Clustering of gout-related comorbidities and their relationship with gout flares: a data-driven cluster analysis of eight comorbidities.

OBJECTIVES: To study the aggregation of multiple comorbidities in people with gout and explore differences in prognosis of gout flares among different subgroups. METHODS: Hierarchical clustering was performed to identify homogeneous subgroups among 2639 people with gout using eight comorbidities. A one-year follow-up of acute gout flares in 463 of these people was conducted; the incidence and the timing of gout flares in each cluster were assessed to explore prognosis of gout flares. Binary logistic regression was applied to assess factors associated with gout flares. RESULTS: In baseline study, we identified five subgroups (C1-C5). C1 (n = 671, 25%) was characterized by isolated gout with few comorbidities. C2 (n = 258, 10%) were all obese. Almost all people in C3 (n = 335, 13%) had diabetes (99.7%). All people in C4 (n = 938, 36%) had dyslipidemia. C5 (n = 437, 17%) had the highest proportion of cardiovascular disease (CVD, 53%), chronic kidney disease (CKD, 56%), and cancer (7%). In follow-up study, C5 had the highest incidence (71.9%) and earliest onset (median 3 months) of gout flares. C2 had the lowest incidence (52.1%) and the latest onset (median 10 months) of gout flares. The highest relative risk for gout recurrent was seen for C5 (OR = 2.09). Other factors associated with the risk of gout flares were age at diagnosis of gout, duration of gout, presence of tophi, and smoking ≥ 20 cigarettes/day. CONCLUSIONS: We clustered people with gout into five groups with varying comorbidities. People with CVD, CKD, and cancer had the highest risk of gout flares and should receive comprehensive care.

Identification of potential diagnostic and prognostic biomarkers for papillary thyroid microcarcinoma (PTMC) based on TMT-labeled LC-MS/MS and machine learning.

OBJECTIVES: To explore the molecular mechanisms underlying aggressive progression of papillary thyroid microcarcinoma and identify potential biomarkers. METHODS: Samples were collected and sequenced using tandem mass tag-labeled liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified and further analyzed using Mfuzz and protein-protein interaction analysis (PPI). Parallel reaction monitoring (PRM) and immunohistochemistry (IHC) were performed to validate the DEPs. RESULTS: Five thousand, two hundred and three DEPs were identified and quantified from the tumor/normal comparison group or the N1/N0 comparison group. Mfuzz analysis showed that clusters of DEPs were enriched according to progressive status, followed by normal tissue, tumors without lymphatic metastases, and tumors with lymphatic metastases. Analysis of PPI revealed that DEPs interacted with and were enriched in the following metabolic pathways: apoptosis, tricarboxylic acid cycle, PI3K-Akt pathway, cholesterol metabolism, pyruvate metabolism, and thyroid hormone synthesis. In addition, 18 of the 20 target proteins were successfully validated with PRM and IHC in another 20 paired validation samples. Based on machine learning, the five proteins that showed the best performance in discriminating between tumor and normal nodules were PDLIM4, ANXA1, PKM, NPC2, and LMNA. FN1 performed well in discriminating between patients with lymph node metastases (N1) and N0 with an AUC of 0.690. Finally, five validated DEPs showed a potential prognostic role after examining The Cancer Genome Atlas database: FN1, IDH2, VDAC1, FABP4, and TG. Accordingly, a nomogram was constructed whose concordance index was 0.685 (confidence interval: 0.645-0.726). CONCLUSIONS: PDLIM4, ANXA1, PKM, NPC2, LMNA, and FN1 are potential diagnostic biomarkers. The five-protein nomogram could be a prognostic biomarker.

[Multidisciplinary regenerative treatment and mechanisms for rescuing a severe calciphylaxis patient with human amnion-derived mesenchymal stem cells].

Calciphylaxis is a rare disease with severe pain and high-mortality due to cutaneous ischemic necrosis and infection that currently lacks proved effective therapies. The occurrence of calciphylaxis in end stage kidney disease (ESKD) patients is known as calcific uremic arteriolopathy (CUA), which is characterized histologically by dermal microvessel calcification, intimal fibroplasia and microthrombosis. Here we innovatively treated a severe CUA patient with human amnion-derived mesenchymal stem cells (hAMSCs). A 34-year-old uremic woman was presented with progressive, painful malodorous ulcers in buttocks and mummified lower limbs. Skin pathological features supported the diagnosis of calciphylaxis. The patient was refractory to conventional multidisciplinary symptomatic therapies. With the approval of our hospital ethics committee, she was treated with hAMSCs including intravenous and local intramuscular injection, and external application of hAMSC culture supernatant to the wound area. During 15-month follow-up, the patient had regeneration of skin and soft tissues, with improved blood biochemical, inflammatory, mineral and bone metabolic indices and immunoregulation effects. After 15-month hAMSC treatment, the score of pain visual analog scale (VAS) decreased from 10 to 0, Bates-Jensen wound assessment tool (BWAT) score decreased from 65 to 13, and wound-quality of life (Wound-QoL) questionnaire score decreased from 68 to 0. We propose that hAMSC treatment is promising for CUA patients. The therapy is potentially involved in the multiple beneficial effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, modulating adverse inflammatory and immunologic responses, promoting re-epithelialization and restoring skin integrity.

Zhuyu Annao decoction promotes angiogenesis in mice with cerebral hemorrhage by inhibiting the activity of PHD3.

Some traditional Chinese decoctions, such as Zhuyu Annao, exert favorable therapeutic effects on acute cerebral hemorrhage, hemorrhagic stroke, and other neurological diseases, but the underlying mechanism remains unclear. This study aimed to determine whether Zhuyu Annao decoction (ZYAND) protects the injured brain by promoting angiogenesis following intracerebral hemorrhage (ICH) and elucidate its specific mechanism. The effect of ZYAND on the nervous system of mice after ICH was explored through behavioral experiments, such as the Morris water maze and Rotarod tests, and its effects on oxidative stress were explored by detecting several oxidative stress markers, including malondialdehyde, nitric oxide, glutathione peroxidase, and superoxide dismutase. Real-time quantitative RT-PCR and WB were used to detect the effects of ZYAND on the levels of prolyl hydroxylase domain 3 (PHD3), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) in the brain tissues of mice. The effect of ZYAND on the NF-κB signaling pathway was detected using a luciferase reporter gene. A human umbilical cord vascular endothelial cell angiogenesis experiment was performed to determine whether ZYAND promotes angiogenesis. The Morris water maze test and other behavioral experiments verified that ZYAND improved the neurobehavior of mice after ICH. ZYAND activated the PHD3/HIF-1α signaling pathway, inhibiting the oxidative damage caused by ICH. In angiogenesis experiments, it was found that ZYAND promoted VEGF-induced angiogenesis by upregulating the expression of HIF-1α, and NF-κB signaling regulated the expression of HIF-1α by inhibiting PHD3. ZYAND exerts a reparative effect on brain tissue damaged after ICH through the NF-κB/ PHD3/HIF-1α/VEGF signaling axis.

Thyroid surgery during coronavirus-19 pandemic phases I, II and III: lessons learned in China, South Korea, Iran and Italy.

OBJECTIVE: We compared demographic and clinic-pathological variables related to the number of surgeries for thyroid conditions or for cancer, morbidity, and fine needle aspiration (FNA) practices among Covid19 pandemic phases I, II, III and the same seasonal periods in 2019. METHODS: The prospective database of the Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, China was used for this study. Covid19 emergency levels were stratified according to the World Health Organization: phase I (January 25-February 25, 2020), phase II (February 26-March 19), phase III (March 20-April 20). RESULTS: There were fewer outpatient FNAs and surgeries in 2020 than in 2019. There were no thyroid surgeries during phase I. There were also fewer surgeries for cancer with a significant reduction of advanced stage cancer treatments, mainly stage T1b N1a in phase II and T3bN1b in phase III. Operative times and postoperative stays were significantly shorter during the pandemic compared to our institutional baseline. In phase III, vocal cord paralysis (VCP) increased to 4.3% of our baseline numbers (P = 0.001). There were no cases of Covid19-related complications during the perioperative period. No patients required re-admission to the hospital. CONCLUSION: The Covid19 outbreak reduced thyroid surgery patient volumes. The decrease of Covid19 emergency plans contributed to unexpected outcomes (reduction of early stage cancer treatment, decreased operative times and hospital stays, increased VCP rate).

[Non-occupational post-exposure prophylaxis in men who have sex with men in Guangxi Zhuang Autonomous Region].

Objective: To analyze the effects of HIV non-occupational post-exposure prophylaxis (nPEP) in men who have sex with men (MSM) in Nanning and Liuzhou, Guangxi Zhuang Autonomous Region. Methods: Participants were recruited through community publicity and advocacy under a "Trinity" approach among non-governmental organizations (NGO), CDCs/hospitals and pharmacies. Basic information, drug taking and follow-up tests of participants who had enrolled for 28 days of the research were collected. Descriptive statistics were used for data analysis. Results: From September 2017 to March 2019, a total of 213 MSM cases consulted for nPEP service, 159 of them were eligible for nPEP, and 154 were enrolled in the study for drug taking. For 132 cases enrolled in the study for 28 days and above, 118 completed the 28-day course of antiretroviral therapy (ART), while 10 failed to complete the 28-day course of ART, and 4 could not be confirmed whether completed the full course of ART due to loss of contact. For those who completed 28-day course of ART, 94.1% (111/118) and 75.4% (89/118) respectively received HIV tests at 4-6 weeks and 3 months after exposure, the results were all HIV negative. Conclusion: Under the "Trinity" approach, taking antiviral drugs earlier after HIV non-occupational exposure can effectively reduce the risk of HIV infection and to some extent, reduce the new infection cases.

Influence of body mass index on the clinicopathological features of 13,995 papillary thyroid tumors.

PURPOSE: This retrospective study aimed to assess the association between obesity, gender, and specific clinicopathological features in patients with papillary thyroid cancer (PTC) and whether diagnostic ultrasonography (US) is adversely affected by obesity in these patients. MATERIALS AND METHODS: This study retrospectively analyzed 13,995 adult patients with PTC from a single medical center in China. Data stratification was performed to assess the association of obesity with US features and aggressive clinicopathological features in different models according to the World Health Organization Body Mass Index (WHO-BMI) and Chinese BMI classification (CN-BMI). The odds ratio (OR) of malignant US features and aggressive clinicopathological features was calculated from binary logistic regression models. RESULTS: The BMI, obesity ratio, malignant US features, and aggressive pathological characteristics of males were significantly higher than those of females. After adjusting for confounding factors, the association of obesity with malignant US features and aggressive pathological characteristics was found to be sex-dependent. Next, obesity (WHO-BMI) was found to have an "interfering effect" on the US assessment of PTC (OR = 0.754, 95% CI 0.609-0.932, P = 0.009) in women. Among both sexes, obesity (WHO-BMI) increased the risk of tumor size (ORmale = 1.539 and ORfemale = 1.521) and multifocality (ORmale = 1.659 and ORfemale = 1.449). However, obesity did not increase the risk of capsular invasion or tumor staging in males. The above results are consistent with the CN-BMI. In addition, age was found to have an "interfering effect" on the US evaluation of malignant nodules in both sexes. CONCLUSION: The results of our study confirm that higher BMI is significantly associated with aggressive clinicopathological features of PTC. Gender differences were present with obesity ratios and aggressive clinicopathological features being significantly higher in men.

Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation.

Since the publication of the above article, the authors have noted that the input data in Fig. 6E is incorrect. The correct data are included in the below Fig. 6E. The mistake does not affect the conclusions of the paper as the levels of input proteins remain similar between samples. We apologise for any inconvenience caused by this error.

[Screening different HPV genotypes infection and type-specific in cervical exfoliated cells of women in Yili area of Xinjiang Uygur Autonomous Region, China].

Objective: To investigate the infection status and genotype distribution of cervical human papillomavirus (HPV) in women of different ethnic groups and different ages in Yili, Xinjiang Uygur Autonomous Region (Xinjiang). Methods: By using the convenient sampling method, 54 760 women from November 2015 to May 2017 seeking for service in gynecological clinics in a general hospital in Yili, Xinjiang, were selected as the research subjects, and 3 445 samples of cervical mucous exfoliative cells were collected, and the social information of their ethnic and age was collected at the same time. The inclusion criteria were those with sexual life, cervical integrity, and ethnic groups for Han or Uygur or Kazak. PCR-reverse dot blot hybridization was used to detect HPV genotyping in exfoliated cells, and chi-square test was used to compare the difference of HPV positive rate among different ethnic groups. Then, according to ethnicity and age, the differences in positive rates of different ages and ethnic groups were compared in each layer. Results: The positive rate of HPV was 25.6% (882 cases), of which the Han, Uygur and Kazakh were 27.9% (564 cases), 22.9% (196 cases) and 21.6% (122 cases), and the difference was statistically significant (χ(2)=13.80, P=0.001). The most prevalent high-risk genotypes of Han women were HPV16/52/58, accounting for 24.8% (140 cases), 17.7% (100 cases) and 9.8% (55 cases), respectively. The most prevalent high-risk genotypes of Uygur women were HPV16/52/53, accounting for 34.2% (67 cases), 12.8% (25 cases), 9.2% (18 cases), respectively. The most prevalent high-risk genotypes of Kazak were HPV16/52/53, accounting for 37.7% (46 cases), 17.2% (21 cases), 12.3% (15 cases), respectively. The highest rate of HPV in Uygur patients aged ≥61 years was 41.5% (22 cases), and the lowest in group 36-40 years old, 15.9% (21 cases), the difference between different age groups was statistically significant (χ(2)=35.01, P<0.001). Conclusion: The positive rate of HPV infection among Han, Uygur and Kazak in Yili Prefecture of Xinjiang was different, and the HPV positive genotype differs among different ethnic groups.

Concurrent chemoradiotherapy with weekly nedaplatin versus radiotherapy alone in elderly patients with non-small-cell lung cancer.

PURPOSE: We conduct this study to compare the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) concurrent weekly nedaplatin (NDP) versus IMRT alone in the stage III/IV non-surgical elderly patients with non-small-cell lung cancer (NSCLC). METHODS: 117 patients were enrolled into our study. The patients were assigned into two different groups: radiotherapy (RT) group and chemoradiotherapy (CRT) group. Patients in RT group were treated with IMRT at a single daily dose of 2 Gy for 5 days per week, totally 52-66 Gy. The CRT group, IMRT concurrent weekly NDP at a dose of 25 mg/m2. RESULTS: In CRT group, the median survival was 11.0 months (95% confidence interval [CI], 8.894-13.106 months) and in RT group, it was 7.0 months (95% CI 5.771-8.229 months). The 1-year, 2-year, 3-year, survival rates in the combined treatment arm were higher than the radiation therapy arm (46.8 vs 25.9%, 25.1 vs 11.8%, 14.7 vs 8.0%; p < 0.001). The Cox's multiple regression analysis showed that CRT had significantly better overall survival than RT (HR 0.523; 95.0% CI 0.338-0.807; p = 0.003). The objective response rate provided that 73.3% treated with CRT compared with 51.1% (p = 0.018) received RT alone. Of the hematologic toxicities, leukocytes (35.0 vs 0%; p < 0.001), neutrophils (33.3 vs 0%; p < 0.001) were significantly more common in the CRT group than the RT group. CONCLUSIONS: We first discovered that NDP concurrent IMRT for treating stage III/IV non-surgical elderly patients with NSCLC was good curative effect of better objective response rate and well-tolerated. However, within the low number of patients, only stage IV gained a survival benefit.

Treatment of a Pediatric Case of Severe Hemorrhagic Cystitis: Case Report and Review of Literature.

Hemorrhagic cystitis is one of the complications of allogeneic hematopoietic stem cell transplantation. Treatment of hemorrhagic cystitis is difficult, especially in pediatric patients. A pediatric case of severe hemorrhagic cystitis after hematopoietic stem cell transplantation was treated in our hospital with arterial embolization combined with corticosteroid therapy because the conventional therapy was invalid for him. After the treatment, hemorrhagic cystitis was cured. During follow-up, the patient was in stable condition, with normal urine, blood cells returned to normal, bone marrow was in complete remission state, and disease-free survival for more than 8 months. Selective bladder arterial embolism followed by corticosteroid therapy successfully treated the patient.

Retrospective analysis of icotinib neoadjuvant therapy of 63 lung cancer patients.

OBJECTIVE: This study aims to explore the feasibility of icotinib neoadjuvant therapy for nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: This was a retrospective analysis of the clinical data for 63 NSCLC patients (61 cases of adenocarcinoma and two cases of squamous cell carcinoma) receiving surgical resection of lung lesions after oral intake of icotinib from December 2011 to November 2013 in the PLA General Hospital. Preoperative oral intake of the patients was icotinib 125 mg tid, drug side effects were evaluated according to the American National Cancer Institute Common Toxicity Criteria Version 4.0; computed tomography scan was done on the day taking medicine and 2 weeks later to determine tumor changes. After oral intake of Icotinib for 2 to 22 weeks (5 cases for 2 weeks,13 cases for 3 to 22 weeks), all patients receive surgical resection of lung cancer lesions, and testing of removed tumor to evaluate the epidermal growth factor receptor (EGFR) gene mutation status was performed by fluorescence polymerase chain reaction. The patients with sensitive EGFR mutations receive Icotinib as postoperative adjuvant therapy. RESULTS: Side effects of medication within 2 weeks included rash (44.4%, 28/63), dry skin (34.9%, 22/63), diarrhea (14.3%, 9/63), and oral ulcer (1.6%, 1/63); there were no icotinib-associated thoracic surgery complications during the perioperational period. 71.4% patients (45/63) achieve an average reduction of 23.5% ±10.7%(10%-53.5%) after 2 weeks medication of Icotinib(regressive tumor[RT]) .28.6% patients(18/63) achieve stable tumor(ST),enlargement of 8.7% to reduction of 8.7% of the maximum diameter of lung cancer after 2 weeks medication of Icotinib. Of the RT group, 68.9% (31/45) of the tumors were detected with EGFR-sensitive mutation (exon 19 or 21 mutation), 24.4% (11/45) with wild-type EGFR, and three cases of exon 20 mutation. Of the ST group, 77.8% (14/18) were detected with wild-type EGFR, three cases of exon 20 mutation, and one case of exon 19 deletion mutation (tumor reduction by 7.9%). 45 cases in RT group and 1 case with EGFR 19 exon metation in ST group receive Icotinib as adjuvant therapy. Among 45 cases in RT group and 18 cases in ST group, there was no difference in gender, age, smoking history, tumor diameter, tumor differentiation degree, and incidence of side effects (P = 0.076). There was significant difference (P < 0.0001) in terms of symptom remission rate after medication and EGFR gene-sensitive mutation rate in RT and ST groups. CONCLUSION: Icotinib neoadjuvant therapy for NSCLC is safe and feasible, and the reactivity of lung cancer patients to icotinib can be determined within 2 weeks of medication. People sensitive to preoperative selection of drugs can more accurately determine the sensitivity of tumors to drugs, thus providing evidence for postoperative adjuvant therapy.

[Role of different scale structures of titanium implant in the biological behaviors of human umbilical vein endothelial cells].

OBJECTIVE: To study the role of different scale structure of Ti implants on the biological behaviors of human umbilical vein endothelial cell (HUVECs) and to reveal the role of material surface topographical features on peri-implant angiogenesis. METHODS: Titanium (Ti) discs with different surface structures (Ti discs with smooth surface, Ti discs with nano scale structure, Ti discs with micro scale structure and Ti discs with micro/nano scale structure, named as SM-Ti, Nano-Ti, Micro-Ti and Micro/Nano-Ti, respectively) were prepared and their surface topographical features were confirmed via scanning electron microscopy (SEM) observation. HUVECs were cultured on these Ti discs. Biological outcomes of HUVECs on different surfaces were carried out, including cell adhesive capacity, proliferation, vascular endothelial growth factor (VEGF) production and intracellular expression of Ca(2+). RESULTS: The results of SEM images and immunofluorescence double staining of rhodamine-phalloidin and DAPI showed that compared with the SM-Ti and Nano-Ti group, the adhesive capacity and proliferation behavior of HUVECs on the surfaces of Micro-Ti and Micro/Nano-Ti was decreased. The results of culturing HUVECs on different groups of Ti discs after 24 hours showed that the cells number grew from (18±4) to (42±6)/ vision on SM-Ti, (28±6) to (52±10)/vision on Nano-Ti, (20±4) to (21±6)/vision on Micro-Ti and (16±4) to (18±6)/vision on Micro/Nano-Ti. Moreover, compared with the adhesion and proliferation of HUVECs on SM-Ti group and Nano-Ti, the adhesion and proliferation of HUVECs on Micro-Ti group and Micro/Nano-Ti group was significantly reduced (P<0.05).The results of enzyme-linked immunosorbent assay (ELISA) showed that the VEGF productions of SM-Ti, Nano-Ti, Micro-Ti and Micro/Nano-Ti were (690±35) ng/L, (560±20) ng/L, (474±43) ng/L and (517±29) ng/L, respectively. Moreover, compared with the VEGF production of HUVECs on SM-Ti group, the VEGF production of HUVECs on Micro-Ti group and Micro/Nano-Ti group was significantly reduced (P<0.05). The results of Ca(2+) ion detection showed that the Ca(2+) expression of HUVECs on Micro-Ti and Micro/Nano-Ti was significantly higher than that on the surface of SM-Ti and Nano-Ti. These results implied that the over expressed Ca(2+) might contributed to the impaired biological function of HUVECs on Micro-Ti and Micro/Nano-Ti. CONCLUSION: Different topographical features on titanium influenced the biological behaviors of the HUVECs, which may illustrate how topographical features of Ti implant affect peri-implant angiogenesis. These results also suggest that the biological behaviors of HUVECs might be relative to the changed expression of intracellular Ca(2+).

Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts.

BACKGROUND: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study. METHODS: Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis. RESULTS: EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments. CONCLUSIONS: EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and 'second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment.

The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation.

Estrogen receptor α (ERα) is initially expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression by regulating the transcription of genes linked to cell proliferation. ERα status is of clinical importance, as ERα-positive breast cancers can be successfully treated by adjuvant therapy with antiestrogens or aromatase inhibitors. Complications arise from the frequent development of drug resistance that might be caused by multiple alterations, including components of ERα signaling, during tumor progression and metastasis. Therefore, insights into the molecular mechanisms that control ERα expression and stability are of utmost importance to improve breast cancer diagnostics and therapeutics. Here we report that the atypical E3 ubiquitin ligase RNF31 stabilizes ERα and facilitates ERα-stimulated proliferation in breast cancer cell lines. We show that depletion of RNF31 decreases the number of cells in the S phase and reduces the levels of ERα and its downstream target genes, including cyclin D1 and c-myc. Analysis of data from clinical samples confirms correlation between RNF31 expression and the expression of ERα target genes. Immunoprecipitation indicates that RNF31 associates with ERα and increases its stability and mono-ubiquitination, dependent on the ubiquitin ligase activity of RNF31. Our data suggest that association of RNF31 and ERα occurs mainly in the cytosol, consistent with the lack of RNF31 recruitment to ERα-occupied promoters. In conclusion, our study establishes a non-genomic mechanism by which RNF31 via stabilizing ERα levels controls the transcription of estrogen-dependent genes linked to breast cancer cell proliferation.

Effect of chemoradiotherapy and neoadjuvant chemoradiotherapy in resectable pancreatic cancer: a systematic review and meta-analysis.

OBJECTIVE: Controversy remains existed whether chemoradiotherapy (CRT), especially neoadjuvant chemoradiotherapy (neoadjuvant CRT) achieves a significant benefit in resectable pancreatic cancer (PC) treatment. In this meta-analysis, we aimed to clarify the benefits of CRT and neoadjuvant CRT in resectable PC. METHODS: Eligible trials were identified from MEDLINE, EMBASE, Cochrane center, China National Knowledge Internet and Wanfang database since their inception to July 31, 2013. Only patients with resectable PC, who underwent tumor resection and received CRT and/or neoadjuvant CRT, were enrolled. The treatment outcomes were overall survival (OS) and progression-free survival (PFS). Hazard ratio (HR) with a 95% confidence interval (CI) was used to measure the pooled effect according to a fixed-effects model. The statistical heterogeneity between trials was detected by χ(2) and I (2) test. Sensitivity analyses were also carried out. RESULTS: A total of 28 studies were identified as relevant, but only 17 studies with a total of 3,088 patients were included in the comparison between CRT versus non-CRT, and a total number of three studies with 189 patients included in the comparison between neoadjuvant CRT versus postoperative CRT. The comparison between CRT and non-CRT showed that the overall pooled HR for death was 0.96 (95% CI 0.89-1.03; P = 0.28). The HR for progress was 0.83 (95% CI 0.68-1.03, P = 0.09). Comparison between neoadjuvant CRT and adjuvant CRT revealed a pooled HR of 0.93 (95% CI 0.69-1.25; P = 0.62). CONCLUSIONS: This meta-analysis showed that CRT showed no significant effect on OS and PFS when compared to non-CRT. Neoadjuvant CRT showed no significant effect over postoperative adjuvant CRT.

Palatable food avoidance and acceptance learning with different stressors in female rats.

Stress activates the hypothalamus-pituitary-adrenal (HPA) axis leading to the release of glucocorticoids (GC). Increased activity of the HPA axis and GC exposure has been suggested to facilitate the development of obesity and metabolic syndrome. Nonetheless, different stressors can produce distinct effects on food intake and may support different directions of food learning e.g. avoidance or acceptance. This study examined whether interoceptive (LiCl and exendin-4) and restraint stress (RS) support similar or distinct food learning. Female rats were exposed to different stressors after their consumption of a palatable food (butter icing). After four palatable food-stress pairings, distinct intakes of the butter icing were observed in rats treated with different stressors. Rats that received butter icing followed by intraperitoneal injections of LiCl (42.3mg/kg) and exendin-4 (10µg/kg) completely avoided the palatable food with subsequent presentations. In contrast, rats experiencing RS paired with the palatable food increased their consumption of butter icing across trials and did so to a greater degree than rats receiving saline injections. These data indicate that interoceptive and psychosocial stressors support conditioned food avoidance and acceptance, respectively. Examination of c-Fos immunoreactivity revealed distinct neural activation by interoceptive and psychosocial stressors that could provide the neural basis underlying opposite direction of food acceptance learning.

Additive feeding inhibitory and aversive effects of naltrexone and exendin-4 combinations.

OBJECTIVE: One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone (Nal), an opioid antagonist acting on the reward system, and exendin-4 (Ex-4), a glucagon-like peptide 1 agonist acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined. METHODS: In Experiment 1, the acute anorectic effects of Nal (0.32-3.2 mg kg(-1); intraperitoneally (i.p.)) and Ex-4 (1-10 µg kg(-1); i.p.) were assessed alone or in combination. Combinational doses were further investigated by the repeated daily administration of 1 mg kg(-1) Nal+3.2 µg kg(-1) Ex-4 for 4 days. In Experiment 2, both compounds alone or in combination were used as unconditioned stimuli in a series of CTA tests. RESULTS: Nal and Ex-4, alone or in combination, suppressed food intake in a dose-dependent manner, and the interaction on food intake between Nal and Ex-4 was additive. In the CTA paradigm, Nal (1 mg kg(-1)) alone did not support acquisition, whereas a CTA was evident with doses of Ex-4 (1 or 3.2 µg kg(-1)). Combinations of Nal and Ex-4 also resulted in a more rapid and robust acquisition of a CTA. CONCLUSION: Given that the Nal and Ex-4 combination produces additive effects on not only food intake reduction but also food aversion learning, this specific drug combination does not have the benefit of minimizing the adverse effects associated with each individual drug. These data suggest that it is necessary to evaluate both the positive and adverse effects at early stages of combinational drug development.