bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated biopsies in patients with prostate cancer on active surveillance: clinical implications of interobserver variation in histopathological assessment
Authors: Thomsen Frederik B. , Marcussen Niels , Berg Kasper D. , Christensen Ib J. , Vainer Ben , Iversen Peter , Brasso Klaus 
Published: June 2014

ObjectiveTo investigate the clinical implications of interobserver variation in the assessment of re‐biopsies obtained during active surveillance (AS) of prostate cancer.Patients and MethodsIn all, 107 patients with low‐risk prostate cancer with 93 diagnostic biopsy sets and 109 re‐biopsy sets were included. The International Society of Urological Pathology 2005 Gleason scoring system was used for the histopathological assessment of all biopsies. Three different definitions of histopathological progression were applied. Unweighted and linear weighted Kappa (κ) statistics were used to compare the interobserver agreement.ResultsThe overall Gleason score agreement was 68.8% with a weighted κ of 0.670. The interobserver agreement was 79.6% for meeting the AS selection criteria. According to the three progression definitions applied, overall agreement was between 80.7% and 89.0% with weighted κ values of 0.746–0.791. Treatment recommendations would have changed in up to 10.1% (95% confidence interval 5.4–17.7%) of the 109 re‐biopsy sets.ConclusionKappa statistics showed strong agreement between the histological evaluations. However, up to 10% of patients on AS would receive a different treatment recommendation depending upon which histopathological evaluation of re‐biopsies was used for treatment planning.
Massive renal size is not a contraindication to a laparoscopic approach for bilateral native nephrectomies in autosomal dominant polycystic kidney disease (ADPKD)
Authors: Wisenbaugh Eric S. , Tyson Mark D. , Castle Erik P. , Humphreys Mitchell R. , Andrews Paul E. 
Published: June 2014

ObjectiveTo determine if massive renal size should be a contraindication for attempting a laparoscopic approach to bilateral native nephrectomies in patients with autosomal dominant polycystic kidney disease (ADPKD).Patients and MethodsWe retrospectively reviewed all laparoscopic bilateral nephrectomies performed for ADPKD at our institution from 1 January 2000 to 31 December 2012. We stratified patients by kidney weight (with or without at least one kidney weighing >2500 g) and compared perioperative data, complications, and status of kidney allografts. Additionally, the subset of patients with at least one kidney weighing >3500 g was compared with the rest of the cohort.ResultsWe identified 68 patients; mean (range) individual kidney weight was 1984 (197–5042) g. In all, 24 patients had at least one kidney weighing >2500 g, yet patients in this group were not significantly different from the rest of the cohort for complications, estimated blood loss, transfusion rate, or duration of hospitalisation. For those who underwent simultaneous renal allotransplantation, native kidney size was not associated with graft outcomes. Additionally, of the six patients with at least one kidney weighing >3500 g, only one required a blood transfusion, and the group had no intraoperative or postoperative Clavien grade ≥3 complications. None of the cohort required conversion to open surgery.ConclusionMassive size of polycystic kidneys is not a contraindication to attempting a laparoscopic approach to bilateral nephrectomies in an experienced, high‐volume centre.
Lack of association of joint hypermobility with urinary incontinence subtypes and pelvic organ prolapse
Authors: Derpapas Alex , Cartwright Rufus , Upadhyaya Purnima , Bhide Alka A. , Digesu Alex G. , Khullar Vik 
Published: June 2014

ObjectiveTo test the hypothesis that joint hypermobility (JHM) is associated with specific urinary incontinence (UI) subtypes and uterovaginal prolapse.Patients and MethodsIn all, 270 women scheduled to undergo urodynamic investigations were invited to self‐complete a validated five‐item JHM questionnaire. Women underwent history taking, symptoms assessing via the King's Health Questionnaire and clinical examination using the Pelvic Organ Prolapse Quantification system. Associations between JHM and pelvic floor disorders in univariate and multivariate ordinal regression were reported using odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe prevalence of JHM was 31.1%. JHM had a negative association with age (OR 0.98/year, P = 0.04). There was no association between JHM and either urodynamic (P = 0.41), or symptomatic stress UI (P = 0.48). Nor was there association with detrusor overactivity or symptomatic urgency UI. Multivariate ordinal regression of JHM with maximum prolapse stage, adjusting for age, showed a significant relationship (OR 1.26/stage, 95% CI 1.06–1.46, P < 0.05).ConclusionAlthough JHM is highly prevalent amongst women with lower urinary tract symptoms (LUTS), there is no strong association of JHM with any UI subtype. There is a trend towards higher prolapse staging in women with JHM, which becomes significant only after adjustment for the confounding negative association between age and JHM.
Indications for intervention during active surveillance of prostate cancer: a comparison of the Johns Hopkins and Prostate Cancer Research International Active Surveillance (PRIAS) protocols
Authors: Kates Max , Tosoian Jeffrey J. , Trock Bruce J. , Feng Zhaoyong , Carter H. Ballentine , Partin Alan W. 
Published: June 2014

ObjectiveTo analyse how patients enrolled in our biopsy based surveillance programme would fare under the Prostate Cancer Research International Active Surveillance (PRIAS) protocol, which uses PSA kinetics.Patients and MethodsSince 1995, 1125 men with very‐low‐risk prostate cancer have enrolled in the AS programme at the Johns Hopkins Hospital (JHH), which is based on monitoring with annual biopsy. The PRIAS protocol uses a combination of periodic biopsies (in years 1, 4, and 7) and prostate‐specific antigen doubling time (PSADT) to trigger intervention. Patients enrolled in the JHH AS programme were retrospectively reviewed to evaluate how the use of the PRIAS protocol would alter the timing and use of curative intervention.ResultsOver a median of 2.1 years of follow up, 38% of men in the JHH AS programme had biopsy reclassification. Of those, 62% were detected at biopsy intervals corresponding to the PRIAS criteria, while 16% were detected between scheduled PRIAS biopsies, resulting in a median delay in detection of 1.9 years. Of the 202 men with >5 years of follow‐up, 11% in the JHH programme were found to have biopsy reclassification after it would have been identified in the PRIAS protocol, resulting in a median delay of 4.7 years to reclassification. In all, 12% of patients who would have undergone immediate intervention under PRIAS due to abnormal PSA kinetics would never have undergone reclassification on the JHH protocol and thus would not have undergone definitive intervention.ConclusionsThere are clear differences between PSA kinetics‐based AS programmes and biopsy based programmes. Further studies should address whether and how the differences in timing of intervention impact subsequent disease progression and prostate cancer mortality.
Controlling the activation of the Bv8/prokineticin system reduces neuroinflammation and abolishes thermal and tactile hyperalgesia in neuropathic animals
Authors: Maftei D , Marconi V , Florenzano F , Giancotti L A , Castelli M , Moretti S , Borsani E , Rodella L F , Balboni G , Luongo L , Maione S , Sacerdote P , Negri L , Lattanzi R 
Published: June 2014

Background and PurposeChemokines are involved in neuroinflammation and contribute to chronic pain processing. The new chemokine prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. In the present study, we investigated the involvement of PROK2 and its receptors in neuropathic pain.Experimental ApproachEffects of single, intrathecal, perineural and s.c. injections of the PKR antagonist PC1, or of 1 week s.c. treatment, on thermal hyperalgesia and tactile allodynia was evaluated in mice with chronic constriction of the sciatic nerve (CCI). Expression and localization of PROK2 and of its receptors at peripheral and central level was evaluated 10 days after CCI, following treatment for 1 week with saline or PC1. IL‐1β and IL‐10 levels, along with glia activation, were evaluated.Key ResultsSubcutaneous, intrathecal and perineural PC1 acutely abolished the CCI‐induced hyperalgesia and allodynia. At 10 days after CCI, PROK2 and its receptor PKR2 were up‐regulated in nociceptors, in Schwann cells and in activated astrocytes of the spinal cord. Therapeutic treatment with PC1 (s.c., 1 week) alleviated established thermal hyperalgesia and allodynia, reduced the injury‐induced overexpression of PROK2, significantly blunted nerve injury‐induced microgliosis and astrocyte activation in the spinal cord and restored the physiological levels of proinflammatory and anti‐inflammatory cytokines in periphery and in spinal cord.Conclusion and ImplicationsThe prokineticin system contributes to pain modulation via neuron–glia interaction. Sustained inhibition of the prokineticin system, at peripheral or central levels, blocked both pain symptoms and some events underlying disease progression.
PAR1‐dependent COX‐2/PGE2 production contributes to cell proliferation via EP2 receptors in primary human cardiomyocytes
Authors: Chien Peter Tzu‐Yu , Hsieh Hsi‐Lung , Chi Pei‐Ling , Yang Chuen‐Mao 
Published: June 2014

Background and PurposeDifferent protease‐activated receptors (PARs) activated by thrombin are involved in cardiovascular disease, via up‐regulation of inflammatory proteins including COX‐2. However, the mechanisms underlying thrombin‐regulated COX‐2 expression in human cardiomyocytes remain unclear.Experimental ApproachHuman cardiomyocytes were used in the study. Thrombin‐induced COX‐2 protein and mRNA expression, and signalling pathways were determined by Western blot, real‐time PCR and COX‐2 promoter luciferase reporter assays, and pharmacological inhibitors or siRNAs. PGE2 generation and cell proliferation were also determined.Key ResultsThrombin‐induced COX‐2 protein and mRNA expression, promoter activity and PGE2 release was attenuated by the PAR1 antagonist (SCH79797) or the inhibitors of proteinase activity (PPACK), MEK1/2 (U0126), p38 MAPK (SB202190) or JNK1/2 (SP600125), and transfection with small interfering RNA (siRNA) of PAR1, p38, p42 or JNK2. These results suggested that PAR1‐dependent MAPKs participate in thrombin‐induced COX‐2 expression in human cardiomyocytes. Moreover, thrombin stimulated phosphorylation of MAPKs, which was attenuated by PPACK and SCH79797. Furthermore, thrombin‐induced COX‐2 expression was blocked by the inhibitors of AP‐1 (tanshinone IIA) and NF‐κB (helenalin). Moreover, thrombin‐stimulated phosphorylation of c‐Jun/AP‐1 and p65/NF‐κB was attenuated by tanshinone IIA and helenalin, respectively, suggesting that thrombin induces COX‐2 expression via PAR1/MAPKs/AP‐1 or the NF‐κB pathway. Functionally, thrombin increased human cardiomyocyte proliferation through the COX‐2/PGE2 system linking to EP2 receptors, as determined by proliferating cell nuclear antigen and cyclin D1 expression.Conclusions and ImplicationsThese findings demonstrate that MAPKs‐mediated activation of AP‐1/NF‐κB pathways is, at least in part, required for COX‐2/PGE2/EP2‐triggered cell proliferation in human cardiomyocytes.
Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi‐1 expression
Authors: Dong Qinghua , Chen Long , Lu Qunwei , Sharma Sherven , Li Lei , Morimoto Sachio , Wang Guanyu 
Published: June 2014

Background and PurposeDoxorubicin‐based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin‐induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi‐1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin‐mediated protection against doxorubicin‐induced cardiotoxicity.Experimental ApproachEffects of quercetin on doxorubicin‐induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre‐treatment.Key ResultsIn H9c2 cells, quercetin reduced doxorubicin‐induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double‐strand breaks. The quercetin‐mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl‐2 and Bmi‐1. Bmi‐1 siRNA abolished the protective effect of quercetin against doxorubicin‐induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin‐induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi‐1 and anti‐oxidative superoxide dismutase.Conclusions and ImplicationsOur results demonstrate that quercetin decreased doxorubicin‐induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up‐regulation of Bmi‐1 expression. The findings presented in this study have potential applications in preventing doxorubicin‐induced cardiomyopathy.
A novel 1,2‐benzenediamine derivative FC‐99 suppresses TLR3 expression and ameliorates disease symptoms in a mouse model of sepsis
Authors: Gong Wei , Hu Erling , Dou Huan , Song Yuxian , Yang Liu , Ji Jianjian , Li Erguang , Tan Renxiang , Hou Yayi 
Published: June 2014

Background and PurposeSepsis is a clinical condition characterized by overwhelming systemic inflammation with high mortality rate and high prevalence, but effective treatment is still lacking. Toll‐like receptor 3 (TLR3) is an endogenous sensor, thought to regulate the amplification of immune response during sepsis. Modulators of TLR3 have an advantage in the treatment of sepsis. Here, we aimed to explore the mechanism of a monosubstituted 1,2‐benzenediamine derivative FC‐99 {N1‐[(4‐methoxy)methyl]‐4‐methyl‐1,2‐benzenediamine}on modulating TLR3 expression and its therapeutic potential on mouse model of sepsis.Experimental ApproachCells were pretreated with FC‐99 followed by poly(I:C) or IFN‐α stimulation; TLR3 and other indicators were assayed. Female C57BL/6 mice were subjected to sham or caecal ligation puncture (CLP) surgery after i.p. injection of vehicle or FC‐99; serum and tissues were collected for further experiments.Key ResultsFC‐99 suppressed inflammatory response induced by poly(I:C) with no effect on cell viability or uptake of poly(I:C). FC‐99 also inhibited TLR3 expression induced by not only poly(I:C) but also by exogenous IFN‐α. This inhibition of FC‐99 was related to the poly(I:C)‐evoked IRF3/IFN‐α/JAK/STAT1 signalling pathway. In CLP‐induced model of sepsis, FC‐99 administration decreased mice mortality and serum levels of inflammatory factors, attenuated multiple organ dysfunction and enhanced bacterial clearance. Accordingly, systemic and local expression of TLR3 was reduced by FC‐99 in vivo.Conclusion and ImplicationsFC‐99 reversed TLR3 expression and ameliorate CLP‐induced sepsis in mice. Thus, FC‐99 will be a potential therapeutic candidate for sepsis.
Invisible populations: LGBTQ people and federal health policy in Canada
Authors: Mulé Nick J. , Smith Miriam 
Published: June 2014

AbstractThis article reviews the state of federal health policy discourse toward the LGBTQ population in Canada. Despite the advent of greater attention to diversity and gender mainstreaming in federal public policy and the shift to legalized rights protections for LGBTQ people, symbolized by policies such as same‐sex marriage, LGBTQ health concerns continue to be marginalized in federal health policy. Based on a systematic review of federal policy documents and websites as well as a small number of interviews with federal policy‐makers, the research demonstrates the extent to which LGBTQ health concerns are rendered invisible in federal health policy. The article suggests several ways in which a commitment to gender‐based policy analysis could be expanded to take account of diverse health needs of LGBTQ Canadians.
The protein tyrosine phosphatase PTPN22 controls forkhead box protein 3 T regulatory cell induction but is dispensable for T helper type 1 cell polarization
Authors: Fousteri G , Jofra T , Debernardis I , Stanford S M , Laurenzi A , Bottini N , Battaglia M 
Published: June 2014

SummaryProtein tyrosine phosphatases (PTPs) regulate T cell receptor (TCR) signalling and thus have a role in T cell differentiation. Here we tested whether the autoimmune predisposing gene PTPN22 encoding for a PTP that inhibits TCR signalling affects the generation of forkhead box protein 3 (FoxP3)+ T regulatory (Treg) cells and T helper type 1 (Th1) cells. Murine CD4+ T cells isolated from Ptpn22 knock-out (Ptpn22 KO) mice cultured in Treg cell polarizing conditions showed increased sensitivity to TCR activation compared to wild-type (WT) cells, and subsequently reduced FoxP3 expression at optimal-to-high levels of activation. However, at lower levels of TCR activation, Ptpn22 KO CD4+ T cells showed enhanced expression of FoxP3. Similar experiments in humans revealed that at optimal levels of TCR activation PTPN22 knock-down by specific oligonucleotides compromises the differentiation of naive CD4+ T cells into Treg cells. Notably, in vivo Treg cell conversion experiments in mice showed delayed kinetic but overall increased frequency and number of Treg cells in the absence of Ptpn22. In contrast, the in vitro and in vivo generation of Th1 cells was comparable between WT and Ptpn22 KO mice, thus suggesting PTPN22 as a FoxP3-specific regulating factor. Together, these results propose PTPN22 as a key factor in setting the proper threshold for FoxP3+ Treg cell differentiation.
Twelve‐Year Retrospective Follow‐Up of Machined Implants in the Posterior Maxilla: Radiographic and Peri‐Implant Outcome
Authors: Simion Massimo , Gionso Luca , Grossi Giovanni Battista , Briguglio Francesco , Fontana Filippo 
Published: June 2014

AbstractPurposeTo retrospectively evaluate the survival rate of machined implants in sinus‐lifted posterior maxilla after 12 years, with special reference to radiographic outcome and peri‐implantitis.Materials and MethodsFrom 37 possible candidates, 29 patients with 59 implants were evaluated. Implants were placed in the posterior maxilla in combination with a sinus elevation procedure (27 patients) or 6 months after sinus elevation (2 patients). Marginal bone level changes were radiographically evaluated at baseline and 1, 7, and 12 years post‐loading. Probing depth was measured; presence/absence of plaque and bleeding on probing were recorded.ResultsFour out of 59 implants failed in 4 out of 29 patients (cumulative survival rate = 93.2%). The mean bone loss was 0.78 mm (± 0.88) after 12 years. Changes in the mean bone level were statistically significant between baseline and all the other follow‐up intervals (p < .001). Statistically significant differences could be demonstrated for the first‐ to 12th‐year interval (p < .05) and for the seventh‐ to 12th‐year interval (p < 0.001). No statistically significant differences could be demonstrated at the first‐ to seventh‐year interval (p = .32). The mean overall probing depth was 2.9 ± 0.66 mm. Probing depth was moderately correlated with the marginal bone changes at 7 year and after 12 year follow up (p = .05). No signs of peri‐implantitis were reported during the 12‐year follow‐up period.ConclusionsThis follow‐up demonstrates a very good prognosis when implants with machined surfaces are used. The frequencies of implant failures were very small. Within the limits of the results from this study, the risk of peri‐implantitis in the posterior maxilla might be considered a minor problem when implants with machined surfaces are used.
MicroRNAs as oncogenes or tumour suppressors in oesophageal cancer: potential biomarkers and therapeutic targets
Authors: Huang J. , Zhang S.‐Y. , Gao Y.‐M. , Liu Y.‐F. , Liu Y.‐B. , Zhao Z.‐G. , Yang K. 
Published: June 2014

AbstractMicroRNAs are a class of small, non‐coding RNAs that can negatively regulate protein‐coding genes, and are associated with almost all known physiological and pathological processes, especially cancer. The number of studies documenting miRNA expression patterns in malignancy continues to expand rapidly, with continuously gained critical information regarding how aberrantly expressed miRNAs may contribute to carcinogenesis. miRNAs can influence cancer pathogenesis, playing a potential role as either oncogenes or tumour suppressors. Recently, several miRNAs have been reported to exert different regulatory functions in oesophageal cancer – the carcinoma typically arising from the epithelial lining of the oesophagus. These miRNAs also have potential clinical applications towards developing biomarkers or targets for possible use in diagnosis or therapy in oesophageal cancer. In this review, we have summarized the two (oncogenic or tumour suppressive) roles of miRNAs here, and their applications as potential biomarkers or therapeutic targets, which may illuminate future treatment for oesophageal cancer.
Association of COPD exacerbation frequency with gene expression of pattern recognition receptors in inflammatory cells in induced sputum
Authors: Kinose Daisuke , Ogawa Emiko , Kudo Megumi , Marumo Satoshi , Kiyokawa Hirofumi , Hoshino Yuma , Hirai Toyohiro , Chin Kazuo , Muro Shigeo , Mishima Michiaki 
Published: June 2014

AbstractBackgroundBacteria and viruses are major causes of chronic obstructive pulmonary disease (COPD) exacerbations. Molecular components of these pathogens are recognized by pattern‐recognition receptors (PRRs) expressed by various cells in the airway, which leads to initiation of inflammatory processes. Expression levels of PRRs in airway inflammatory cells are expected to affect susceptibility to COPD exacerbation.AimsThis prospective observational study was conducted to detect any association between exacerbation and PRR expression.MethodsThirty‐one male COPD patients were recruited. At baseline, clinical history, lung function measurements, peripheral blood samples and induced sputum were obtained. Using sputum samples, we performed gene expression analysis of TLR2, TLR3, TLR4, NOD1, NOD2, RIG‐I and MDA‐5 by quantitative reverse transcription‐polymerase chain reaction in addition to quantitative bacterial culture. COPD exacerbations were assessed based on Anthonisen's criteria using symptom diaries for the following 1‐year period.ResultsDuring 1‐year follow‐up period, 13 patients experienced at least one exacerbation, but 18 patients did not. Those with exacerbations tended to be more severe COPD and showed larger neutrophil fraction in their induced sputum. Among PRRs, only TLR3 gene expression was increased in COPD patients with exacerbation compared with those without exacerbations. Multivariate logistic regression analysis including neutrophil fraction and TLR3 gene expression as predictor variables demonstrated that only an increase of neutrophil fraction, but not TLR3 gene expression, was a significant predictor for COPD exacerbation.ConclusionTLR3 expression in inflammatory cells might affect the susceptibility to COPD exacerbation.