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1.  Schwannoma of the colon: A case report 
Oncology Letters  2014;8(6):2511-2512.
Schwannomas are rare tumors originating from the Schwann cells, which form the neural sheath. These tumors occur most frequently in the head, neck, arms and limbs. Primary schwannomas of the colon and rectum are extremely rare; they are usually benign, but in extremely rare cases (2%), they can present with malignant degeneration if not surgically removed. The current study presents the case of a 65-year-old male with blood in the feces who underwent a colonoscopy that revealed an oval-shaped mass covered by ulcerated mucosa. A standard biopsy examination indicated a gelatinous carcinoma, and the patient consequently underwent a laparoscopic resection of the left colon. Histological examination revealed a schwannoma. Immunohistochemistry showed the tumor to be positive for S100 and vimentin, but negative for cluster of differentiation (CD)117, cytokeratin (CK)7, CK20, chromogranin, actin and synaptophysin, with a Ki-67 proliferative index of 3%. Lymph nodes were not involved. Overall, pre-operative biopsy examinations may be difficult for schwannomas, and immunohistochemistry is necessary for the correct diagnosis of this condition. In contrast to gastrointestinal stromal tumors, schwannomas are negative for CD117 and positive for S100 protein and vimentin. A Ki-67 index of ≥5% is strictly correlated with greater tumor aggressiveness. Therefore, the gold standard treatment for schwannomas is oncological radical surgical resection.
doi:10.3892/ol.2014.2545
PMCID: PMC4214396  PMID: 25360169
immunohistochemistry; schwannoma; colon; tumor; surgery
2.  Genome Sequence and Annotation of a Human Infection Isolate of Escherichia coli O26:H11 Involved in a Raw Milk Cheese Outbreak 
Genome Announcements  2015;3(1):e01568-14.
The consumption of raw milk cheese can expose populations to Shiga toxin-producing Escherichia coli (STEC). We report here the genome sequence of an E. coli O26:H11 strain isolated from humans during the first raw milk cheese outbreak described in France (2005).
doi:10.1128/genomeA.01568-14
PMCID: PMC4335332
3.  Efficacy of contemporary chemotherapy in stage IIIC endometrial cancer: A histologic dichotomy 
Gynecologic oncology  2014;132(3):578-584.
Background
Treatment failures in stage IIIC endometrial carcinoma (EC) are predominantly due to occult extrapelvic metastases (EPM). The impact of chemotherapy on occult EPM was investigated according to grade (G), G1/2EC vs G3EC.
Methods
All surgical-stage IIIC EC cases from January 1, 1999, through December 31, 2008, from Mayo Clinic were included. Patient-, disease-, and treatment-specific risk factors were assessed for association with overall survival, cause-specific survival, and extrapelvic disease-free survival (DFS) using Cox proportional hazards regression.
Results
109 cases met criteria, with 92 (84%) having systematic lymphadenectomy (>10 pelvic and >5 paraaortic lymph nodes resected). In patients with documented recurrence sites, occult EPM accounted for 88%. Among G1/2EC cases (n = 48), the sole independent predictor of extrapelvic DFS was grade 2 histology (hazard ratio [HR], 0.28; 95% CI, 0.08–0.91; P = .03) while receipt of adjuvant chemotherapy approached significance (HR 0.13; 95% CI, 0.02, 1.01; P = .0511). The 5-year extrapelvic DFS with and without adjuvant chemotherapy was 93% and 54%, respectively (log-rank, P = .02). Among G3EC (n = 61), the sole independent predictor of extrapelvic DFS was lymphovascular space involvement (HR, 2.63; 95% CI, 1.16–5.97; P = .02). Adjuvant chemotherapy did not affect occult EPM in G3EC; the 5-year extrapelvic DFS for G3EC with and without adjuvant chemotherapy was 43% and 42%, respectively (log-rank, P = .91).
Conclusions
Chemotherapy improves extrapelvic DFS for stage IIIC G1/2EC but not stage IIIC G3EC. Future efforts should focus on prospectively assessing the impact of chemotherapy on DFS in G3EC and developing innovative phase I and II trials of novel systemic therapies for advanced G3EC.
doi:10.1016/j.ygyno.2014.01.007
PMCID: PMC4310003  PMID: 24434057
Chemotherapy efficacy; Occult extrapelvic metastases; Stage IIIC endometrial cancer; Survival
4.  Incidence and Predictors of Venous Thromboembolism After Debulking Surgery for Epithelial Ovarian Cancer 
Objective
The aim of this study was to determine the incidence and the risk factors of venous thromboembolism (VTE) within 30 days after primary surgery for epithelial ovarian cancer (EOC).
Methods
In a historical cohort study, we estimated the postoperative 30-day cumulative incidence of VTE among consecutive Mayo Clinic patients undergoing primary cytoreduction for EOC between January 2, 2003, and December 29, 2008. We tested perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program, >130 variables) as potential predictors of postoperative VTE using the Cox proportional hazards modeling.
Results
Among 569 cases of primary EOC cytoreduction and/or staging and no recent VTE, 35 developed symptomatic VTE within 30 days after surgery (cumulative incidence = 6.5%; 95% confidence interval, 4.4%–8.6%). Within the cohort, 95 (16.7%) received graduated compression stockings (GCSs), 367 (64.5%) had sequential compression devices + GCSs, and 69 (12.1%) had sequential compression devices + GCSs + postoperative heparin, with VTE rates of 1.1%, 7.4%, and 5.8%, respectively (P = 0.07, χ2 test). The remaining 38 (6.7%) received various other chemical and mechanical prophylaxis regimens. In the multivariate analysis, current or past tobacco smoking, longer hospital stay, and a remote history of VTE significantly increased the risk for postoperative VTE.
Conclusions
Venous thromboembolism is a substantial postoperative complication among women with EOC, and the high cumulative rate of VTE within 30 days after primary surgery suggests that a more aggressive strategy is needed for VTE prevention. In addition, because longer hospital stay is independently associated with a higher risk for VTE, methods to decrease length of stay and minimize factors that contribute to prolonged hospitalization are warranted.
doi:10.1097/IGC.0b013e3182a80aa7
PMCID: PMC4307403  PMID: 24172104
Venous thromboembolism; Deep vein thrombosis; Ovarian cancer; Surgery
5.  Early Direct and Indirect Impact of Quadrivalent HPV (4HPV) Vaccine on Genital Warts: a Systematic Review 
Advances in Therapy  2015;32:10-30.
Introduction
Since 2007, many countries have implemented national human papillomavirus (HPV) vaccination programs with the quadrivalent HPV (4HPV) vaccine that has been shown to be efficacious in clinical trials involving 25,000 subjects. Two vaccine serotypes, HPV16 and 18, are responsible for cervical cancer and other HPV-related cancers, but the impact of the 4HPV vaccine on these cancers cannot be seen immediately as there is a considerable lag between infection with HPV and cancer development. The other two serotypes, HPV6 and 11, are responsible for genital warts (GWs), which develop within a few months after infection, making GWs an early clinical endpoint for the assessment of the impact of 4HPV vaccination.
Methods
We performed a systematic literature search in PubMed to identify all published studies on 4HPV vaccination, including those that assessed the impact of 4HPV vaccination programs on the incidence of GWs at a population level around the world.
Results
A total of 354 records were identified in the PubMed search. After screening and obtaining full papers for 56 publications, 16 publications presenting data on the impact or effectiveness of 4HPV vaccination on GWs were identified. These reported data on the impact or effectiveness of 4HPV in six countries [Australia (n = 6), New Zealand (n = 2), United States (n = 3), Denmark (n = 2), Germany (n = 1), and Sweden (n = 2)]. In Australia, no GWs were diagnosed in women aged <21 years who reported being vaccinated. A 92.6% reduction in GWs incidence was reported for all women in this age group, where the vaccine uptake rate (VUR) was 70% for 3 doses. The highest reductions were reported in countries with high VURs, mostly through school-based vaccination programs, although high VURs were obtained with some non-school-based programs.
Conclusion
The results are coherent with the GWs incidence reduction reported in clinical trials and are an early indicator of what can be expected for the long-term clinical impact on vaccine-type HPV-related cancers.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-015-0178-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-015-0178-4
PMCID: PMC4311067  PMID: 25620536
4HPV vaccine; Gardasil; Genital warts; Human papillomavirus; Quadrivalent human papillomavirus vaccine; Vaccine effectiveness; Vaccine impact
6.  Long-term survival after mitral valve surgery for post-myocardial infarction papillary muscle rupture 
Background
Papillary muscle rupture (PMR) is a rare, but dramatic mechanical complication of myocardial infarction (MI), which can lead to rapid clinical deterioration and death. Immediate surgical intervention is considered the optimal and most rational treatment, despite high risks. In this study we sought to identify overall long-term survival and its predictors for patients who underwent mitral valve surgery for post-MI PMR.
Methods
Fifty consecutive patients (mean age 64.7 ± 10.8 years) underwent mitral valve repair (n = 10) or replacement (n = 40) for post-MI PMR from January 1990 through May 2014. Clinical data, echocardiographic data, catheterization data, and surgical data were stored in a dedicated database. Follow-up was obtained in June of 2014; mean follow-up was 7.1 ± 6.8 years (range 0.0-22.2 years). Univariate and multivariate Cox proportional hazard regression analyses were performed to identify predictors of long-term survival. Kaplan-Meier curves were compared with the log-rank test.
Results
Kaplan-Meier cumulative survival at 1, 5, 10, 15, and 20 years was 71.9 ± 6.4%, 65.1 ± 6.9%, 49.5 ± 7.6%, 36.1 ± 8.0% and 23.7 ± 9.2%, respectively. Univariate and multivariate analyses revealed logistic EuroSCORE ≥40% and EuroSCORE II ≥25% as strong independent predictors of a lower overall long-term survival. After removal of the EuroSCOREs from the model, preoperative inotropic drug support and mitral valve replacement (MVR) without (partial or complete) preservation of the subvalvular apparatus were independent predictors of a lower overall long-term survival.
Conclusions
Logistic EuroSCORE ≥40%, EuroSCORE II ≥25%, preoperative inotropic drug support and MVR without (partial or complete) preservation of the subvalvular apparatus are strong independent predictors of a lower overall long-term survival in patients undergoing mitral valve surgery for post-MI PMR. Whenever possible, the subvalvular apparatus should be preserved in these patients.
doi:10.1186/s13019-015-0213-1
PMCID: PMC4320582  PMID: 25622516
Myocardial infarction; Papillary muscle (rupture); Mitral regurgitation; Mitral valve repair; Mitral valve replacement; Outcome
7.  Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation 
Background
Alzheimer’s disease (AD) is a multifactorial disorder associated with the accumulation of soluble forms of beta-amyloid (Aβ) and its subsequent deposition into plaques. One of the major contributors to neuronal death is chronic and uncontrolled inflammatory activation of microglial cells around the plaques and their secretion of neurotoxic molecules. A shift in microglial activation towards a phagocytic phenotype has been proposed to confer benefit in models of AD. Peroxisome proliferator activator receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory activation properties and PPARδ agonism leads to reduction in brain Aβ levels in 5XFAD mice. This study was carried out to elucidate the involvement of microglial activation in the PPARδ-mediated reduction of Aβ burden and subsequent outcome to neuronal survival in a 5XFAD mouse model of AD.
Methods
5XFAD mice were orally treated with the PPARδ agonist GW0742 for 2 weeks. The brain Aβ load, glial activation, and neuronal survival were assessed by immunohistochemistry and quantitative PCR. In addition, the ability of GW0742 to prevent direct neuronal death as well as inflammation-induced neuron death was analyzed in vitro.
Results
Our results show for the first time that a short treatment period of 5XFAD mice was effective in reducing the parenchymal Aβ load without affecting the levels of intraneuronal Aβ. This was concomitant with a decrease in overall microglial activation and reduction in proinflammatory mediators. Instead, microglial immunoreactivity around Aβ deposits was increased. Importantly, the reduction in the proinflammatory milieu elicited by GW0742 treatment resulted in attenuation of neuronal loss in vivo in the subiculum of 5XFAD mice. In addition, whereas GW0742 failed to protect primary neurons against glutamate-induced cell death, it prevented inflammation-induced neuronal death in microglia-neuron co-cultures in vitro.
Conclusions
This study demonstrates that GW0742 treatment has a prominent anti-inflammatory effect in 5XFAD mice and suggests that PPARδ agonists may have therapeutic utility in treating AD.
doi:10.1186/s12974-014-0229-9
PMCID: PMC4310027  PMID: 25592770
Alzheimer’s disease; Microglia; Phagocytosis; Aβ; Neurodegeneration; Nuclear receptor; Inflammation; PPARδ
8.  Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia 
Leukemia  2014;29(1):86-95.
Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16- locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P = 0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions.
doi:10.1038/leu.2014.139
PMCID: PMC4198514  PMID: 24732594
9.  Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy 
British Journal of Cancer  2013;110(1):26-33.
Background:
Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients.
Methods:
EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model.
Results:
Increasing IL8T1 level associated with lower response probability at covariance analysis (P=0.010). Both IL8T0 (P=0.019) and IL8T1 (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8T1 best-predicted OS after backward selection. The NRI for this model was 39%.
When analysed as a time-varying covariate, IL8T1 level<80 pg ml−1 portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level⩾80.
Conclusion:
IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.
doi:10.1038/bjc.2013.719
PMCID: PMC3887307  PMID: 24231947
transitional cell carcinoma; urothelial cancer; biomarkers; angiogenesis; pazopanib
10.  Expression levels of p53 and p73 isoforms in stage I and stage III ovarian cancer 
The p53 gene has been investigated for its role in epithelial ovarian cancer but data collected until now are contradictory. The evidence that p53 belongs with p63 and p73 to a family of transcription factors re-opened interest in this gene family.
Here, we used quantitative real time RT-PCR to determine expression levels of TAp53, TAp73 and their N-terminal splice variants in a cohort of 169 ovarian cancer patients with stage I and stage III disease. The TAp73 levels in stage III biopsies differed by 100-fold depending on the p53 status and overall survival appears to be significantly related to ΔNp73 expression. Kaplan–Meyer analyses did not suggest a correlation between overall survival and levels of TAp73, ΔNp73 or the ΔNp73/TAp73 ratio. In conclusion, these data suggest that at least in our patient cohort p53 and p73 expression levels are not correlated to malignant progression of ovarian cancer. They might, however, play a role in tumour initiation.
doi:10.1016/j.ejca.2007.10.011
PMCID: PMC4286202  PMID: 18039564
p53; p73; Ovarian cancer; Splice variants
11.  Comparison of the interleukin-1β-inducing potency of allergenic spores from higher fungi (Basidiomycetes) in a cryopreserved human whole blood system 
Background
Spores from basidiomycete fungi (basidiospores) are highly prevalent in the atmosphere of urban and rural settings. Studies have confirmed their potential to affect human health as allergens. Less is known about their potential to serve as stimuli of the innate immune system and induce pro-inflammatory reactions.
Methods
In this study, we evaluated the pro-inflammatory potential of spores from 11 allergenic gilled (Pleurotus ostreatus, Oudemansiella radicata, Armillaria tabescens, Coprinus micaceus, Pluteus cervinus, Chlorophyllum molybdites) and non-gilled (Pisolithus arhizus, Merulius tremullosus, Calvatia cyathiformis, Lycoperdon pyriforme, Boletus bicolor) basidiomycetes fungi based on their potency to induce the release of the pro-inflammatory cytokine interleukin (IL)-1β in a cryopreserved human whole blood system. In addition, the role of morphological features of the spores (surface area, shape, and pigmentation) were examined for their role in the spores’ interleukin (IL)-1β-including potency. Peripheral blood from healthy volunteers was collected, pooled, and cryopreserved. After stimulating the cryopreserved pooled blood with 106 to 103 basidiospores/ml, the concentration of IL-1β in culture supernatants was determined with ELISA.
Results
Basidiospores manifested concentration-dependent IL-1β-inducing potency, which was more noteworthy among basidiospores from gilled basidiomycetes. At higher concentrations of basidiospores, the IL-1β-inducing potency was able to be differentiated in the cryopreserved human whole blood system. Morphological features did not correlate with the IL-1β-inducing potency of the basidiospores, suggesting that non-morphological properties modulate the IL-1β-inducing potency.
Conclusion
Our data provides evidence of the pro-inflammatory potential of basidiospores, and the utility of cryopreserved human whole blood as a human-based in-vitro system to study the immune reactivity of allergenic basidiospores.
doi:10.1159/000357036
PMCID: PMC3931459  PMID: 24356469
basidiospores; human-whole blood; pro-inflammatory; IL-1β; potency
12.  Posterior approach lumbar and thoracolumbar hemivertebra resection in congenital scoliosis in children under 10 years of age: results with 3 years mean follow up 
European Spine Journal  2013;23(1):209-215.
Introduction
The authors present 15 cases of congenital scoliosis with lumbar or thoracolumbar hemivertebra in children under 10 years of age (mean age at the time of surgery was 5.5 years). Patients were treated by posterior hemivertebra resection and pedicle screws two levels stabilization or three or more levels stabilization in the case of deformity above or under hemivertebra or for severe curve deformities.
Materials and methods
All operated patients had worsening curves; mean follow up was 40 months. The mean scoliosis curve value was 44° Cobb, and reduced to a mean 11° Cobb after surgery. The mean segmental kyphosis value was 19.7° Cobb, and reduced to a mean −1.8° Cobb after surgery. We did not consider total dorsal kyphosis value as all hemivertebras treated were at lumbar or thoracic lumbar level. No major complications emerged (infections, instrumentation mobilization or failure, neurological or vascular impairment) and only one pedicle fracture occurred.
Results
Our findings show that the hemivertebra resection with posterior approach instrumentation is an effective procedure, which has led to significant advances in congenital deformity control, which include excellent frontal and sagittal correction, excellent stability, short segment arthrodesis, low neurological impairment risk, and no necessity for further anterior surgery.
Conclusion
Surgery should be considered as soon as possible in order to avoid severe deformity and the use of long segment arthrodesis. The youngest patient we treated, with a completed dossier at the end the follow up was 24 months old at the time of surgery; the youngest patient treated by this procedure was 18 months old at the time of surgery.
doi:10.1007/s00586-013-2933-z
PMCID: PMC3897828  PMID: 23934348
Hemivertebra; Posterior approach lumbar hemivertebra resection; Congenital scoliosis
13.  Bilateral and multifocal Warthin’s tumor of parotid gland: two case reports and review of literature 
Oral & Implantology  2014;7(1):25-31.
SUMMARY
Warthin’s tumor is the second most common benign neoplasm of the parotid. Most of cases are represented by a single localization, while only a small percentage of patients presents bilateral lesions or unilateral multifocal pattern. Warthin’s tumor has an excellent prognosis due to the low rate of recurrence after surgical treatment. Malignant transformation occurs in less than 1% of cases. The aim of this article is to present two unusual cases of Warthin’s tumor and an updated review of the latest scientific literature.
PMCID: PMC4302740
Warthin’s tumor; major salivary glands neoplasm; parotid benign neoplasm; multifocal lesions; bilateral lesions; parotidectomy
14.  Outcome of endotherapy for pancreas divisum in patients with acute recurrent pancreatitis 
World Journal of Gastroenterology : WJG  2014;20(46):17468-17475.
AIM: To assess the rate of relapses of acute pancreatitis (AP), recurrent AP (RAP) and the evolution of endosonographic signs of chronic pancreatitis (CP) in patients with pancreas divisum (PDiv) and RAP.
METHODS: Over a five-year period, patients with PDiv and RAP prospectively enrolled were divided into two groups: (1) those with relapses of AP in the year before enrollment were assigned to have endoscopic therapy (recent RAP group); and (2) those free of recurrences were conservatively managed, unless they relapsed during follow-up (previous RAP group). All patients in both groups entered a follow-up protocol that included clinical and biochemical evaluation, pancreatic endoscopic ultrasonography (EUS) every year and after every recurrence of AP, at the same time as endoscopic retrograde cholangiopancreatography (ERCP).
RESULTS: Twenty-two were treated by ERCP and 14 were conservatively managed during a mean follow-up of 4.5 ± 1.2 years. In the recent RAP group in whom dorsal duct drainage was achieved, AP still recurred in 11 (57.9%) after the first ERCP, in 6 after the second ERCP (31.6%) and in 5 after the third ERCP (26.3%). Overall, endotherapy was successful 73.7%. There were no cases of recurrences in the previous RAP group. EUS signs of CP developed in 57.9% of treated and 64.3% of untreated patients. EUS signs of CP occurred in 42.8% of patients whose ERCPs were successful and in all those in whom it was unsuccessful (P = 0.04). There were no significant differences in the rate of AP recurrences after endotherapy and in the prevalence of EUS signs suggesting CP when comparing patients with dilated and non-dilated dorsal pancreatic ducts within each group.
CONCLUSION: Patients with PDiv and recent episodes of AP can benefit from endoscopic therapy. Effective endotherapy may reduce the risk of developing EUS signs of CP at a rate similar to that seen in patients of previous RAP group, managed conservatively. However, in a subset of patients, endotherapy, although successful, did not prevent the evolution of endosonographic signs of CP.
doi:10.3748/wjg.v20.i46.17468
PMCID: PMC4265607  PMID: 25516660
Endoscopic retrograde cholangiopancreatography; Magnetic resonance cholangiopancreatography with secretin stimulation; Minor papilla endotherapy; Pancreatic stenting; Endoscopic ultrasonography
15.  Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer 
PLoS ONE  2014;9(12):e114750.
Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality.
doi:10.1371/journal.pone.0114750
PMCID: PMC4259392  PMID: 25485872
16.  Rectal ulcer: Due to ketoprofen, argon plasma coagulation and prostatic brachytherapy 
World Journal of Gastroenterology : WJG  2014;20(45):17244-17246.
Prostatic brachytherapy with permanent seed implants is a recent and safe radiation therapy technique associated with radiation-induced digestive disease. Argon plasma coagulation procedure is a validated modality in the management of haemorrhagic radiation proctitis, which is known to occasionally induce chronic rectal ulcers. We report here an original case report of an acute painful rectal ulcer as a consequence of the combination of short-term therapy with non-steroidal anti-inflammatory drugs therapy, prostatic brachytherapy with malposition of seed implants and argon plasma coagulation procedure in a patient with haemorrhagic radiation proctitis. The description of this clinical observation is essential to recommend the discontinuation of non-steroidal anti-inflammatory drugs therapy and the control of the position of seed implants in case of prostatic brachytherapy before argon plasma coagulation for radiation-induced proctitis.
doi:10.3748/wjg.v20.i45.17244
PMCID: PMC4258597  PMID: 25493041
Radiation proctitis; Prostatic brachytherapy; Argon plasma coagulation; Non-steroidal anti-inflammatory drugs
17.  Do withdrawal-like symptoms mediate increased marijuana smoking in individuals treated with venlafaxine-XR? 
Drug and alcohol dependence  2014;144:42-46.
Background and aims
Cannabis-dependent participants with depressive disorder are less likely to achieve abstinence with venlafaxine-XR (VEN-XR) treatment. Individuals on VEN-XR reported more severe withdrawal, despite not reducing their smoking behavior. We hypothesized that withdrawal-like symptoms, likely medication side effects, led to continued marijuana smoking in this group.
Methods
We conducted a secondary analysis using Marijuana Withdrawal Checklist (MWC) scores and urine THC to test whether severity of withdrawal-like symptoms mediates the relationship between VEN-XR treatment and continued marijuana smoking. We included 103 participants (VEN-XR = 51, Placebo = 52). Marijuana use was dichotomized into smoking (THC > 100 ng/ml) and non-smoking (THC ≤ 100 ng/ml) weeks. MWC scores were obtained weekly. We used three models in a regression based mediation analysis.
Results
The estimated risk of smoking marijuana was greater for individuals on VEN-XR in weeks 7–9, even when controlling for MWC scores (week 7 Risk Difference (RD) = 0.11, p = 0.034; week 8 RD = 0.20, p = 0.014), and higher scores mediated this effect. In weeks 10 and 11, the estimated effect was stronger (week 10 RD = 0.03, p = 0.380; week 11 RD = 0.07, p = 0.504), and worse withdrawal-like symptoms more fully accounted for continued marijuana smoking in the VEN-XR group, according to the models.
Conclusions
Individuals treated with VEN-XR had more severe withdrawal-like symptoms, which mediated their continued marijuana smoking. Noradrenergic agents, such as VEN-XR, may negatively impact treatment outcomes in cannabis-dependent patients attempting to reduce or stop their use.
doi:10.1016/j.drugalcdep.2014.06.040
PMCID: PMC4252763  PMID: 25283697
Cannabis; Marijuana; Treatment; Venlafaxine; Cannabis Withdrawal; Marijuana Withdrawal
18.  Mitral valve repair for post-myocardial infarction papillary muscle rupture 
OBJECTIVES
Papillary muscle rupture (PMR) is a rare, but serious mechanical complication of myocardial infarction (MI). Although mitral valve replacement is usually the preferred treatment for this condition, mitral valve repair may offer an improved outcome. In this study, we sought to determine the outcome of mitral valve repair for post-MI PMR and to provide a systematic review of the literature on this topic.
METHODS
Between January 1990 and December 2010, 9 consecutive patients (mean age 63.5 ± 14.2 years) underwent mitral valve repair for partial post-MI PMR. Clinical data, echocardiographic data, catheterization data and surgical reports were reviewed. Follow-up was obtained in December of 2012 and it was complete; the mean follow-up was 8.7 ± 6.1 (range 0.2–18.8 years).
RESULTS
Intraoperative and in-hospital mortality were 0%. Intraoperative repair failure rate was 11.1% (n = 1). Freedom from Grade 3+ or 4+ mitral regurgitation and from reoperation at 1, 5, 10 and 15 years was 87.5 ± 11.7%. Estimated 1-, 5-, 10- and 15-year survival rates were 100, 83.3 ± 15.2, 66.7 ± 19.2 and 44.4 ± 22.2%, respectively. There were 3 late deaths, and 2 were cardiac-related. All late survivors were in New York Heart Association Class I or II. No predictors of long-term survival could be identified.
CONCLUSIONS
Mitral valve repair for partial or incomplete post-MI PMR is reliable and provides good short- and long-term results, provided established repair techniques are used and adjacent tissue is not friable. PMR type and adjacent tissue quality ultimately determine the feasibility and durability of repair.
doi:10.1093/ejcts/ezt150
PMCID: PMC3858020  PMID: 23520228
Myocardial infarction; Papillary muscle; Mitral regurgitation; Mitral valve repair; Outcome
19.  Sugar-sweetened beverage intake and the risk of type I and type II endometrial cancer among postmenopausal women 
Background:
Sugar-sweetened beverage (SSB) intake has been associated with an increased risk of obesity and type II diabetes. However, its association with endometrial cancer is unclear.
Methods:
We evaluated dietary intake of SSB, fruit juice, sugar-free beverages, sweets/baked goods, starch, and sugars among 23,039 postmenopausal women in the Iowa Women’s Health Study. Incident estrogen-dependent type I and estrogen-independent type II endometrial cancers were identified via linkage with the SEER Registry. Risks of type I and type II endometrial cancers were separately compared by energy-adjusted dietary intake in Cox proportional hazards regression models.
Results:
From 1986 to 2010, 506 type I and 89 type II incident endometrial cancers were identified. An increased risk of type I endometrial cancer was observed with increasing SSB intake after adjustment for BMI and other cofounders (ptrend=0.0005). Compared to non-drinkers of SSB, the risk was 78% higher (95% CI=1.32-2.40) among women in the highest quintile of SSB intake. The observed association was not modified by BMI, physical activity, history of diabetes, or cigarette smoking. Higher risk of type I endometrial cancer was also observed with higher intake of sugars. None of the dietary items included in the analysis was associated with type II endometrial cancer risk.
Conclusion:
Higher intake of SSB and sugars were associated with an increased risk of type I, but not type II, endometrial cancer.
Impact:
SSB intake may be a risk factor for type I endometrial cancer regardless of other lifestyle factors.
doi:10.1158/1055-9965.EPI-13-0636
PMCID: PMC3892378  PMID: 24273064
Sugar-sweetened beverage; endometrial cancer; postmenopausal
20.  Bilateral Simultaneous Femoral Neck Fracture Mimicking Abdominal Pain in a Cerebral Palsy Patient 
Case Reports in Orthopedics  2014;2014:925201.
Simultaneous bilateral femoral neck fractures are unusual lesions, generally associated with an underlying condition which causes impaired bone mineralization, triggered by an increased bone stress. We present a 24-year-old cerebral palsy patient, who was previously evaluated in another institution due to inability to walk, interpreted as abdominal pain. No alteration in blood analysis or abdominal X-rays was found. As no response to treatment was observed, a new abdominal X-ray was taken, which incidentally depicted bilateral medial femoral neck fracture. He was referred to our practice after a resection arthroplasty was offered in another institution. After admission, bilateral one-stage THA was performed. Several reports emphasize bone disease as a major precipitating factor, and there is an increased incidence of hip fractures in chronic epilepsy, renal osteodystrophy, and chronic steroid use. Femoral head resection has been proven to be effective in immobilized patients, whereas this was not a reasonable option in this patient who presented walking ability. Despite the treatment election, primary care physicians should be aware of and alert to the possibility of fractures in patients with neurological disorders and calcium metabolism alterations. Late diagnosis of orthopedic injuries in this type of patients may lead to permanent disability.
doi:10.1155/2014/925201
PMCID: PMC4258342  PMID: 25506016
21.  Genetic structure of pike (Esox lucius) reveals a complex and previously unrecognized colonization history of Ireland 
Journal of Biogeography  2013;41(3):548-560.
Aim
We investigated genetic variation of Irish pike populations and their relationship with European outgroups, in order to elucidate the origin of this species to the island, which is largely assumed to have occurred as a human-mediated introduction over the past few hundred years. We aimed thereby to provide new insights into population structure to improve fisheries and biodiversity management in Irish freshwaters.
Location
Ireland, Britain and continental Europe.
Methods
A total of 752 pike (Esox lucius) were sampled from 15 locations around Ireland, and 9 continental European sites, and genotyped at six polymorphic microsatellite loci. Patterns and mechanisms of population genetic structure were assessed through a diverse array of methods, including Bayesian clustering, hierarchical analysis of molecular variance, and approximate Bayesian computation.
Results
Varying levels of genetic diversity and a high degree of population genetic differentiation were detected. Clear substructure within Ireland was identified, with two main groups being evident. One of the Irish populations showed high similarity with British populations. The other, more widespread, Irish strain did not group with any European population examined. Approximate Bayesian computation suggested that this widespread Irish strain is older, and may have colonized Ireland independently of humans.
Main conclusions
Population genetic substructure in Irish pike is high and comparable to the levels observed elsewhere in Europe. A comparison of evolutionary scenarios upholds the possibility that pike may have colonized Ireland in two ‘waves’, the first of which, being independent of human colonization, would represent the first evidence for natural colonization of a non-anadromous freshwater fish to the island of Ireland. Although further investigations using comprehensive genomic techniques will be necessary to confirm this, the present results warrant a reappraisal of current management strategies for this species.
doi:10.1111/jbi.12220
PMCID: PMC4238397  PMID: 25435649
Conservation biogeography; dispersal; management; molecular markers; non-anadromous freshwater fish; phylogeography; population genetics; post-glacial biota
22.  Open-label pilot study of quetiapine treatment for cannabis dependence 
Background
There are no efficacious pharmacotherapies for cannabis dependence. The effects of quetiapine are well matched to the symptoms of cannabis withdrawal and could be useful in the treatment of cannabis dependence.
Objectives
To evaluate quetiapine for the treatment of cannabis dependence and determine the optimal dosing.
Methods
In an eight-week open-label outpatient pilot trial, we evaluated the feasibility of quetiapine treatment for cannabis dependence in 15 outpatients. Quetiapine was gradually titrated to 600 mg or the maximum tolerated dose.
Results
The mean study retention was 6.5 weeks (±2.3), with 67% of participants completing all eight weeks of the trial. The mean maximum dose achieved was 197 mg/day (range: 25–600 mg/day). Only two of the 15 participants were able to achieve the target dose of 600 mg daily. There were no serious adverse events and no participants were discontinued from the trial due to adverse effects. The most common reported adverse effects were fatigue (80% of participants) and somnolence (47%). From baseline to week 8, the modeled overall decrease in daily dollar value of marijuana was 76.3% (CI: 63.4%, 84.7%). Over the eight weeks of the study, there was a 46.9% (CI: 11%, 68.3%) decrease in urine tetrahydrocannabinol-9-carboxylic acid (THCOOH) levels.
Conclusions
These preliminary results are promising in that quetiapine treatment was tolerated by cannabis-dependent patients and associated with decreased cannabis use. The recommended maximum target dose for cannabis-dependent patients is 300 mg daily. These preliminary data support further evaluation of quetiapine as a treatment for cannabis dependence.
doi:10.3109/00952990.2014.884102
PMCID: PMC4232231  PMID: 24963729
Cannabis; dependence; pharmacotherapy; quetiapine; treatment
23.  Identification of Novel Genetic Risk Loci in Maltese Dogs with Necrotizing Meningoencephalitis and Evidence of a Shared Genetic Risk across Toy Dog Breeds 
PLoS ONE  2014;9(11):e112755.
Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10−7) and 15 (chr15:53338796A>G, p = 1.5×10−7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10–11 and p = 2.5×10−7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.
doi:10.1371/journal.pone.0112755
PMCID: PMC4231098  PMID: 25393235
24.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
25.  The Self-Medication Hypothesis and Psychostimulant Treatment of Cocaine Dependence: An Update 
Background
Stimulant medications have shown promise as a treatment for cocaine dependence (CD) for several decades, yet these treatments have not been widely studied and substantial barriers to clinical implementation remain. The “Self-Medication Hypothesis,” posits that an individual's choice to use a particular substance is to some degree based on the substance's effect on subjective painful affects or unpleasant emotional states which may or may not be associated with a psychiatric disorder.
Objectives
The Self-Medication Hypothesis remains relevant, particularly when considering the scenario of cocaine dependence, both with and without and co-occurring attention-deficit/hyperactivity disorder (ADHD).
Methods
Two case studies (N = 2) and a review of the relevant literature are provided in this clinical update on psychostimulant treatment of cocaine dependence.
Results
Two case studies are presented in which psychostimulant treatment of cocaine dependence was associated with a good clinical outcome.
Discussion
While the use of psychostimulant medication for the treatment of cocaine dependence is controversial, emerging evidence suggests potential utility for this approach.
Conclusions
Cocaine use in individuals with CD may represent self-medication, and prescribed psychostimulants may have benefit in restoring dopaminergic function.
Scientific Significance
Psychostimulant treatment of cocaine dependence is consistent with the Self-Meidcation Hypothesis and is deserving of further study.
doi:10.1111/j.1521-0391.2013.12086.x
PMCID: PMC4227391  PMID: 25187055

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