studied and controversial entity, with those of patients with early-onset schizophrenia and normal subjects.The authors evaluated 25 patients who met DSM-III-R criteria as well as their own research criteria for late-onset schizophrenia (i.e., schizophrenia with onset after age 45) and compared them with 39 patients with early-onset schizophrenia and 35 normal subjects in this nonepidemiologic study.Patients with late-onset schizophrenia were similar to patients with early-onset schizophrenia and different from normal subjects on most clinical and neuropsychological variables assessed, such as psychopathology, family history, childhood social adjustment, and overall pattern of neuropsychological impairment. Compared with the early-onset group, the group with late-onset schizophrenia had a higher percentage of patients who were ever married, a better work history, and a greater frequency of paranoid subtype.These results support the diagnostic validity of schizophrenia with onset after the age of 45 years.
Degos disease associated with protein S deficiency
Authors: Y. Gilaberte, C. Coscojuela, A. Lezaún, M.A. Marigil
Journal: British Journal of Dermatology (2005)

Journal Article Degos disease associated with protein S deficiency Get access Y. Gilaberte, Y. Gilaberte Departments of Dermatology, Haematology Search for other works by this author on: Oxford Academic Google Scholar C. Coscojuela, C. Coscojuela Departments of Dermatology, Haematology Search for other works by this author on: Oxford Academic Google Scholar A. Lezaún, A. Lezaún Departments of Dermatology, Haematology Search for other works by this author on: Oxford Academic Google Scholar M.A. Marigil M.A. Marigil Pathology, Hospital San Jorge, Avenue Martínez de Velasco 34, 22004 Huesca, Spain E‐mail: ygilaberte@salud.aragob.es Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 153, Issue 3, 1 September 2005, Pages 666–667, https://doi.org/10.1111/j.1365-2133.2005.06764.x Published: 01 September 2005