tbuckley/cabot-search huggingface dataset:
Abstract 2632: The COX inhibitor, diclofenac induces mantle cell lymphoma apoptosis independent of p53 status
Authors: Hesham M. Hassan, Michelle L. Varney, Aalia M. Aly, Shantaram S. Joshi, Rakesh K. Singh, Bhavana J. Dave
Journal: Cancer Research (2015)

Abstract Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapses and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome in MCL. Diclofenac has been reported to increase p53 pathway activity, upregulates p73 expression and inhibit cell growth; hence we investigated the ability of diclofenac to induce apoptosis and/or cell cycle arrest in MCL, and its dependence on p53 status. To investigate the response of MCL to diclofenac, wild-type p53 [Granta-519 and JVM-2] and mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines and primary human cells isolated from MCL patients were used. Cell proliferation, apopotosis, and expression of down-stream signaling p53 targets were analyzed. Nontoxic concentrations of diclofenac induced concentration- and duration-dependent inhibition of MCL cell growth independent of p53 status. Diclofenac treatment also resulted in cell cycle arrest and cell death. Molecularly, diclofenac treatment was associated with increased activity of caspases 3, 7, and 8. Increased p53 pathway activity was demonstrated by duration-dependent induction of p53 transcriptional target genes, including the cell cycle regulatory molecule p21 and pro-apoptotic molecules including, PUMA, NOXA, BIM, and CD95. Most importantly, diclofenac treatment was associated with enhanced expression of the pro-apoptotic isoforms of the p53 homologue TAp73. Our data demonstrates that diclofenac treatment results in decreased cell cycle progression, and increased apoptosis that is associated with increased p53 pathway activity, independent of p53 status, and increased activity of its family member p73. Citation Format: Hesham M. Hassan, Michelle L. Varney, Aalia M. Aly, Shantaram S. Joshi, Rakesh K. Singh, Bhavana J. Dave. The COX inhibitor, diclofenac induces mantle cell lymphoma apoptosis independent of p53 status. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2632. doi:10.1158/1538-7445.AM2015-2632
Abstract P2-06-11: Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation
Authors: Z-Y Zheng, W Bu, L Tian, C Fan, X Gao, X Zhang, C Yu, H Wang, Y-H Liao, Y Li, MT Lewis, D Edwards, TP Zwaka, SG Hilsenbeck, D Medina, CM Perou, CJ Creighton, XH Zhang, EC Chang
Journal: Cancer Research (2016)

Abstract "Basal-like" breast cancer (BLBC) is a very aggressive subtype of breast cancer. BLBC has very poor prognosis — median time to distant recurrence is just 2.6 years vs. 5 years overall, and survival time from diagnosis of distant metastatic disease is 9 months vs. 22 months. BLBC tumors usually do not express ER, Her2, or progesterone receptor. As such, they cannot be treated by the current targeted therapies, which target these molecules. What drive the formation and progression of BLBCs is largely unclear. Ras GTPases are best known for mediating growth factor signaling. Oncogenic mutations in the RAS genes, K-RAS in particular, are found in more than 30% of human tumors. Surprisingly, oncogenic RAS mutations are rare in breast cancer. However, we found that wild-type N-RAS is overexpressed in BLBCs, possibly partly via promoter demethylation, but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, while overexpressing it enhances these processes even in preinvasive BLBC cells. In contrast, in breast cancer cells of other subtypes, repressing N-RAS expression does not affect growth and transforming activities. We identified N-Ras-responsive genes, most of which encode chemokines and cytokines, e.g., IL8. High expression levels of these N-Ras-responsive genes as well as of N-RAS itself in tumors correlate with poor patient outcome. N-Ras, but not K-Ras, induces IL8 by binding and activating the cytoplasmic pool of JAK2; IL8 then acts on both the cancer cells and stromal fibroblasts. In conclusion, N-Ras drives BLBC by promoting transformation in epithelial cells, which may in turn remodel the tumor microenvironment to create a proinvasive state. Although oncogenic mutations affecting RAS are common in many other human cancers, tumorigenesis in an important subset of breast cancers is driven instead by increasing activity of wild-type N-Ras. Thus, to fully assess the impact of Ras on tumorigenesis, the role of wild-type as well as mutant Ras proteins must be carefully examined. Citation Format: Zheng Z-Y, Bu W, Tian L, Fan C, Gao X, Zhang X, Yu C, Wang H, Liao Y-H, Li Y, Lewis MT, Edwards D, Zwaka TP, Hilsenbeck SG, Medina D, Perou CM, Creighton CJ, Zhang XH, Chang EC. Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-11.
Porphyria Cutanea Tarda in Three Generations of a Single Family
Authors: Anthony V. Benedetto, James P. Kushner, James S. Taylor
Journal: New England Journal of Medicine (1978)

We examined conjugal and blood relatives of one kindred for evidence of porphyria cutanea tarda. The disease was identified in eight family members in three generations. Four were classified as having overt porphyria cutanea tarda because of four criteria: photo-enhanced dermatosis; excessive urinary excretion of uroporphyrins; characteristic thin-layer chromatographic pattern of urinary porphyrins; and decreased activity of erythrocyte uroporphyrinogen decarboxylase. Two patients with excessive excretion of uroporphyrins or characteristic chromatograms, or both, and decreased uroporphyrinogen decarboxylase activity were classified as having subclinical porphyria cutanea tarda, and two with decreased uroporphyrinogen decarboxylase activity only were classified as having latent porphyria cutanea tarda. This study provides further evidence that prophyria cutanea tarda can be a familial disease inherited in an autosomal dominant fashion. We propose a reclassification of porphria cutanea tarda as an overt, subclinical or latent disorder.
Case 26-2003
Authors: Clyde S. Crumpacker, R. Gilberto Gonzalez, Robert S. Makar
Journal: New England Journal of Medicine (2003)

Presentation of CaseA 50-year-old man was admitted to the hospital because of fever, a seizure, and confusion.The patient was a native of Colombia who had traveled to the United States six weeks before admission to visit relatives. Two weeks before admission, he had had a respiratory infection characterized by sore throat, coryza, and fever. Three days before admission, fever, headache, and dizziness developed, and his family observed progressive confusion. One day before admission, his wife noticed that he appeared pale and then “blue” and then lost consciousness for 10 to 15 minutes, during which time he made extension . . .
Case 34-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, John L. Brusch, Eugene J. Mark
Journal: New England Journal of Medicine (1993)

Presentation of CaseA 36-year-old man with the acquired immunodeficiency syndrome (AIDS) was admitted to the hospital because of increasing dyspnea and respiratory failure.The patient was homosexual; his companion was known to have human immunodeficiency virus (HIV) antibodies, without clinically obvious disease. Thirty-two months before admission herpetic proctitis developed, and a test for HIV antibodies was positive; the CD4+ cell count was 194 per cubic millimeter. Acyclovir was given, resulting in control of the proctitis. Trimethoprim-sulfamethoxazole prophylaxis was begun, but a rash ensued and dapsone was substituted. Seborrheic dermatitis and thrush developed. During the next few months a chronic . . .
Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood
Authors: Gilad Twig, Gal Yaniv, Hagai Levine, Adi Leiba, Nehama Goldberger, Estela Derazne, Dana Ben-Ami Shor, Dorit Tzur, Arnon Afek, Ari Shamiss, Ziona Haklai, Jeremy D. Kark
Journal: New England Journal of Medicine (2016)

In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood.
Prognostic Impact of Gender in Diffuse Large B Cell Lymphoma Patients Treated with R-CHOP Therapy
Authors: Hiroyuki Takahashi, Naoto Tomita, Yasufumi Ishiyama, Satoshi Koyama, Kazuho Miyashita, Yuki Nakajima, Yukako Hattori, Kenji Motohashi, Hirotaka Takasaki, Rika Kawasaki, Maki Hagihara, Chizuko Hashimoto, Sachiya Takemura, Katsumichi Fujimaki, Jun Taguchi, Rika Sakai, Hiroyuki Fujita, Shin Fujisawa, Hiroshi Harano, Yoshiaki Ishigatsubo
Journal: Blood (2014)
Protein identification and immunoassay evaluation of a panel of biomarkers discovered through proteomic profiling for the detection of ovarian cancer
Authors: Zhen Zhang, Lori J. Sokoll, Jason M. Rosenzweig, Xiao-Ying Meng, Eric T. Fung, Daniel W. Chan
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1063 

In a previously reported multi-center study, we analyzed serum protein profiles of 503 samples from women with ovarian cancer or benign pelvic masses, and from healthy controls using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF/MS). Three biomarkers at mass charge ratios (m/z) of 28kD, 12.8kD, and 3272D were discovered and independently validated for their ability to detect early stage ovarian cancer from healthy controls and their complementary value to the existing tumor marker CA125. To facilitate further evaluation, we have since identified the protein identities of these markers to be (1) apolipoprotein A1 (m/z 28kD, down-regulated in cancer), (2) a truncated form of transthyretin (m/z 12.8kD, down-regulated in cancer), and (3) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (m/z 3272, up-regulated in cancer). With protein identification, we were able to further evaluate two of the markers using commercially available immunoassays on archived serum samples from healthy women (n=41) and patients with ovarian (n=41), breast (n=20), colon (n=20), and prostate (n=20) cancers collected at the Johns Hopkins Medical Institutions. As shown in the figure, serum levels of apolipoprotein A1 and transthyretin were both down-regulated among the patients with late stage ovarian cancer compared to the healthy controls (P < 0.002, 0.0002, and 0.00001, respectively). The mean serum apolipoprotein A1 level among the healthy controls was not significantly different from that of patients with breast or colorectal cancer (P = 0.844, 0.330, respectively) and only marginally different from that of patients with prostate cancer (P < 0.05). The mean serum transthryetin level was down-regulated among patients with colorectal cancer (P < 0.01) albeit to a lesser degree than that in patients with ovarian cancer. There were no significant differences in mean serum transthyretin levels between the healthy controls and patients with breast or prostate cancer (P = 0.929, 0.547, respectively). It needs to be noted that the transthyretin immunoassay was not specific to the particular truncated form that we had identified. However, in a separate analysis, we were able to show that several transthyretin variants as well as the relative proportions among them were also informative for the detection of early stage ovarian cancer. The current results demonstrated a fairly high level of site specificity of two of the identified biomarkers for ovarian cancer.



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Informed Consent for Major Medical Treatment of Mentally Disabled People
Authors: Clarence J. Sundram
Journal: New England Journal of Medicine (1988)

When an incompetent mentally disabled person has no family member or guardian available, obtaining informed consent for major medical treatment usually requires a court order--an often time-consuming, formal, and expensive process that does not provide for much substantive review of the decision about treatment. Consequently, there is a temptation to circumvent the requirement that informed consent be obtained for treatment of the residents of institutions as well as of those in community mental-health and mental-retardation programs. Under a new pilot program established by the New York State legislature, volunteer committees are empowered to make decisions about medical care in such cases. The law protects physicians from liability when they rely on the committees' decisions. The results of the program after one year indicate that this is an effective approach, which provides quick yet careful individualized decisions, in an informal and accessible forum. Advocates for the mentally disabled and health care providers agree that this approach is preferable to the judicial process for making decisions about medical care for incompetent mentally disabled persons. This type of program may prove workable for other groups of incompetent people who lack family members or guardians to act as surrogate decision makers.
Predisposition to Hypertension and Susceptibility to Renal Disease in Insulin-Dependent Diabetes Mellitus
Authors: A S Krolewski, M Canessa, J H Warram, L M Laffel, A R Christlieb, W C Knowler, L I Rand
Journal: New England Journal of Medicine (1988)

Only one third of patients with juvenile-onset insulin-dependent diabetes seem to be susceptible to diabetic nephropathy. To test whether this susceptibility is related to a predisposition to hypertension, we investigated the association of nephropathy with markers of risk for hypertension. We randomly selected 89 patients with insulin-dependent diabetes from a roster of children and adolescents who were seen between 1968 and 1972 at about the time the diagnosis was made. These 89 patients were recalled for examination, as young adults, in 1986 and 1987. Patients with nephropathy (cases, n = 33) were compared with controls without nephropathy (n = 56). Having a parent with hypertension tripled the risk of nephropathy (odds ratio, 3.7; 95 percent confidence interval, 1.4 to 10.1). Moreover, cases had significantly higher values for maximal velocity of lithium–sodium countertransport in red cells than controls (mean maximal velocity ±SE, 0.51 ±0.04 vs. 0.38±0.02 mmol per liter of cells per hour; P<0.05). The excess risk associated with both these indicators of a predisposition to hypertension was evident principally in patients with poor glycemic control during their first decade of diabetes; the odds ratios were 4.5 (95 percent confidence interval, 1.1 to 18.7) for patients with a parental history of hypertension and 7.7 (95 percent confidence interval, 1.8 to 33.8) for patients with a maximal velocity of lithium–sodium countertransport ≥0.35 mmol per liter of cells per hour. We conclude that the risk of renal disease in patients with juvenile-onset insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Predisposition to hypertension appears to increase susceptibility for renal disease principally in patients with poor glycemic control. (N Engl J Med 1988; 318:140–5.)
P71 The Relationship between the Leicester Cough Questionnaire, Eosinophilic Airway inflammation and Asthma Patient Related Outcome Measures in Severe Asthma
Authors: S Siddiqui, R Free, P Bradding, L McGarvey
Journal: Thorax (2015)

<h3>Background</h3> Severe asthma is characterised by a variety of symptoms which include chronic cough, although the mechanisms responsible are poorly understood. Modulation of cough reflex sensitivity by eosinophilic airway inflammation is considered likely but has not been well studied. Likewise the impact of chronic cough on patients health status is not well known as existing asthma patient related outcome instruments such as the Juniper Asthma Control Score (ACQ-6), Asthma Quality of Life Questionnaire (AQLQ) were not primarily designed to capture cough and its related morbidity in asthma. We sought to evaluate (i) the Leicester Cough Questionnaire (LCQ) in a severe asthma population, (ii) the relationship between the Leicester Cough Questionnaire (LCQ) and the ACQ-6, AQLQ and (iii) airway inflammation in sputum in severe asthma patients. <h3>Methods</h3> 312 patients [mean (SD) age of 60.4(16.2) years, median (IQR) GINA treatment score 5[4–5] and median (IQR) sputum eosinophil percentage of 3.0(0.5–16.6)] attending the Leicester difficult asthma service were evaluated with the LCQ, ACQ-6 and AQLQ at a single clinical visit. Induced sputum samples were also acquired at the same visit for differential cell count. <h3>Results</h3> The LCQ demonstrated the following distribution properties: mean 15.30, standard deviation 4.49, range 4.04–21 and 10<sup>th</sup> percentile point of 8.52. Domain specific scores were LCQ (physical) 4.8(1.45), LCQ (psychological) 5.30 (1.55) and LCQ (social) 5.19(1.67). There were modest correlations between LCQ and ACQ-6 (r = -0.60; p &lt; 0.001) but not with AQLQ (r = -0.067). There was no correlation between LCQ and sputum eosinophilis/neutrophils. <h3>Discussion</h3> Severe asthma is associated with a high degree of cough related morbidity that appears to be independent of eosinophilic airway inflammation and not captured fully by available patient reported outcome instruments. Further research is required to determine the validity of the LCQ and its responsiveness in severe asthma populations.
A Randomized, Controlled Trial of Prophylactic Ganciclovir for Cytomegalovirus Pulmonary Infection in Recipients of Allogeneic Bone Marrow Transplants
Authors: G M Schmidt, D A Horak, J C Niland, S R Duncan, S J Forman, J A Zaia
Journal: New England Journal of Medicine (1991)

Cytomegalovirus (CMV)-associated interstitial pneumonia is a major cause of death after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir in recipients of bone marrow transplants who had asymptomatic pulmonary CMV infection. We also sought to identify risk factors for the development of CMV interstitial pneumonia.
Cancer patients’ preferences for return of somatic and germline whole-exome sequencing results: Data from the CANSEQ study.
Authors: Stacy W. Gray, Nikhil Wagle, Judy Ellen Garber, Irene R. Rainville, Elaine Hiller, Yolanda Martins, Nelly Oliver, Carol Lowenstein, Julie S. Najita, Eliezer VanAllen, Pasi A. Janne, Lynette M. Sholl, Neal Ian Lindeman, Levi A. Garraway, Steven Joffe
Journal: Journal of Clinical Oncology (2014)

1535 Background: The introduction of whole-exome sequencing (WES) into routine cancer care presents novel challenges for patient education and informed consent. In light of the recent American College of Medical Genetics and Genomics recommendations for the return of actionable germline incidental findings, it is imperative to understand patients' preferences for the return of WES findings. Methods: Advanced lung and colorectal cancer patients were offered WES. Preferences for the return of somatic and germline findings were obtained at consent. Attitudes about genetic testing and genetic knowledge were elicited through a baseline survey. Results: We approached 97 patients for participation, of whom 92 (95%) enrolled. Eighty-six patients completed the survey (completion rate 93%); 49% lung, 58% female, mean age 65 (standard deviation (sd) 11.4), 79% white, 21% ≤ high school education, 22% ≥ advanced degree. The vast majority of patients wanted to learn about somatic and germline WES findings. Preferences for return of results were highest for somatic findings that can be used to select a clinical trial (97%) and for positive prognostic findings (99%). Most patients also wanted return of germline pharmacogenetic (cancer-related 99%; non-cancer related 94%), cancer risk (96%), and treatable non-cancer risk (96%) results. Preferences for the return of somatic results with negative prognostic implications (86%), results indicating germline risk for non-treatable, non-cancer conditions (85%), and carrier status (88%) were slightly lower. Patients had highly positive attitudes about genetic testing but relatively low genetic knowledge, answering a mean of 54% of items correctly on a 7-item scale (sd 24.7). Conclusions: Patients with advanced lung and colorectal cancer express strong preferences for the return of somatic and germline WES findings. Despite patients' positive attitudes about genetic testing, relatively low levels of genetic knowledge may present challenges to adequate informed consent and highlight the need for high-quality sequencing-related patient education.
Thyroid Diseases after Treatment of Hodgkin's Disease
Authors: Steven L. Hancock, Richard S. Cox, I. Ross McDougall
Journal: New England Journal of Medicine (1991)

Thyroid disease, especially hypothyroidism, is common in patients with Hodgkin's disease who have been treated with irradiation. We reviewed the records of 1787 patients (740 women and 1047 men) with Hodgkin's disease who were treated with radiation therapy alone (810 patients), radiation and chemotherapy (920 patients), or chemotherapy alone (57 patients) at Stanford University between 1961 and 1989. Among these patients, 1533 were alive at the last follow-up, and 254 had died of causes other than Hodgkin's disease. Four other patients were excluded from the analysis because they had undergone thyroidectomy before treatment for Hodgkin's disease. The thyroid was irradiated in 1677 patients. Follow-up averaged 9.9 years.