tbuckley/cabot-search huggingface dataset:
The emerging role of histone lysine demethylases in prostate cancer
Authors: Francesco Crea, Lei Sun, Antonello Mai, Yan Chiang, William L Farrar, Romano Danesi, Cheryl D Helgason
Journal: Molecular Cancer (2012)

Early prostate cancer (PCa) is generally treatable and associated with good prognosis. After a variable time, PCa evolves into a highly metastatic and treatment-refractory disease: castration-resistant PCa (CRPC). Currently, few prognostic factors are available to predict the emergence of CRPC, and no curative option is available. Epigenetic gene regulation has been shown to trigger PCa metastasis and androgen-independence. Most epigenetic studies have focused on DNA and histone methyltransferases. While DNA methylation leads to gene silencing, histone methylation can trigger gene activation or inactivation, depending on the target amino acid residues and the extent of methylation (me1, me2, or me3). Interestingly, some histone modifiers are essential for PCa tumor-initiating cell (TIC) self-renewal. TICs are considered the seeds responsible for metastatic spreading and androgen-independence. Histone Lysine Demethylases (KDMs) are a novel class of epigenetic enzymes which can remove both repressive and activating histone marks. KDMs are currently grouped into 7 major classes, each one targeting a specific methylation site. Since their discovery, KDM expression has been found to be deregulated in several neoplasms. In PCa, KDMs may act as either tumor suppressors or oncogenes, depending on their gene regulatory function. For example, KDM1A and KDM4C are essential for PCa androgen-dependent proliferation, while PHF8 is involved in PCa migration and invasion. Interestingly, the possibility of pharmacologically targeting KDMs has been demonstrated. In the present paper, we summarize the emerging role of KDMs in regulating the metastatic potential and androgen-dependence of PCa. In addition, we speculate on the possible interaction between KDMs and other epigenetic effectors relevant for PCa TICs. Finally, we explore the role of KDMs as novel prognostic factors and therapeutic targets. We believe that studies on histone demethylation may add a novel perspective in our efforts to prevent and cure advanced PCa.
<b> <i>NBS1</i> </b> Is a Prostate Cancer Susceptibility Gene
Authors: C. Cybulski, B. Górski, T. Dębniak, B. Gliniewicz, M. Mierzejewski, B. Masojć, A. Jakubowska, J. Matyjasik, E. Złowocka, A. Sikorski, S. A. Narod, J. Lubiński
Journal: Cancer Research (2004)

To evaluate whether an inactivating mutation in the gene for the Nijmegen breakage syndrome (NBS1) plays a role in the etiology of prostate cancer, we compared the prevalence of the 657del5 NBS1 founder allele in 56 patients with familial prostate cancer, 305 patients with nonfamilial prostate cancer, and 1500 control subjects from Poland. Loss of heterozygosity analysis also was performed on DNA samples isolated from 17 microdissected prostate cancers, including 8 from carriers of the 657del5 mutation. The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001), 7 of 305 (2.2%) patients with nonfamilial prostate cancer (odds ratio, 3.9; P = 0.01), and 9 of 1500 control subjects (0.6%). The wild-type NBS1 allele was lost in seven of eight prostate tumors from carriers of the 657del5 allele, but loss of heterozygosity was seen in only one of nine tumors from noncarriers (P = 0.003). These findings suggest that heterozygous carriers of the NBS1 founder mutation exhibit increased susceptibility to prostate cancer and that the cancers that develop in the prostates of carriers are functionally homozygous for the mutation.
Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer
Authors: J.-C. Soria, A. Mauguen, M. Reck, A.B. Sandler, N. Saijo, D.H. Johnson, D. Burcoveanu, M. Fukuoka, B. Besse, J.-P. Pignon
Journal: Annals of Oncology (2012)
Cytoprotective Effect of Somatostatin in A Rat Model of Hepatic Ischemic Reperfusion
Authors: Ignacio Landa, Javier Arias, Manuel Gómez, Manuel Quadros, Ana Moreno, José Luis Balibrea
Journal: Hepatology (1992)

To evaluate the possible cytoprotective effect of somatostatin in hepatic ischemic reperfusion injury we used 75 adult male Wistar rats randomly separated into four groups. The rats in group 1 underwent sham operations, and those in group 2 underwent resection of the median and left lateral lobes. The rats in group 3 underwent a 90-min period of ischemia of the right lateral lobe, which we induced by temporarily occluding the right portal vein and the hepatic artery. On restoration of flow to the right lateral lobe, the median and left lateral lobes (about 80% of total liver mass) were excised (and later assayed for thymidine kinase basal activity). The rats in group 4 were given the same treatment as group 3 rats except that a saline solution of somatostatin was infused at a rate of 2 micrograms/min starting at laparotomy and lasting 24 hr. The rats in groups 1, 2 and 3 were infused with saline. Rats in groups 2, 3 and 4 were randomly assigned to two subgroups; one of these subgroups was observed until spontaneous death, and rats in the other group were killed 24 hr after the procedure for obtaining peripheral blood and liver samples. Somatostatin infusion improved the animals' survival rates from 0% (group 3) to 60% (group 4) (p < 0.05) and decreased bilirubin levels (0.78 +/- 0.17 mg/dl, n = 15 [group 4] vs. 1.69 +/- 0.04 mg/dl, n = 15 [group 3]; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Radiotherapy and chemotherapy for elderly patients with stage I–II unresected lung cancer
Authors: Juan P. Wisnivesky, Marcelo Bonomi, Linda Lurslurchachai, Grace Mhango, Ethan A. Halm
Journal: European Respiratory Journal (2012)

Radiotherapy (RT) is the standard therapy for unresected stage I–II nonsmall cell lung cancer (NSCLC). Using population-based data, we compared survival and toxicity among unresected elderly patients treated with combined chemoradiotherapy (CRT) or RT alone. Using the Surveillance, Epidemiology and End Results (SEER) registry (National Cancer Institute, Bethesda, MD, USA) we identified 3,006 cases of unresected stage I–II NSCLC. We used propensity score methods to compare survival and rates of toxicity of patients treated with RT <i>versus</i> CRT. Overall, 844 (28%) patients received CRT. Adjusted analyses showed that CRT was associated with improved survival (hazard ratio 0.85, 95% CI 0.78–0.94). Combination therapy was also associated with better survival among stage I patients treated with intermediate complexity RT (HR 0.80, 95% CI 0.70–0.90); however, no difference in survival was observed among patients treated with complex RT. In stage II patients, CRT was associated with improved survival regardless of the RT technique (HR 0.61–0.72). CRT was associated with increased odds of toxicity. Despite increased toxicity, CRT may improve survival of elderly unresected patients with stage II disease as well as stage I NSCLC treated with intermediate RT complexity. Randomised trials are needed to clarify the balance of benefits and risk of CRT in unresected patients.
Neurobehavioral Function in School-Age Children Exposed to Manganese in Drinking Water
Authors: Youssef Oulhote, Donna Mergler, Benoit Barbeau, David C. Bellinger, Thérèse Bouffard, Marie-Ève Brodeur, Dave Saint-Amour, Melissa Legrand, Sébastien Sauvé, Maryse F. Bouchard
Journal: Environmental Health Perspectives (2014)

Background: Manganese neurotoxicity is well documented in individuals occupationally exposed to airborne particulates, but few data are available on risks from drinking-water exposure.Objective: We examined associations of exposure from concentrations of manganese in water and hair with memory, attention, motor function, and parent- and teacher-reported hyperactive behaviors.Methods: We recruited 375 children and measured manganese in home tap water (MnW) and hair (MnH). We estimated manganese intake from water ingestion. Using structural equation modeling, we estimated associations between neurobehavioral functions and MnH, MnW, and manganese intake from water. We evaluated exposure–response relationships using generalized additive models.Results: After adjusting for potential confounders, a 1-SD increase in log10 MnH was associated with a significant difference of –24% (95% CI: –36, –12%) SD in memory and –25% (95% CI: –41, –9%) SD in attention. The relations between log10 MnH and poorer memory and attention were linear. A 1-SD increase in log10 MnW was associated with a significant difference of –14% (95% CI: –24, –4%) SD in memory, and this relation was nonlinear, with a steeper decline in performance at MnW &gt; 100 μg/L. A 1-SD increase in log10 manganese intake from water was associated with a significant difference of –11% (95% CI: –21, –0.4%) SD in motor function. The relation between log10 manganese intake and poorer motor function was linear. There was no significant association between manganese exposure and hyperactivity.Conclusion: Exposure to manganese in water was associated with poorer neurobehavioral performances in children, even at low levels commonly encountered in North America.Citation: Oulhote Y, Mergler D, Barbeau B, Bellinger DC, Bouffard T, Brodeur ME, Saint-Amour D, Legrand M, Sauvé S, Bouchard MF. 2014. Neurobehavioral function in school-age children exposed to manganese in drinking water. Environ Health Perspect 122:1343–1350; http://dx.doi.org/10.1289/ehp.1307918
The Role of Polo-like Kinase 1 in Carcinogenesis: Cause or Consequence?
Authors: Brian D. Cholewa, Xiaoqi Liu, Nihal Ahmad
Journal: Cancer Research (2013)

Polo-like kinase 1 (Plk1) is a well-established mitotic regulator with a diverse range of biologic functions continually being identified throughout the cell cycle. Preclinical evidence suggests that the molecular targeting of Plk1 could be an effective therapeutic strategy in a wide range of cancers; however, that success has yet to be translated to the clinical level. The lack of clinical success has raised the question of whether there is a true oncogenic addiction to Plk1 or if its overexpression in tumors is solely an artifact of increased cellular proliferation. In this review, we address the role of Plk1 in carcinogenesis by discussing the cell cycle and DNA damage response with respect to their associations with classic oncogenic and tumor suppressor pathways that contribute to the transcriptional regulation of Plk1. A thorough examination of the available literature suggests that Plk1 activity can be dysregulated through key transformative pathways, including both p53 and pRb. On the basis of the available literature, it may be somewhat premature to draw a definitive conclusion on the role of Plk1 in carcinogenesis. However, evidence supports the notion that oncogene dependence on Plk1 is not a late occurrence in carcinogenesis and it is likely that Plk1 plays an active role in carcinogenic transformation.
Cholangiocytes and primary biliary cirrhosis: prediction and predication
Authors: M. Eric Gershwin, Judy Van de Water
Journal: Journal of Clinical Investigation (2001)

Although there have been descriptions of primary biliary cirrhosis (PBC) for more than 100 years, this condition first attracted the attention of immunologists in 1965, when patients’ sera were found to have antimitochondrial antibodies (AMAs) (1). The mitochondrial autoantigens, which are highly conserved among mitochondria and even chloroplasts (2) of divergent species, have been identified as the E2 components of the 2-oxo-acid dehydrogenase family — particularly the 74-kDa E2 subunit of the pyruvate dehydrogenase complex, which catalyzes the formation of acetyl CoA. The structurally and functionally related mitochondrial proteins BCOADC-E2 and OGDC-E2, as well as the E3 binding protein (3), are also found as autoantigens in PBC patients. Work with recombinant autoantigens has shown that the presence of AMAs is virtually diagnostic of PBC and that, while they may be detected in the sera of asymptomatic people years before the clinical diagnosis of PBC, they are very rarely found in non-PBC individuals (4, 5).

The B cell epitope of PDC-E2 is found on the lipoyl domains, and antibody binding occurs when the antigen is complexed with lipoic acid (6). In fact, there are only five proteins in mammals that contain lipoic acid, and four of the five are autoantigens in PBC. Lipoic acid is bound to the lysine residue of the inner lipoyl domain, where it functions as a swinging arm to capture electrons during oxidative phosphorylation. Related work using cloned PDC-E2–specific T cell lines shows that the immunodominant T cell epitope also falls within the lipoyl domains. Interestingly, the frequency of PDC-E2–specific CD4+ T cell precursors is 100-fold higher in the liver than in PBMCs (7) in PBC patients, suggesting that these cells are recruited to the liver during the progression of the disease. However, the precise pathogenic role of these T cells is still under investigation.

Despite the advances in the molecular characterization of immunoreactivity, a number of unexplained questions remain regarding the epidemiology and tissue specificity of this disease (3). Why is PBC overwhelmingly more common in women? Why is PBC not found in childhood? Why are granulomas found, and why is eosinophilia present in periductal inflammatory infiltrates? Why is PBC relatively more specific for small bile ducts than large bile ducts? Why should PBC recur following liver transplantation? Why is the incidence of PBC so much higher in families with an index case, even when there is no obvious MHC class I or class II association? What is the significance of the observation that some monoclonal antibodies to mitochondria appear to uniquely stain the bile duct cells in patients with PBC? Finally, why does the immune response induce damage to only a minor population of cells, those of the small ducts and ductules of the biliary and salivary epithelia?
Rapid molecular diagnosis of chronic skin ulcers – Authors' reply
Authors: Oriol Mitjà, Sheila A Lukehart
Journal: The Lancet Global Health (2014)

1 Mitja O, Lukehart SA, Pokowas G, et al. Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study. Lancet Glob Health 2014; 2: e235–41. 2 Liang C, Chu Y, Cheng S, et al. Multiplex loop-mediated isothermal amplifi cation detection by sequence-based barcodes coupled with nicking endonuclease-mediated pyrosequencing. Anal Chem 2012; 84: 3758–63. 3 Ablordey A, Amissah DA, Aboagye IF, et al. Detection of Mycobacterium ulcerans by the loop mediated isothermal amplifi cation method. PLoS Negl Trop Dis 2012; 6: e1590. 4 Ussher JE, Wilson E, Campanella S, Taylor SL, Roberts SA. Haemophilus ducreyi causing chronic skin ulceration in children visiting Samoa. Clin Infect Dis 2007; 44: e85–87. 5 Thornton AC, O’Mara EM Jr, Sorensen SJ, et al. Prevention of experimental Haemophilus ducreyi infection: a randomized, controlled clinical trial. J Infect Dis 1998; 177: 1608–13. 6 Roberts SA, Taylor SL. Haemophilus ducreyi: a newly recognised cause of chronic skin ulceration. Lancet Glob Health 2014; 2: e187–88. 7 Ayove T, Houinei W, Wangnapi R, et al. Sensitivity and specifi city of a rapid point-ofcare test for active yaws: a comparative study. Lancet Glob Health 2014; published online May 30. http://dx.doi.org/10.1016/S2214109X(14)70231-1 Rapid molecular diagnosis of chronic skin ulcers
Is Natural Ventilation a Useful Tool to Prevent the Airborne Spread of TB?
Authors: Peter Wilson
Journal: PLoS Medicine (2007)

Airborne transmission of infections such as tuberculosis (TB) can be a major problem in health care establishments. Health care workers infected with TB can be unwitting disseminators of the infection, and expensive retrospective screening (of other health workers and patients) is required when the diagnosis is made. In the past, the benefits of natural ventilation in the treatment of TB were implicit in the design of the sanatoria wards (Figure 1). More recently, expensive negative pressure facilities have been installed to accommodate patients with TB, particularly following outbreaks of TB among patients with HIV/AIDS [1].



Figure 1

Los Angeles Sanatorium, Duarte, California, United States (Photo: City of Hope).



Room air should be changed 10–12 times every hour to ensure sufficient dilution of the bacterial load. Actual room air changes often fall below this level because of deficiencies in the facility and lack of maintenance. Respiratory masks provide protection, but are often inadequately fitted to the face and are not used before diagnosis is reached. Communal areas such as waiting rooms do not even approach these criteria and remain a risk for transmission. In a single incident of a mother and child with undiagnosed TB in a ward over several weeks, 6.7% of patients and 1.9% of pediatric health care workers had tuberculin skin test conversions [2]. Screening was required in 16 pediatric patients and 293 health care workers.

In many poorer countries, negative pressure ventilation may not be installed or monitored adequately [3]. Current recommendations are directed at the importance of early diagnosis and treatment in these areas, yet practice can often be less than ideal. In India facilities may be crowded and poorly ventilated, and they may lack infection control procedures [4]. The trainee medical staff is at particularly high risk of acquisition of TB [5]. However, many cases of nosocomial transmission are avoidable since the need for respiratory isolation can be accurately predicted on the basis of clinical and chest radiographic findings [6].
Properties of electrogenic Pi transport by a human renal brush border Na+/Pi transporter.
Authors: A E Busch, C A Wagner, A Schuster, S Waldegger, J Biber, H Murer, F Lang
Journal: Journal of the American Society of Nephrology (1995)

Inorganic phosphate (Pi) induced an inward current (IP) in Xenopus oocytes expressing the human renal Na+/Pi cotransporter NaPi-3. At 100mM Na+, Pi-transport was independent of the holding potential and resulted in an apparent Km of 0.08 mM; lowering the Na+ concentration to 50 mM resulted in an increase of the apparent Km to 0.22 mM at -50 mV and to 0.31 mM at -90 mV. In contrast, the apparent Km for Na+ was not significantly influenced by the holding potential. A decrease of the pH from 7.8 to 6.8 resulted in a decrease of IP at 50 mM Na+, but not at 150 mM Na+. Arsenate induced inward currents through NaPi-3 and decreased the apparent Km in measurements of IP. Phosphonoformic acid itself induced no currents, but inhibited Pi-induced currents with an apparent Ki of 3.6 mM. In summary, NaPi-3 displays characteristic Na+/Pi cotransporter properties with relevant interactions with arsenate (transport substrate) and phosphonoformic acid (inhibitor). Monovalent and divalent Pi both appear to be transported by NaPi-3.
More people are waiting longer in A&amp;E since targets were dropped
Authors: A. O'Dowd
Journal: BMJ (2011)

The number of people waiting more than four hours for treatment in Accident and Emergency (A&E) departments in England has risen by 67% during the last three months of 2010 compared with the same period a year before.

The Department of Health has defended the trend saying the rise is part of overall growing attendances at emergency departments.

Figures from the department show that the number of people who had to wait more than four hours at A&E rose from 110 738 between October and December 2009 to 184 374 people in the same period in 2010.

The additional 73 636 patients waiting longer has arisen since health secretary Andrew Lansley dropped the previous government’s four hour waiting …
Heterogeneity of coronary heart disease risk factors in Indian, Pakistani, Bangladeshi, and European origin populations: cross sectional study
Authors: R. Bhopal, N. Unwin, M. White, J. Yallop, L. Walker, K G M M Alberti, J. Harland, S. Patel, N. Ahmad, C. Turner, B. Watson, D. Kaur, A. Kulkarni, M. Laker, A. Tavridou
Journal: BMJ (1999)

Objective: To compare coronary risk factors and disease prevalence among Indians, Pakistanis, and Bangladeshis, and in all South Asians (these three groups together) with Europeans. Design: Cross sectional survey. Setting: Newcastle upon Tyne. Participants: 259 Indian, 305 Pakistani, 120 Bangladeshi, and 825 European men and women aged 25-74 years. Main outcome measures: Social and economic circumstances, lifestyle, self reported symptoms and diseases, blood pressure, electrocardiogram, and anthropometric, haematological, and biochemical measurements. Results: There were differences in social and economic circumstances, lifestyles, anthropometric measures and disease both between Indians, Pakistanis, and Bangladeshis and between all South Asians and Europeans. Bangladeshis and Pakistanis were the poorest groups. For most risk factors, the Bangladeshis (particularly men) fared the worst: smoking was most common (57%) in that group, and Bangladeshis had the highest concentrations of triglycerides (2.04 mmol/l) and fasting blood glucose (6.6 mmol/l) and the lowest concentration of high density lipoprotein cholesterol (0.97 mmol/l). Blood pressure, however, was lowest in Bangladeshis. Bangladeshis were the shortest (men 164 cm tall v 170 cm for Indians and 174 cm for Europeans). A higher proportion of Pakistani and Bangladeshi men had diabetes (22.4% and 26.6% respectively) than Indians (15.2%). Comparisons of all South Asians with Europeans hid some important differences, but South Asians were still disadvantaged in a wide range of risk factors Findings in women were similar. Conclusion: Risk of coronary heart disease is not uniform among South Asians, and there are important differences between Indians, Pakistanis, and Bangladeshis for many coronary risk factors. The belief that, except for insulin resistance, South Asians have lower levels of coronary risk factors than Europeans is incorrect, and may have arisen from combining ethnic subgroups and examining a narrow range of factors. #### Key messages
Conflicts of Interest
Authors: Oscar W. Clarke
Journal: JAMA (1992)

In this report, the Council on Ethical and Judicial Affairs revisits the question of referral of patients to medical facilities in which physicians have financial interests ("self-referral"). The Council issued safeguards in 1986 to prevent abuses of self-referral and most recently updated the guidelines in 1989. Recent studies, however, have suggested that problems with self-referral persist; these problems undermine the commitment of physicians to professionalism. The Council has concluded that, in general, physicians should not refer patients to a health care facility outside their office practice at which they do not directly provide care or services when they have an investment interest in the facility. Physicians may invest in and refer to an outside facility if there is a demonstrated need in the community for the facility and alternative financing is not available. (<i>JAMA</i>. 1992;267:2366-2369)