tbuckley/cabot-search huggingface dataset:
Comment: National Cooperative Studies
Authors: Philip Rubin
Journal: JAMA (1968)

Renal carcinoma is not a common malignancy; it constitutes no more than 1% to 2% of all cancers. Although there are trends in the literature which suggest possible approaches to improving results, it is impossible for any one individual or even an active university hospital to mount therapeutic trials. To overcome this obstacle, a national cooperative protocol has been developed. The aim of such a controlled clinical study is to demonstrate the superiority of different types and combinations of treatment. This is done by having a number of participating institutions supply the number of patients needed. The limitation of such efforts rests on the quality of care in each clinic, whereas its strength lies in the cross-sectional representation, the standardization of treatment, and reporting of results that evolve.  During the span of the past threedecades, nephrectomy has yielded a five-year survival of 31% to 50% and a ten-year figure
Anxiety Disorders in Primary Care: Prevalence, Impairment, Comorbidity, and Detection
Authors: Kurt Kroenke, Robert L. Spitzer, Janet B.W. Williams, Patrick O. Monahan, Bernd Löwe
Journal: Annals of Internal Medicine (2007)

Background: Anxiety, although as common as depression, has received less attention and is often undetected and undertreated. Objective: To determine the current prevalence, impairment, and comorbidity of anxiety disorders in primary care and to evaluate a brief measure for detecting these disorders. Design: Criterion-standard study performed between November 2004 and June 2005. Setting: 15 U.S. primary care clinics. Participants: 965 randomly sampled patients from consecutive clinic patients who completed a self-report questionnaire and agreed to a follow-up telephone interview. Measurements: 7-item anxiety measure (Generalized Anxiety Disorder [GAD]-7 scale) in the clinic, followed by a telephone-administered, structured psychiatric interview by a mental health professional who was blinded to the GAD-7 results. Functional status (Medical Outcomes Study Short Form-20), depressive and somatic symptoms, and self-reported disability days and physician visits were also assessed. Results: Of the 965 patients, 19.5% (95% CI, 17.0% to 22.1%) had at least 1 anxiety disorder, 8.6% (CI, 6.9% to 10.6%) had posttraumatic stress disorder, 7.6% (CI, 5.9% to 9.4%) had a generalized anxiety disorder, 6.8% (CI, 5.3% to 8.6%) had a panic disorder, and 6.2% (CI, 4.7% to 7.9%) had a social anxiety disorder. Each disorder was associated with substantial impairment that increased significantly (P < 0.001) as the number of anxiety disorders increased. Many patients (41%) with an anxiety disorder reported no current treatment. Receiver-operating characteristic curve analysis showed that both the GAD-7 scale and its 2 core items (GAD-2) performed well (area under the curve, 0.80 to 0.91) as screening tools for all 4 anxiety disorders. Limitation: The study included a nonrandom sample of selected primary care practices. Conclusions: Anxiety disorders are prevalent, disabling, and often untreated in primary care. A 2-item screening test may enhance detection.
Suppression of contact sensitivity by local hyperthermia treatment due to reduced Langerhans cell population in mice
Authors: A. YOSHIOKA, Y. MIYACHI, S. IMAMURA, M. HIRAOKA, S. JO, M. ABE
Journal: British Journal of Dermatology (1989)

The effects of local hyperthermia treatment on contact sensitivity (CS) and on the number of Langerhans cells (LCs) were studied in mice. CS was significantly suppressed when mice were sensitized in the hyperthermia treated skin I, 2 or 4 days after treatment (43 degrees C for 45 min). This suppressive effect was not observed 7 or 14 days after the treatment. CS was also suppressed when mice were sensitized in non-treated skin I day after the treatment. The density of LCs detected as ATPase-positive cells also decreased significantly 1, 2, 4 and 7 days after the treatment. There appeared to be a positive correlation between the number of LCs and the extent of CS when mice were sensitized at hyperthermia treated skin. It was observed that this suppressive effect on CS was dose- and temperature-dependent. It could be transferred by spleen cells from the hyperthermia treated and DNFB-sensitized donors, and was antigen specific when spleen cells were transferred before sensitization of the recipient mice. This indicated it was, in part, associated with the induction of suppressor cells. These findings suggest that local hyperthermia treatment reduces the number of LCs with subsequent suppression of the induction phase of delayed-type hypersensitivity by the generation of antigen-specific suppressor cells.
The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis
Authors: N Hosen, T Shirakata, S Nishida, M Yanagihara, A Tsuboi, M Kawakami, Y Oji, Y Oka, M Okabe, B Tan, H Sugiyama, I L Weissman
Journal: Leukemia (2007)
Abstract 172: Utility of retinoid treatment in the reversion of the malignant phenotype of mammary tumors with alterations in the expression of protein kinase C (PKC) isoforms
Authors: Maria I. Diaz Bessone, Damian E. Berardi, Stefano Ciriglaino, Paola B. Campodonico, Elisa Bal de Kier Joffe, Laura B. Todaro, Alejandro J. Urtreger
Journal: Cancer Research (2012)

Abstract Some of the most promising signaling pathways for breast cancer treatment include the PKC family, involved in proliferation and apoptosis, and the retinoid system mainly involved in differentiation. In this work we have developed a murine model of mammary adenocarcinoma-derived cells (LM3) that overexpress α or ≤ PKC isoforms in order to analyze whether elevated levels of these kinases alter cell sensitivity to retinoid treatment (ATRA). LM3 cells are poorly responsive to ATRA. The overexpression of PKCα induced alterations in LM3 in vitro behavior that could be associated with tumor progression. In this sense, PKCα increased proliferation and motility (wound coverage: 69.3±8.3% vs 41.2±5.1% in control cells p&amp;lt;0.05) of the transfected LM3 cells. Interestingly, at the same time PKCα sensitized LM3 cells to ATRA treatment as evidenced by a significant reduction in both parameters. Upon othotopic inoculation into syngeneic mice LM3-PKCα cells formed tumors with higher growth rate and metastatic potential than LM3-vector cells. In vivo treatment with an ATRA pellet reduced both the local tumor growth and the number of spontaneous lung metastases (Md [Range]: 9 [0-27] vs 55 [20-75] for LM3-PKCα treated or not respectively p&amp;lt;0.05). On the contrary PKC ≤ overexpression did not affect LM3 cells behavior either in vitro or in vivo. LM3 cells response to ATRA was not modulated by PKC∈ either. However, through a RARE-luciferase gene reporter assay, we could determine that the overexpression of PKC∈ increased the activity of the retinoic acid receptors. Our results show that PKCα overexpression induced a more aggressive phenotype but also conferred ATRA sensitivity to mammary tumor cells. On the other side high PKC∈ levels increased the activity of retinoid receptors but did not modulate biological cell responses to retinoids. We believe that the use of retinoids may be beneficial in patients with aggressive breast tumors associated with high PKCα expression levels. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 172. doi:1538-7445.AM2012-172
Paroxysmal Nocturnal Porphyrinuria
Authors: Joseph A. Smith, Abraham M. Frumin
Journal: New England Journal of Medicine (1956)

PORPHYRIA is a relatively uncommon metabolic disorder that has engaged the interest of many investigators. The protean manifestations have led to a classification of the various types as seen in clinical practice.1 , 2 We have recently observed a form of chronic porphyria characterized by the paroxysmal nocturnal nature of the porphyrinuria. Observations on the possible mechanism of these findings are presented along with the clinical and biochemical determinations.Case ReportR.G., a 43-year-old Negro, was admitted to the Nazareth Hospital on July 17, 1955, because of the voiding of "bloody urine" in the morning on arising. He had noticed this for . . .
Naevi in allogeneic bone marrow transplantation recipients: the effect of graft-versus-host disease on naevi
Authors: V. Andreani, M.A. Richard, D. Blaise, J. Gouvernet, J.J. Grob
Journal: British Journal of Dermatology (2002)

Non-melanoma skin carcinoma is more common in transplant recipients, probably because of immunosuppression. An increased risk of developing melanoma could be a late effect of transplantation. The number of naevi, which is a risk marker for melanoma, is increased in renal transplant recipients of all ages and may be related to immunosuppression. The risk of melanoma has been suspected to be particularly high after bone marrow transplantation. Cutaneous graft-versus-host disease (GVHD) might be an interesting model for the study of interactions between naevi and the immune system.To assess whether aBMT exposes an individual to a particularly high risk of melanoma, using naevi as a surrogate measure of the risk. To improve our knowledge of the effect of the immune system on naevi, using GVHD as a model.We carried out an epidemiological case-control study with two age-, sex- and hair colour-matched controls for each case. The results were analysed with analysis of variance, a general linear model analysis and multivariate analysis.The number of naevi was not significantly increased in aBMT patients, as compared with controls, although there was a significant excess on the palms and legs. In exploratory subgroup case-control comparisons and with the general linear model, patients who were conditioned with a combination of two alkylating drugs at high doses, and patients who had an aBMT before the age of 20 years tended to have a higher count of naevi (P = 0.002 and P = 0.06, respectively). Conversely, there was a trend in favour of a lower count of naevi in patients with diffuse skin lesions of chronic GVHD (P = 0.01). These data were corroborated by multivariate analysis, which showed that conditioning with high-dose chemotherapy, the absence of severe chronic cutaneous GVHD and a young age at transplantation were the main variables that independently predicted an excess of naevi.This study of aBMT patients confirms that chemotherapy stimulates naevus growth. It also suggests for the first time that diffuse lesions of chronic cutaneous GVHD are associated with a decreased number of naevi. Whether allo-immunity, chronic skin inflammation or the masking of naevi by pigmentation and fibrosis is responsible for the decreased number of naevi requires further investigation. With respect to the long-term risk of melanoma in aBMT recipients, our results support an increased risk particularly when aBMT is performed at a young age, and when conditioning is with high doses of alkylating drugs.
Multiple significance tests: the Bonferroni correction
Authors: P. Sedgwick
Journal: BMJ (2012)

Researchers assessed the effects of hormone replacement therapy, consisting of combined oestrogen and progestogen, on health related quality of life. A randomised placebo controlled, double blind trial study design was used. Women were recruited if they were postmenopausal, had a uterus, and were aged 50-69 at randomisation. Outcome measures included health related quality of life and psychological wellbeing. The study period was one year.1

The researchers investigated the effects of combined hormone replacement therapy compared with placebo at one year, using a 0.05 (5%) critical level of significance and adjusting this with the Bonferroni correction. The researchers concluded that combined hormone replacement therapy started many years after the menopause can improve health related quality of life.

For which of the following does the Bonferroni correction reduce the probability of occurring?

The Bonferroni correction reduces the …
Class effects of tyrosine kinase inhibitors on osteoclastogenesis in vitro
Authors: G. Mayr, S. Bluml, T. Puchner, G. Superti-Furga, J. Smolen, K. Redlich
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background/objectives</h3> Bone destruction in rheumatoid arthritis (RA) is mediated by osteoclasts (OCs). Imatinib, a tyrosine kinase inhibitor (TKI), has been shown to exert an inhibitory effect on osteoclastogenesis. The aim of this study was to investigate the effects of novel TKIs other than imatinib, namely dasatinib, inno 406 and sunitinib on osteoclastogenesis including the generation of OC precursors (pOCs) and the fusion of pOCs into mature OCs. The authors also wished to assess, whether TKIs also affect the bone resorbing capacity of mature OCs. <h3>Material and methods</h3> The impact of TKIs on in vitro OC formation was assessed, including the number of OCs, generation of pOCs and the number of OC nuclei. Apoptosis of pOCs was measured by annexin V staining. The influence of TKIs on the mRNA expression of OC effector molecules was investigated by quantitative PCR. The effect of TKIs was also assessed in pit resorption assays. <h3>Results</h3> The authors demonstrate that all four TKIs (imatinib, dasatinib, inno 406, sunitinib) have a pronounced inhibitory effect on the formation of pOCs. Moreover, all of them show a dose-dependent inhibition of OC numbers at clinically relevant concentrations. Furthermore, TKIs inhibit the bone resorbing capacity of OCs. Annexin V labelling has demonstrated that TKIs do not induce apoptosis in pOCs. In addition, imatinib and inno 406 also reduce the mRNA levels of OC effector molecules cathepsin K and matrix metalloproteinase 9, which are important for extracellular matrix degradation. <h3>Conclusions</h3> These data show that various TKIs potently inhibit osteoclastogenesis and therefore might be able to prevent joint destruction in patients with RA or other diseases associated with increased bone loss, such as osteoporosis.
Prevention of psychosocial problems in adolescence
Authors: Sabina Dosani
Journal: BMJ (2006)

<h3>Introduction</h3> HLA class I is associated with the outcome of hepatitis C virus (HCV) infection. Tapasin is a member of the peptide loading complex that loads self and viral peptides onto HLA class I. Presentation of viral peptides by HLA class I is critical in generating an effective cytotoxic T lymphocyte (CTL) response, and hence in clearing HCV infection. However, not all HLA alleles require tapasin for efficient peptide loading. Thus polymorphisms in the tapasin gene could affect clearance of HCV in combination with specific “tapasin-dependent” HLA class I alleles. The SNP rs2071888 is a non-synonymous polymorphism in exon 4 of the <i>Tapasin</i> gene causing an arginine to threonine change that could affect tapasin function. We have investigated the effect of this SNP in resolving hepatitis C virus (HCV) infection in a cohort of 336 patients from the UK. <h3>Aim</h3> We have investigated the effect of the SNP rs2071888 in resolving hepatitis C virus (HCV) infection in a cohort of 336 patients from the UK. <h3>Method</h3> Genomic DNA from 216 chronically infected individuals and 120 spontaneous resolvers of HCV was genotyped with an allele specific PCR designed to identify the G/C SNP in exon 4 of the <i>Tapasin</i> gene. Individuals were also typed for HLA-A, -B and -C. Results were analysed for association with hepatitis C outcome. <h3>Results</h3> Overall the G allele of tapasin was associated with protection against chronic HCV infection (p=0.018, OR=1.99, 95% CI 1.14 to 3.46). Interestingly, in combination with heterozygosity at the HLA-B locus, heterozygosity at the tapasin locus was also protective (Abstract OP04 figure 1, p trend =0.005). Furthermore, we identified specific HLA-B alleles associated with protection in the context of the Tapasin G, but not Tapasin C allele. Specifically the G allele was most protective in the context of B*0702 (p=0.029, OR=4.56, 95% CI 1.2 to 17.27), and B*5701 (p=0.029, OR=12, 95% CI 1.2 to 120). Tapasin has been shown to bind specifically to amino acids 114 and 116 of HLA class I. Consistent with this functional interaction we found that aspartate at position 114 and serine at 116 were most beneficial in the context of both the G allele (D114/TapG, p&lt;0.0001, OR=3.3, 95% CI 1.83 to 5.98; S116/TapG, p&lt;0.0001, OR=2.73, 95% CI 1.57 to 4.76). <h3>Conclusion</h3> The G allele of tapasin was associated with protection from chronic HCV infection, both alone and in combination with specific HLA class I alleles. Individuals who are heterozygous for both tapasin and HLA-B are relatively protected from chronic HCV infection. This heterozygosity may allow them to present a broader range of peptides to CTL and thus mount a more effective anti-HCV immune response.
Patients with sickle cell disease have increased sensitivity to cold and heat
Authors: Amanda M. Brandow, Cheryl L. Stucky, Cheryl A. Hillery, Raymond G. Hoffmann, Julie A. Panepinto
Journal: American Journal of Hematology (2012)

Sickle cell disease (SCD) pain is associated with colder temperatures and touch and described as "cold," "hot," and "shooting" suggesting hypersensitivity to tactile stimuli. Sickle mice exhibit hypersensitivity to thermal (cold, heat) and mechanical stimuli compared to controls. It is unknown whether humans experience this same hypersensitivity. Thus, we quantified thermal and mechanical sensitivity differences between patients with SCD and controls. Our primary hypothesis was that patients with SCD will exhibit hypersensitivity to thermal and mechanical stimuli compared to race-matched controls. Our secondary hypothesis was this hypersensitivity will be associated with older and female subjects, and with frequent pain and hemolysis in patients with SCD. A total of 55 patients and 57 controls ≥7 years completed quantitative sensory testing. Patients with SCD detected the sensation of cold and warm temperatures sooner as seen in their significantly lower median cold and heat detection thresholds [29.5°C vs. 28.6°C, P = 0.012 and 34.5°C vs. 35.3°C, P = 0.02] and experienced cold and heat pain sooner as seen in their significantly lower median cold and heat pain thresholds [21.1°C vs. 14.8°C, P = 0.01 and 42.7°C vs. 45.2°C, P = 0.04]. We found no mechanical threshold differences. Older age was associated with lower cold, heat, and mechanical pain thresholds in both groups. No association with pain, gender, or hemolysis was found. Patients with SCD exhibit hypersensitivity to thermal stimuli suggesting peripheral or central sensitization may exist and could contribute to SCD pain.
Profound bradycardia in response to atrial fibrillation in the Wolff-Parkinson-White syndrome.
Authors: A J Camm, D E Ward, R A Spurrell
Journal: BMJ (1978)

At this time the T4 concentration had fallen to slightly below normal and the T3 concentration was within the normal range for the first time, although the TRH test remained suppressed (basal TSH 1-3, at 20 min 1-2, and at 60 min 1-0 mU/l).A thyroid scan showed uptake confined largely to the left lobe of Comment Patients with Hashimoto's thyroiditis may be hyperthyroid, euthyroid, or hypothyroid depending on the duration of the disease and the stage at which they are first seen and assessed.For example, in a review of 217 patients2 77 9% were euthyroid, 18 4% were hypothyroid, and 3-7% were hyperthyroid.Hyperthyroidism due to T3 toxicosis seems to be unusual.We were unable to find another report of a convincing case of T3 toxicosis proceeding to hypothyroidism in the absence of treatment.Our patient, on no antithyroid medication, progressed in 11 months from a state of undoubted T3 toxicosis to hypothyroidism associated with the expected rise in serum TSH concentrations.
Growing pressure on BMJ's obituaries
Authors: L. Crossan, R. Smith
Journal: BMJ (1995)

cases, which do not necessitate admission to hospital, will generally occur in babies aged 3 months or more, born at term, who are feeding well and whose respiratory rate is < 50 breaths/min.Moderate cases necessitate admission to hospital or at least management at home with small, frequent feeds and frequent observations.In these cases the babies are tachy- pnoeic (50-70 breaths/min), with only slight difficulty with feeds.In severe cases the babies are highly tachypnoeic (> 70 breaths/min) or have apnoea, do not feed well, and need urgent admission.Clinical predictors of severity are tachypnoea (>70 breaths/min), age less than 3 months, preterm delivery (particularly before 34 weeks), and an "ill" or "toxic" appearance.21Babies with difficulty in feeding or apnoea should be admitted, and it is probably wise to admit babies with underlying heart, lung, or immune problems who develop bronchiolitis.Cyanosis is a late and sinister sign.Pulse oximetry, if available, is the best predictor of the severity of the disease and need for oxygen.2122Given its valuable role in assessing children with bronchiolitis and, to a lesser extent, other respiratory diseases, general practitioners should strongly consider buying a pulse oximeter.The mortality associated with bronchiolitis is low, but babies can deteriorate rapidly and clinical skills are necessary to reduce the mortality and morbidity still further.
p21 Ablation in Liver Enhances DNA Damage, Cholestasis, and Carcinogenesis
Authors: Haksier Ehedego, Mark V. Boekschoten, Wei Hu, Carina Doler, Johannes Haybaeck, Nikolaus Gaβler, Michael Müller, Christian Liedtke, Christian Trautwein
Journal: Cancer Research (2015)

Abstract Genetic mouse studies suggest that the NF-κB pathway regulator NEMO (also known as IKKγ) controls chronic inflammation and carcinogenesis in the liver. However, the molecular mechanisms explaining the function of NEMO are not well defined. Here, we report that overexpression of the cell-cycle regulator p21 is a critical feature of liver inflammation and carcinogenesis caused by the loss of NEMO. NEMOΔhepa mice develop chronic hepatitis characterized by increased hepatocyte apoptosis and proliferation that causes the development of fibrosis and hepatocellular carcinoma (HCC), similar to the situation in human liver disease. Having identified p21 overexpression in this model, we evaluated its role in disease progression and LPS-mediated liver injury in double mutant NEMOΔhepa/p21−/− mice. Eight-week-old NEMOΔhepa/p21−/− animals displayed accelerated liver damage that was not associated with alterations in cell-cycle progression or the inflammatory response. However, livers from NEMOΔhepa/p21−/− mice displayed more severe DNA damage that was further characterized by LPS administration correlating with higher lethality of the animals. This phenotype was attenuated by genetic ablation of the TNF receptor TNF-R1 in NEMOΔhepa/p21−/− mice, demonstrating that DNA damage is induced via TNF. One-year-old NEMOΔhepa/p21−/− mice displayed greater numbers of HCC and severe cholestasis compared with NEMOΔhepa animals. Therefore, p21 overexpression in NEMOΔhepa animals protects against DNA damage, acceleration of hepatocarcinogenesis, and cholestasis. Taken together, our findings illustrate how loss of NEMO promotes chronic liver inflammation and carcinogenesis, and they identify a novel protective role for p21 against the generation of DNA damage. Cancer Res; 75(6); 1144–55. ©2015 AACR.
Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer
Authors: Charles Catzavelos, Nandita Bhattacharya, Yee C. Ung, James A. Wilson, Luba Roncari, Charanjit Sandhu, Patricia Shaw, Herman Yeger, Isabella Morava-Protzner, Linda Kapusta, Edmée Franssen, Kathleen I. Pritchard, Joyce M. Slingerland
Journal: Nature Medicine (1997)