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Background We conducted a meta-analysis to evaluates the incidence of the gastrointestinal (GI) adverse events with the use of PD-1 inhibitors among patients with advanced non-small cell lung cancer (NSCLC). Methods The PICOs (participants, intervention, comparison, and outcomes) elements were used for the selection of studies to meet the inclusion and exclusion criteria. Google Scholar, PubMed, Science Direct and proceedings of major oncology conferences were systematically searched from their inception to December 2020, to identify studies which reported the GI adverse events of PD-1 inhibitors among patients with NSCLC. Risks of bias were assessed by using a revised methodological index for nonrandomized studies (MINORS). Pooled incidences and weighted relative risk (RR) estimate for GI adverse events, the incidence of treatment discontinuation due to GI adverse events was also calculated. To perform the analysis of qualified studies, the model of random effects was used and the inconsistency of studies with the I2 index was investigated. OpenMeta 10.10, Stata 11.0 and RevMan 5.3 software were used for data analysis. Results The research included 15 studies comprising of a total of 3,716 patients. The incidences of all-grade GI symptoms were: diarrhea 8.6% (95% CI: 6.6–10.6%), nausea 9.2% (95% CI: 7.3–11.0%), vomiting 3.2% (95% CI: 1.9–4.5%), constipation 2.8% (95% CI: 1.8–3.9%), colitis 0.7% (95% CI: 0.4–1.1%), stomatitis (95% CI: 1.0–2.7%), and decreased appetite 10.0% (95% CI: 8.3–11.7%). Therapy using PD-1 inhibitors was discontinued in 2.5% (95% CI: 0.0–5.1%) of patients with nausea, in 3.0% (95% CI: 0.7–5.3%) of those with diarrhea, and in 45.7% (95% CI: 20.6–70.7%) of patients with colitis. Compared with chemotherapy, the use of PD-1 inhibitors showed significant increase in the occurrence of grade 1–4 colitis (RR =3.90, 95% CI: 1.41–10.81, P=0.009) and grade 3–4 colitis (RR =3.76, 95% CI: 1.07–13.26, P=0.04). Discussion This meta-analysis provides a reliable estimate of the incidences of GI adverse events among NSCLC patients. Especially when colitis does occur, it often results in therapy discontinuation. Use of PD-1 inhibitors led to a higher incidence of colitis as compared to the use of chemotherapy.

Background Persistent infection by high-risk human papillomavirus (HPV) is the leading cause of cervical intraepithelial neoplasia and cervical carcinoma. Local hyperthermia at 44ºC has been proven efficacious to clear cutaneous or anogenital warts caused by HPV infection. This study aims to assess the effect of hyperthermia at 44ºC on the clearance of high-risk HPV. Methods A randomized, patient-blind, sham treatment–controlled trial was conducted in 4 medical centers. We enrolled patients with positive high-risk HPVs and normal or insignificant cytological findings (negative/atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion). Participants were randomly assigned (1:1) to receive either hyperthermia at 44ºC or 37ºC, for 30 minutes in each session. Patients in both groups received treatment once a day for 3 consecutive days, plus 2 more sessions 10 ± 3 days later. The primary outcome was clearance rate of HPV 3 months after treatment. Results After a 3-month follow-up, hyperthermia treatment at 44ºC and 37ºC achieved HPV clearance rates of 85.19% (23/27) and 50% (13/26), respectively (P = .014). There was no significant difference of treatment response between patients with single and multiple type of HPV by 44ºC hyperthermia treatment. There were no significant adverse events recorded during the treatment period in both groups. Conclusions Local hyperthermia at 44ºC safely and significantly aids in clearing cervical high-risk HPVs, the effect of which helps halt the progression of cervical transformation and transmission of the virus. Clinical Trials Registration NCT03436251.

This study evaluates the impact of the use of antibiotics on the effectiveness of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). A literature search was conducted in various electronic databases to identify studies, which evaluated the impact of antibiotic use on the survival of patients with advanced/metastatic NSCLC who have been treated with nivolumab. Six studies, comprising a total of 787 patients with 37.2% females and of age range 30–90 years, were included in the study. A lack of smoking history was reported in 14.4% of the patients. A meta-analysis was conducted in 678 and 713 patients for PFS and OS, respectively. The pooled HR was 1.95 (95% CI: 1.13–3.37, P = 0.016) for PFS and 2.70 (95% CI: 1.81–4.02, P < 0.001) for OS. Among patients exposed to antibiotics, the median PFS and OS were reduced by 1.6 months (95% CI: 1.5–1.7) and 8.8 months (95% CI: 8.5–9.1), respectively. Our study indicates that, among patients with advanced/metastatic NSCLC, the use of antibiotics with nivolumab led to a decrease in the median OS by more than 8 months. Studying the mechanism of the effect of antibiotics on the efficacy of nivolumab in patients with NSCLC should also be prioritized.

Prostate cancer is a serious threat to men's health worldwide. While previous studies have demonstrated that long non‑coding RNAs (lncRNAs) are closely associated with the initiation and development of several types of cancer, the role of lncRNAs in the progression of prostate cancer remains incompletely understood. In the present study, the lncRNA brain cytoplasmic RNA 1 (BCYRN1) was found to be overexpressed in prostate tumors compared with healthy tissues. Furthermore, the expression of BCYRN1 was found to be associated with Gleason score and lymph node metastasis. It was demonstrated that BCYRN1 silencing using small interfering RNA (siRNA) inhibited the proliferation of prostate cancer cells. The results of the present study indicated the presence of a reciprocal regulatory association between BCYRN1 and microRNA (miR)‑939‑3p. In addition, it was observed that BCYRN1 directly sponged miR‑939‑3p to upregulate histone deacetylase 11 (HDAC11) expression in prostate cancer cells. Moreover, transfection of recombinant HDAC11 reversed the inhibition of cell proliferation that was induced by BCYRN1 siRNA. A positive correlation between BCYRN1 and HDAC11 mRNA expression levels was also identified in prostate tumor and healthy tissues. Therefore, the findings of the present study may provide novel insight into the effects of lncRNAs on prostate cancer, and may enable the development of new therapeutic methods for patients with prostate cancer.

This study evaluates the efficacy of pembrolizumab for the treatment of advanced/metastatic melanoma. The literature search was conducted in electronic databases for studies that evaluated the efficacy and safety of pembrolizumab either alone or in combination with other treatments advanced/metastatic melanoma patients. Random-effects meta-analyses were performed to achieve pooled effect sizes of response and survival rates. The overall objective response rate (ORR) was 34.2% [95% confidence interval (CI): 30.4, 38.0]. However, ORR differed with respect to the history of prior systemic therapy. ORR was lower in studies with over 50% patients with prior therapy (25.5% [22.4, 28.5]) than in studies with under 50% patients with prior therapy (40.1% [34.1, 46.1]). ORR was higher in pembrolizumab monotherapy (32.9% [28.1, 37.7]) than in pembrolizumab–ipilimumab combination (27.6% [24.0, 31.2]). Overall ORR was inversely associated with visceral metastasis and prior systemic therapy. With pembrolizumab treatment, either alone or in combination, the progression-free survival (PFS) was 5.73 months; 12-, 24-, and 60-month PFS rate were 44%, 27%, and 25%, respectively; and 12-, 24-, and 60-month overall survival rates were 65%, 50%, and 41%, respectively. The percentage of AEs that led to treatment discontinuation was 13%. Pembrolizumab monotherapy is a valuable option for the treatment of advanced/metastatic melanoma patients.

Background Hyperthermia upregulates DNAJA4, a member of heat shock proteins (HSPs) 40 family, in human keratinocytes and HPV-infected tissue. DNAJA4 deficiency enhances growth arrest induced by hyperthermia. Clusterin (CLU) and phosphorylated ERK (p-ERK) play a role in regulating cell proliferation and apoptosis, under environmental stress. Objectives To examine the downstream molecules and signalling pathways of DNAJA4 and assess their roles in cell cycle and apoptosis of keratinocytes in response to hyperthermia. Methods Wild-type and DNAJA4-knockout (KO) HaCaT cells were exposed to either 44 °C (hyperthermia) or 37 °C (control) for 30 min. The expression levels of CLU and p-ERK were determined by RT-PCR and Western blotting. RNAi and PD98059 were used to inhibit the expression of CLU and p-ERK, respectively. Cell viability, cell cycle and apoptosis were analysed by MTS assay and flow cytometry. Fresh biopsy samples of human normal foreskin or condyloma acuminatum (CA) were utilized to examine the expression of CLU and p-ERK after ex vivo culture at 44 °C. Results The expression of CLU and p-ERK was significantly increased by hyperthermia treatment at 44 °C in HaCaT cells, foreskin and HPV-infected tissues. In HaCaT cells subjected to hyperthermia, DNAJA4 deficiency further augmented the expression of CLU and p-ERK. CLU deficiency enhanced the p-ERK expression. Hyperthermia-induced CLU and p-ERK exerted protective roles mainly through inhibiting apoptosis and maintaining cell cycle, respectively. Conclusions In keratinocytes, CLU and p-ERK are induced by hyperthermia, an effect which can be further enhanced by DNAJA4 deficiency. CLU deficiency also increases p-ERK expression. Both CLU and p-ERK are critical protective factors of human keratinocytes from hyperthermia-induced injury.

Background Dysregulation of long non-coding RNAs (lncRNAs) is involved in development of prostate cancer. However, the molecular mechanisms of many lncRNAs in prostate cancer have not been studied yet. Methods The lncRNA Fer-1-like protein 4 (FER1L4) expression was explored in prostate tumors and normal prostate tissues by RT-qPCR and bioinformatic analysis. Overexpression of FER1L4 was performed to evaluate its role in prostate cancer cell proliferation and survival. The molecular mechanism of FER1L4 was investigated by dual luciferase reporter assay, RNA pull down assay, western blotting and RT-qPCR. Results It was found that FER1L4 was lower in prostate cancer tissues than normal tissues. Higher expression of FER1L4 was associated with prostate cancer tissues of early stage (AJCC stage I/II). Overexpression of FER1L4 inhibited cell proliferation and promoted cell apoptosis in prostate cancer cells. Bioinformatic analysis, RT-qPCR, RNA pull down assay and dual luciferase assay showed that FER1L4 upregulated F-box/WD repeat-containing protein 7 (FBXW7) tumor suppressor via sponging miR-92a-3p. Silencing of FBXW7 reversed the cell phenotypes caused by FER1L4 overexpression in prostate cancer cells. Conclusion The data demonstrated that FER1L4, a downregulated lncRNA in prostate cancer, was pivotal for cell proliferation and survival of prostate cancer. The study provided new sights into understanding of the signaling network in prostate cancer and implied that FER1L4 might be a biomarker for patients with prostate cancer.

Diabetes is a global medical problem that causes many deaths every year. Complications caused by diabetes are serious and affect patients' quality of life. Diabetes mellitus erectile dysfunction (DMED) affects more than half of male diabetes patients. In this study, we determined the role of microRNA-874-3p (miR-874-3p) and nuclear protein-1 (Nupr1) in streptozocin-induced DMED rats. Control rats received equal amount of vehicle. These rats were also injected with lentiviral vector or agomir to silence or overexpress miR-874-3p or Nupr1. Apomorphine (100 μg/kg, s.c.) was used to induce erection and time of erection was recorded. Intracavernosal and mean arterial pressure ratio (ICP/MAP) were also recorded. O2- level and concentration of thiobarbituric acid reactive substances (TBARs) were detected using lucigenin-derived chemiluminescence method and Colorimetry. Rat cavernosum tissues were collected for subsequent experiments. Cavernosum smooth muscle cells (CSMCs) were also used for in vitro experiments. Nupr1 was found highly expressed (by RT-qPCR and Western blot analysis) in cavernosum tissues from DMED rats. Nupr1 silencing improved the ICP/MAP ratio and erection time. Nupr1 silencing also reduced CSMC apoptosis (by TUNEL assay) as well as decreased O2- level and TBAR concentration. Nupr1 was targeted and inhibited by miR-874-3p (by luciferase activity and RNA immunoprecipitation assays), which was downregulated in DMED. miR-874-3p downregulation was due to increased methylation at the promoter region (methylation-specific PCR). miR-874-3p overexpression improved erection time and reduced apoptosis. In summary, miR-874-3p was downregulated which led to increased apoptosis and erectile dysfunction in DMED rats, through inhibition of Nupr1-mediated pathway. This study may also provide a new therapeutic direction for the treatment of DMED.

Erectile dysfunction (ED) is a common comorbidity in males with diabetes. In this study, we aimed to investigate how lncRNA-MIAT affects ED in diabetes and the involved mechanism. Microarray analysis was performed to screen ED-related differentially expressed genes, regulatory microRNA (miR) and long noncoding RNA (lncRNA). Highly expressed lipoprotein lipase (LPL) was identified, and subsequently miR-328a-5p and lncRNA-MIAT were determined. Diabetes was induced by streptozotocin in rats, and diabetic rats with ED were selected. Vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) were cocultured. The siRNA against lncRNA-MIAT, miR-328a-5p mimic and overexpression vector of LPL were transfected to investigate the specific effects of miR-328a-5p, lncRNA-MIAT and LPL on ED in diabetes. The expression of LPL, lncRNA-MIAT and miR-328a-5p in the serum of diabetic patients was measured. Increased LPL and lncRNA-MIAT and reduced miR-328a-5p were observed in diabetic patients. In addition, ED led to upregulated LPL and lncRNA-MIAT and downregulated miR-328a-5p in serum of diabetic patients and VSMCs of diabetic rats, especially in those with ED. LncRNA-MIAT directly regulated miR-328a-5p, which directly targeted LPL. LncRNA-MIAT upregulated LPL by acting as a ceRNA of miR-328a-5p. Silencing of lncRNA-MIAT and LPL or miR-328a-5p overexpression reduced VEC apoptosis and increased cell proliferation. In addition, an increased intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio was noted in the corpus cavernosum of rats and inhibited VEC injury. Taken together, our data demonstrated that depleted lncRNA-MIAT suppressed LPL by increasing miR-328a-5p, thereby inhibiting VEC injury to attenuate ED in diabetic rats.

BackgroundMicroRNAs (miRNAs) have been discovered to dictate the development of various tumors. However, studies on the roles of miRNAs in the progression of gastric cancer (GC) are still lacking.MethodsHerein, by analyzing GC cell lines and patients samples, we observed that miR-148b-5p was significantly downregulated in GC. We also confirmed that miR-148b-5p overexpression significantly inhibited GC cell proliferation and invasion in vitro and in vivo.ResultsOverexpression of miR-148b-5p not only reprogrammed the metabolic properties of GC but also regulated the immune microenvironment by shifting lymphocyte and myeloid populations. Mechanistically, ATPIF1, an important glycolysis-associated gene, was identified as a direct target of miR-148b-5p and mediated the effect of miR-148b-5p. Notably, the low level of miR-148b-5p was significantly related with poor prognosis of GC patients (P < 0.001). Importantly, the levels of miR-148b-5p significantly changed the sensitivity of GC cells to several anti-cancer drugs (Doxorubicin, P < 0.05, Paclitaxel, P < 0.01, Docetaxel, P < 0.05).ConclusionsTargeting miR-148b-5p inhibits immunity microenvironment and gastric cancer progression.

As a notable chronic disorder, the incidence of interstitial cystitis (IC) has been documented to have increased among the female population with activity in microRNA-495 (miR-495) implicated in this disease. The current study was aimed at elucidating the effects associated with miR-495 on the inflammatory response and bladder fibrosis in rats with ulcerative IC via the JAK–STAT pathway by targeting JAK3. Ulcerative IC rat models were established. The targeting relationship between JAK3 and miR-495 was evaluated using luciferase reporter assay. After gain- or loss-of-function assays, mast-cell infiltration was assessed using toluidine blue staining, bladder fibrosis using Masson staining, and NO content using nitrate reductase method. JAK3 protein expression was detected by immunohistochemistry, JAK3, STAT1, STAT3, TGFβ-1, Col-I, Col-III, JAK1, JAK2, p-STAT1, and p-STAT3 expression by RT-qPCR and Western blot analysis, and serum IL-6, IL-8, IL-10, IL-17, and TNF-α levels in rats by ELISA. Following transfection of overexpressed miR-495 or siRNA-JAK3, a diminished degree of mast-cell infiltration, number of mast cells, bladder fibrosis, NO content, JAK3-positive expression, mRNA expression of JAK3, STAT1, STAT3, TGFβ-1, Col-I, Col-III, protein expression of JAK1, JAK2, JAK3, p-STAT1, p-STAT3, and expression of IL-6, IL-8, IL-10, IL-17, and TNF-α were identified. Collectively, our key findings provide evidence supporting the notion that the overexpression of miR-495 ameliorates inflammatory response and bladder fibrosis in ulcerative IC rat models via inactivation of the JAK–STAT signaling pathway by inhibiting JAK3.

Hyperthermia has been clinically utilized as an adjuvant therapy in the treatment of cervical carcinoma. However, thermotolerance induced by heme oxygenase-1 (HO-1), a stress-inducible cytoprotective protein, limits the efficacy of hyperthermic therapy, for which the exact mechanism remains unknown. In the present study, we found that heat treatment induced HO-1 expression and decreased copy number of HPV16 in cervical cancer cells and tissues from cervical cancer and precursor lesions. Knockdown of HO-1 stimulated autophagy accompanied by downregulation of X-linked inhibitor of apoptosis protein. Furthermore, silencing of HO-1 led to cell intolerance to hyperthermia, as manifested by inhibition of cell viability and induction of autophagic apoptosis. Moreover, HO-1 modulated hyperthermia-induced, autophagy-dependent antiviral effect. Thus, the findings indicate that blockade of HO-1 enhances hyperthermia-induced autophagy, an event resulting in apoptosis of cervical cancer cells through an antiviral mechanism. These observations imply the potential clinical utility of hyperthermia in combination with HO-1 inhibition in the treatment of cervical cancer.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Cytokines, including interleukin 24 (IL-24), play an important role in HCC. IL-24 inhibits HCC metastasis but the molecular mechanism by which this occurs is still unknown. MicroRNAs (miRNAs) are regulators of cancers including hepatocellular carcinoma (HCC). However, the role that miRNAs play in the regulation of IL-24 in HCC is unclear. The aim of this study was to investigate the effects of regulation of IL-24 by miR-203a-3p.1 on liver cancer cell proliferation and metastasis. IL-24 mRNA and miR-203a-3p.1 were detected by real-time RT-PCR, and IL-24 protein in the cell growth medium was measured by ELISA. A luciferase assay was used to verify that the IL-24 gene was the target of miR-203a-3p.1. Cell survival ability was detected by the MTT assay and colony formation. Cell metastasis was assayed by the Transwell system. The results showed that IL-24 could be down-regulated by miR-203a-3p.1 in HCC cells and that miR-203a-3p.1 acted as an onco-miRNA by targeting IL-24. Inhibition of miR-203a-3p.1 in cells could lead to the reversal of HCC cell proliferation and metastasis. The study highlights a novel molecular interaction between miR-203a-3p.1 and IL-24, which indicates that IL-24 and miR-203a-3p.1 may constitute potential therapeutic targets for HCC.

Purpose: Mapping the distribution of internal mammary sentinel lymph nodes (IM-SLNs) presented on single photon emission computed tomography in conjunction with computed tomography (SPECT/CT) images to explore the value of IM-SLN to guide tailored clinical target volume (CTV) delineation of postoperative prophylactic IMNI. Materials and methods: Ninety-seven patients who underwent preoperative lymphoscintigraphy by SPECT/CT and had imaging of IM-SLN were selected in this study. The imaging IM-SLNs on SPECT/CT of eligible patients were projected onto corresponding anatomical positions of a representative axial CT image. The IMN CTVs were delineated on the representative axial CT images according to the Radiation Therapy Oncology Group (RTOG) and Danish Breast Cancer Cooperative Group (DBCG) guideline, and defined as CTVRTOG and CTVDBCG. The location of the IM-SLNs was compared with the RTOG and DBCG guidelines of IMN target volume delineations, respectively. The intercostal space distribution of IM-SLNs was recorded. The distances from the CTVRTOG and CTVDBCG to the IM-SLNs were measured, respectively. Results: The total number of imaging IM-SLNs was 136. IM-SLNs were mostly found in the first intercostal space (40.4%), with 30.2, 24.3, 4.4, and 0.7% of IM-SLNs in the second, third, fourth, and fifth intercostal space, respectively. The average distance from the edge of the CTVRTOG and the edge of CTVDBCG to the central points of the IM-SLNs was 4.10 mm (SD, 3.3 mm) and 1.60 mm (SD, 2.6 mm), respectively (t = 16.640, P = 0.000). The average distance from the edge of CTVRTOG and the edge of CTVDBCG to the lateral border IM-SLN was 6.40 mm (SD, 3.5 mm) and 3.34 mm (SD, 3.3 mm), respectively (t = 19.815, P = 0.000). Only 18.4% of IM-SLN central points were included in the CTVRTOG, and 60.3% of IM-SLN central points were included in the CTVDBCG. When covering 90 and 100% of the IM-SLN center points, the CTVRTOG needs to expand 8 and 15 mm, respectively, and the CTVDBCG needs to expand 5 and 13 mm, respectively. Conclusion: Neither the RTOG nor DBCG consensus guideline about the delineation of IMN CTV was sufficient to cover 90% of IM-SLNs. For 90% coverage of IM-SLN central points, CTVRTOG needed to be expanded by 8 mm, and CTVDBCG needed to be expanded by 5 mm.

IntroductionSubjective cognitive decline (SCD) refers to individuals’ perceived decline in memory and/or other cognitive abilities relative to their previous level of performance, while objective neuropsychological deficits are not observed. SCD may represent a preclinical phase of Alzheimer’s disease. At this very early stage of decline, intervention could slow the rate of incipient decline to prolong and preserve cognitive and functional abilities. However, there is no effective treatment recommended for individuals with SCD. Acupuncture, as a non-pharmacological intervention, has been widely employed for patients with cognitive disorders.Methods and analysisThe proposed study is a randomised, assessor-blinded and placebo-controlled study that investigates the efficacy and mechanism of acupuncture in SCD. Sixty patients with SCD will be randomly allocated either into an acupuncture group or a sham acupuncture group. They will receive 24 sessions of real acupuncture treatment or identical treatment sessions using a placebo needle. Global cognitive changes based on a multidomain neuropsychological test battery will be evaluated to detect the clinical efficacy of acupuncture treatment at baseline and end of treatment. MRI scans will be used to explore acupuncture-related neuroplasticity changes. Correlation analyses will be performed to investigate the relationships between the changes in brain function and symptom improvement.Ethics and disseminationThe trial was approved by the research ethics committee. The results of the study will be published in a peer-reviewed academic journal and will also be disseminated electronically through conference presentations.Trial registration numberNCT03444896.

Objective To explore the potential mechanism which miR-527 targeting the heparan sulfate 6-O-endosulfatase (SULF2) regulates TGF-β/SMAD signaling pathway induced epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC). Methods 38 pairs of lung tumor biopsies and corresponding paracancerous biopsies were obtained from NSCLC patients with surgical resection, normal human bronchial epithelial BEAS-2B cells and five NSCLS cell lines were applied for our study. miR-527 and SULF2 expression were determined by qRT-PCR and immunohistochemistry. MiR-527 and SULF2 biological link were predicted by Targetscan.org and tested by dual luciferase. Cells proliferation and apoptosis were respectively detected by EDU staining and flow cytometry. Cells migration was examined by transwell and scratch-wound assay. Expression of proteins related to EMT and TGF-β/SMAD signaling pathway, such as E-cadherin, N-cadherin, p-Samd3 and p-Smad2, was detected by western blot. ResultsmiR-527 expression was decreased in lung tumor tissues and NSCLS cell lines, conversely, SULF2 expression was significantly increased. In addition, we found that miR-527 targeted 3'-untranslated regions (3'-UTR) of SULF2 and mediated its expression. Overexpression of miR-527 evidently suppressed NSCLC proliferation, invasion and EMT via TGF-β/SMAD signaling pathway. Moreover, the silence of SULF2 exhibited a similar effect. Conclusion miR-527 targeting SULF2 down-regulated SULF2 expression, concurrently, suppressed NSCLC epithelial-mesenchymal transition and invasion via inhibiting TGF-β/SMAD signaling pathway.

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

Introduction Mild local hyperthermia at 44°C has been proven efficacious in the treatment of cutaneous warts induced by human papillomavirus (HPV), while its effect on cervical intraepithelial neoplasia (CIN) caused by high risk type of HPVs has not been reported. Patient concerns Three patients with low grade CIN and positive high risk HPV types (HPV 16, 31, 52, 56, 58) are reported in this study. Diagnosis The diagnosis was based on identification of HPV types and abnormal cytological findings. Interventions The 3 patients were treated with local hyperthermia from ceramic heating (surface temperature, 44°C) to cervix. The treatment was delivered once a day for 3 consecutive days, plus two similar treatments 10 ± 3 days later, with each session lasting 30 minutes. HPV and cytology test were performed 3 months thereafter. Outcomes All the 3 patients recovered to normal cytological findings. Two of the patients were negative for HPV, the remaining patient with pre-treatment HPV 56 and 58 positivity changed to HPV58 positive alone. Conclusion This pilot observation inspires that mild local hyperthermia be recommended as a new method in the treatment of CIN patients with persistent HPV infection, once validated by qualified RCT.

Objective. A retrospective analysis of clinical characteristics and immunological manifestations of primary Sjogren’s syndrome (pSS) patients with or without renal involvement was conducted in order to elucidate the potential risk factors of renal damage in pSS and evaluate the condition. Methods. A total of 1002 patients, who fulfilled the 2002 classification criteria for pSS from the Second Affiliated Hospital of Shanxi Medical University, were enrolled in the cross-sectional study. Clinical, immunological, and histological characteristics were compared between pSS patients with and without renal involvement, and potential risk factors of renal involvements in pSS patients were examined by multivariate analysis. Results. Among these pSS patients, there were 162 cases (16.17%) with and 840 cases (83.83%) without renal damage. Serious edema of both lower limbs, interstitial nephritis, and renal tubular acidosis were found in the pSS with renal damage group. Compared with simple pSS patients, the levels of creatinine, cystatin C, and alpha-1-microglobulin (α1-MG) in the pSS with renal damage group were significantly increased. The difference between the two groups was statistically significant (P<0.05). The AUC of the combination of creatinine and α1-MG and creatinine, α1-MG, and creatinine was statistically larger than that of creatinine, and the biomarker of the biggest AUC is the combination of creatinine and α1-MG. Conclusion. The main clinical manifestations of pSS with renal damage were edema of the lower limbs, interstitial nephritis, and renal tubular acidosis. Creatinine and α1-MG are effective indicators for renal function in pSS, which may provide a better understanding for clinical decision-making.

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have uncovered the disruptions of functional brain networks in primary insomnia (PI) patients. However, the etiology and pathogenesis underlying this disorder remains ambiguous, and the insomnia related symptoms are influenced by a complex network organization in the brain. The purpose of this study was to explore the abnormal intrinsic functional hubs in PI patients using a voxel-wise degree centrality (DC) analysis and seed-based functional connectivity (FC) approach. Methods: A total of 26 PI patients and 28 healthy controls were enrolled, and they underwent resting-state fMRI. Degree centrality was measured across the whole brain, and group differences in DC were compared. The peak points, which significantly altered DC between the two groups, were defined as the seed regions and were further used to calculate FC of the whole brain. Later, correlation analyses were performed between the changes in brain function and clinical features. Results: Primary insomnia patients showed DC values lower than healthy controls in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) and showed a higher DC value in the right precuneus. The seed-based analyses demonstrated decreased FC between the left MTG and the left posterior cingulate cortex (PCC), and decreased FC was observed between the right precuneus and the right lateral occipital cortex. Reduced DC in the left IFG and decreased FC in the left PCC were positively correlated with the Pittsburgh sleep quality index and the insomnia severity index. Conclusions: This study revealed that PI patients exhibited abnormal intrinsic functional hubs in the left IFG, MTG, and the right precuneus, as well as abnormal seed-based FC in these hubs. These results contribute to better understanding of how brain function influences the symptoms of PI.

Background: Ischemic cerebral infarction is a severe clinical condition that can cause serious mortality. Artesunate, an anti-malarial drug that is widely used in cancer treatment, is known to facilitate accelerated cell apoptosis. The aim of this study is to explore the possible neuroprotective effects of artesunate on hypoxic-ischemic cells in rats. Methods: Middle cerebral artery occlusion (MCAO) rats were treated with artesunate in different doses to observe their survival rate. Primary hippocampal neurons were deprived of oxygen-glucose to induce ischemia symptoms. Western blot was performed to determine the protein expressions of p-mTOR, Beclin-1, and Mcl-1. A five-point scale was used to detect neurological deficit. Cell apoptosis was measured using a TUNEL assay. Results: Artesunate supplementation protected MCAO rats from death and ameliorated brain injury among them. Artesunate administration decreased the expression of p-mTOR, increased the expressions of Beclin-1 and Mcl-1, and decreased the activity of caspase-3 in both the rats' ischemia cerebral cortices and their primary ischemia hippocampal neurons when compared with artesunate-absent ischemic brains and cells. The neuroprotective effects of artesunate were abolished by either leucine (LEU) or 3-MA, while the effects of rapamycin were reversed by 3-MA. In vivo experiments verified the protective effects of artesunate on brain-infarct rats. Conclusion: The results indicate the protectiveness of artesunate against ischemic cerebral infarction, whereas the protectiveness might increase autophagy through regulating the activity of mTOR.

Objective To compare the therapeutic effect of arterial and lymphatic sparing microscopic retroperitoneal varicocelectomy (MRV) with that of microscopic subinguinal varicocelectomy (MSV) for treatment of varicocele in infertile men. Methods We conducted a prospective and controlled study to evaluate the therapeutic efficacy of MRV and MSV for treatment of varicocele in infertile men. A total of 80 patients were randomly chosen to undergo MRV (n = 40) or MSV (n = 40) treatment. All patients were followed up at 3, 6, and 12 months after surgery. Semen parameters, pregnancy, recurrence, and complications were examined. Results Mean operation time in the MRV group was significantly shorter than that in MSV group (38.92 ± 5.67 min vs 91.35 ± 15.08 min), and the number of observed spermatic veins in MRV group was significantly less than that in MSV group (3.59 ± 0.76 vs 18.22 ± 2.83). Sperm count and motility were significantly improved at 12 months follow-up in both groups compared with preoperative values, and the sperm count in the MRV group at 3 months was significantly higher than that in MSV group. Moreover, the incidence of scrotal edema was higher in the MSV group, although natural pregnancy rate was not significantly different between 2 groups at 1-year follow-up (42.1% vs 44.7%). Conclusion MRV with artery and lymphatic sparing is a simple and effective technique for treatment of varicocele in infertile men.

Background Elevated serum and synovial fluid (SF) fractalkine (CX3CL1) levels have been detected in patients with knee osteoarthritis (OA). The current study was carried out to investigate the association between serum and SF fractalkine levels with symptomatic severity in patients with knee OA. Method One hundred ninety-three patients with OA and 182 healthy controls were enrolled in this study. The symptomatic severity was assessed by the Western Ontario McMaster University Osteoarthritis scores. Results Fractalkine levels in SF and serum were both positively associated with self-reported greater pain and physical disability. Conclusions Fractalkine in SF and serum may serve as a biomarker for reflecting symptomatic severity. Therapeutic interventions that target fractalkine signaling pathways to delay OA-related symptoms deserve further study.

Shuai Zhang,1,* Xu Wang,2,* Chao-Qun Yan,1 Shang-Qing Hu,3 Jian-Wei Huo,4 Zhong-Yan Wang,4 Ping Zhou,1 Chun-Hong Liu,1 Cun-Zhi Liu3 1Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, Dongcheng District, Beijing, 2School of Life Sciences, Beijing University of Chinese Medicine, Chaoyang District, Beijing, 3Department of Acupuncture and Moxibustion, Dongfang Hospital, Beijing University of Chinese Medicine, Fengtai District, Beijing, 4Department of Medical Imaging, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, Dongcheng District, Beijing, People’s Republic of China *These authors contributed equally to this work Background: Chronic shoulder pain (CSP) is a common disease causing pain and functional limitation, which is highly prevalent and has substantial negative effects on the quality of life. Acupuncture has gained popularity and has been accepted gradually by many countries because it can successfully treat patients with chronic pain, but the specific brain mechanisms under acupuncture treatment for CSP remain unclear. Therefore, in this study, we aimed to 1) compare the clinical effects between acupuncture at the contralateral and ipsilateral Tiaokou (ST 38) point in patients with unilateral shoulder pain and 2) explore how contralateral- and ipsilateral-acupuncture modulates the regional homogeneity (ReHo) of patients with CSP.Patients and methods: This was a pilot functional magnetic resonance imaging (fMRI) trial. Twenty-four patients with CSP were recruited and randomized to the contralateral acupuncture group (contra-group) and the ipsilateral acupuncture group (ipsi-group). All patients completed resting-state functional magnetic resonance imaging (fMRI) scans before and after acupuncture treatment. Shoulder pain intensity (visual analog scale [VAS]) and shoulder joint function (Constant–Murley score [CMS]) were used to evaluate clinical efficiency of treatment. ReHo was used to assess resting-state brain activity.Results: We found clinical improvement in decreasing pain intensity and increasing shoulder function in both groups, and the mean objective shoulder functional improvement in contra-group was better than that in ipsi-group (p = 0.010). Interestingly, the brain mechanism of contra-acupuncture at ST 38 was distinguishable from ipsi-acupuncture regarding ReHo values.Conclusion: Anterior cingulate cortex (ACC) may play a direct role in the regulation of brain by the contralateral acupuncture at ST 38 in patients with shoulder pain. On the contrary, the pathway of brainstem-thalamus-cortex may be likely to work in mechanism of acupuncture at ipsilateral ST 38.Significance: Our results indicate that the clinical effects and brain mechanisms are different between the stimulation given at contralateral and ipsilateral acupoints in patients with CSP and imply that the selection of either contralateral or ipsilateral acupuncture therapy to treat some chronic pain conditions is necessary. Keywords: region homogeneity, anterior cingulate cortex, brainstem, resting-state fMRI, ST 38

EEG is a useful method to detect electrical activity in the brain. Moreover, it is a widely used diagnostic tool for various neurological conditions, such as epilepsy and neurodegenerative disorders. However, it is technically difficult to obtain EEG recordings in neonates as it requires specialized handling and great care. Here, we present a novel method to record EEG in neonatal rat pups (P8-P15). We designed a simple and reliable electrode using computer pin loci; it can be easily implanted into the skull of a rat pup to record high-quality EEG signals in the normal and epileptic brain. Pups were given an intraperitoneal (i.p.) injection of the neurotoxin kainic acid (KA) to induce epileptic seizures. The surgical implantation performed in this procedure is less expensive than other EEG procedures for neonates. This method allows one to record high-quality and stable EEG signals for more than 1 week. Furthermore, this procedure can also be applied to adult rats and mice to study epilepsy or other neurological disorders.

Ubiquitin-specific protease 26 (USP26) is an X-linked gene exclusively expressed in the testis and codes for the USP26, a peptidase enzyme that belongs to the deubiquitinating enzyme family. Recent studies have indicated that mutations in USP26 affect spermatogenesis and are associated with male infertility in humans and mice. However, the exact role of USP26 in spermatogenesis and how it affects male reproduction remains unknown. In this study, we generated a conventional Usp26 knockout mouse model and found that deletion of Usp26 in male mice (Usp26−/Y) leads to significantly reduced pup numbers per litter and significantly increased intervals between two consecutive offspring. We also found that the serum follicle stimulating hormone and testosterone levels of adult Usp26−/Y mice were significantly decreased compared to those of Usp26+/Y mice. Histological examination results showed that Usp26−/Y mice had significantly increased percentage of abnormal seminiferous tubules at different ages. Flow cytometry results exhibited that Usp26−/Y mice had significantly reduced percentage of mature haploid cells in the testes compared to Usp26+/Y mice. Sperm counts in epididymis were also significantly declined in Usp26−/Y mice compared to those in Usp26+/Y mice. Immunohistochemistry and immunofluorescence staining and immunoprecipitation analysis results showed that USP26 and androgen receptor were co-localized in mouse testicular cells at different ages and they both had physiological interactions. All these results demonstrated that the loss of Usp26 affects spermatogenesis and hormone secretion and causes male subfertility. Our study also provides the evidence on the interactions between USP26 and androgen receptor in mouse testis, whereby pointing to a potential mechanism.

A man developed with multiple warts on his hands and the inner canthus of his left eye. We applied local hyperthermia on a single target lesion on his hand at a surface temperature of 44°C for 30 minutes on Days 1, 2, 3, 17, and 18. All the lesions treated with or without heat cleared 8 weeks after the last treatment. Treatment of a target lesion resolved all other untreated lesions, a fact suggestive that local hyperthermia could induce activation of specific immunity against human papillomavirus on the lesional skin, which lead to resolution of all the warts.

We previously reported a large Chinese pedigree of erythrokeratodermia variabilis (EKV). A unique feature was that some of the affected members experienced transitory pustules on the border of classic lesions. Here we prescribed oral arotinoid ethylester and acitretin to two of the affected members in the pedigree, at starting dosage of 0.03 mg/day for arotinoid ethylester and 30 mg/day for acitretin, maintenance dosage of 0.03 mg every other day and 20 mg/day, respectively. Both patients reached complete clearance of the lesions during the treatment period. Side effect was negligible for the case on arotinoid ethylester. The patient on acitretin experienced elevated level of serum triglyceride and alanine aminotransferase that restrained further use.

Erectile dysfunction (ED) is a major sexual problem for men. Nogo-B receptor (NgBR) has been found to be involved in the regulation of vascular remodeling and angiogenesis. The present study explores the effects of NgBR in penile corpus cavernosum in rats with diabetic ED. Firstly, the ED model of Sprague Dawley rats was established. Hematoxylin-eosin staining and Masson staining were conducted to observe pathological morphology. Immunochemical assay was adopted to detect α-smooth muscle actin (α-SMA), NgBR and intercellular cell adhesion molecule-1 (ICAM-1) expression. Reverse transcription quantitative polymerase chain reaction assay and Western blot analysis were carried out for the assessment of NgBR, factors correlated to ICAM-1, including steroid receptor coactivator (SRC) and proline-rich tyrosine kinase2 (PYK2), and factors associated with apoptosis, including B-cell lymphoma-2 (Bcl-2), Bcl-2 associated protein X (Bax), caspase 3 and cleaved-caspase 3. The results found that capillaries and vascular smooth muscle cell content reduced, and NgBR and ICAM-1 were elevated in rats with diabetic ED. si-NgBR relieved ED by decreasing penile corpus cavernosum smooth muscle systolic percentage and increasing erectile time and rate, intracavernous pressure (ICP)/mean arterial pressure (MAP) and diastolic percentage, improving the pathological changes and inhibiting cavernosum cell apoptosis. si-NgBR also resulted in the down-regulation of ICAM-1 and downstream SRC and PYK2 and promoted α-SMA expression. In conclusion, si-NgBR can provide a potential therapy for diabetic ED in rats by down-regulating ICAM-1, SRC and PYK2, making it a potential therapeutic option for diabetic ED.

To evaluate the diagnostic value of 18F-FDG PET/CT for detection of bone metastasis in comparison with the efficacies of 18F-FDG PET/CT, CT, 18F-FDG PET and conventional planar bone scintigraphy in a series of cancer patients.Five hundred and thirty patients who underwent both 18F-FDG PET/CT and bone scintigraphy within 1 month were retrospectively analyzed. The skeletal system was classified into 10 anatomic segments and interpreted blindly and separately. For each modality, the sensitivity, specificity, accuracy, PPV and NPV were calculated and the results were statistically analyzed.Bone metastases were confirmed in 117 patients with 459 positive segments. On patient-based analysis, the sensitivity, specificity, accuracy, PPV and NPV of 18F-FDG PET/CT were significantly higher than bone scintigraphy, CT and 18F-FDG PET (P0.05). On segment-based analysis, the sensitivity of CT, bone scintigraphy, 18F-FDG PET and 18F-FDG PET/CT were 70.4%, 89.5%, 89.1% and 97.8%, respectively (P0.05, compared with 18F-FDG PET/CT). The overall specificity and accuracy of the four modalities were 89.1%, 91.8%, 90.3%, 98.2% and 90.3%, 90.9%, 89.8%, 98.0%, respectively (P0.05, compared with 18F-FDG PET/CT). The PPV and NPV were 89.8%, 87.6%, 85.6%, 97.2% and 85.6%, 93.2%, 92.8%, 98.6%, respectively. Three hundred and twelve lesions or segments were presented as lytic or sclerotic changes on CT images at the corresponding sites of increased 18F-FDG uptake. In lytic or mixed lesions, the sensitivity of 18F-FDG PET/CT and 18F-FDG PET were better than bone scintigraphy, while in osteoblastic lesions bone scintigraphy had a similar performance with 18F-FDG PET/CT but better than 18F-FDG PET alone.Our data allow the conclusion that 18F-FDG PET/CT is superior to planar bone scintigraphy, CT or 18F-FDG PET in detecting bone metastasis. 18F-FDG PET/CT may enhance our diagnosis of tumor bone metastasis and provide more information for cancer treatment.

Genital warts acquired during pregnancy tend to grow fast, and management is challenging. We treated two cases of primipara with extensive genital warts by local hyperthermia at 44°C for 30 minutes a day for 3 consecutive days plus 2 additional days 1 week later, then once a week till there showed signs of clinical regression. The warty lesions in the patients resolved in 5 and 7 weeks, respectively. There was no sign of recurrence during a 6-month follow-up. This suggests that local hyperthermia seems to be a promising method for treating genital warts in pregnant women.

Genital warts are more extensive and difficult to treat in patients with diabetes mellitus due to defective immune responses.Our aim was to confirm the suitability of local hyperthermia for the treatment of genital warts in patients with diabetes mellitus and to investigate the immune cells in lesional areas at different time intervals after treatment.We treated three diabetic patients with extensive genital warts by local hyperthermia at 44 °C for 30 min a day for 3 consecutive days plus 2 additional days 1 week later, then once a week till there showed signs of clinical clearance. Immunohistochemical profile was described on serial biopsies from a patient with confluent plaques.The warty lesions in the patients resolved in 6, 4 and 9 weeks, respectively. Immunohistochemical staining in the regressing warts revealed abundant infiltrating CD4+ T and CD8+ T lymphocytes (P 0.01), as well as macrophages and CD1a+ dendritic cells.This preliminary study suggested that local hyperthermia was a safe and effective single modality in the treatment of genital warts in diabetic patients and could induce a rapid immune response in lesional skin.

Mosquito Bite Allergy Members of the order Diptera, the family Culicidae, mosquitoes are vectors for the transmission of many diseases worldwide. There are over 3000 different species of mosquitoes, which grouped into more than 40 genera (Garcia Diagnostic Medical Parasitology 682, 2007; Peng and Simons Int Arch Allergy Immunol 133:198–209, 2004). Although many mosquito bites produce only mild and transient cutaneous reactions, more severe allergic reaction as hypersensitivity could also happen. Hypersensitivity to mosquito bites is a rare disease characterized by intense local skin reactions with general symptoms, such as high fever and regional lymphadenopathy after mosquito bites. Chronic active Epstein–Barr virus (EBV) infection and NK cell lymphoproliferative disease have been reported in hypersensitivity to mosquito bite patients.

MicroRNAs (miRNAs) are known to serve a role in tumorigenic programs. The dysregulated expression of miR‑301a‑3p may affect the progression of various types of human cancer; however, the expression and the role of miR‑301a‑3p in prostate cancer are still unclear. The present study aimed to clarify the role and molecular mechanism of miR‑301a‑3p in prostate cancer. The results demonstrated that the expression of miR‑301a‑3p was significantly upregulated in human prostate cancer tissues and in several prostate cancer cell lines. In vitro overexpression of miR‑301a‑3p notably increased prostate cancer cell proliferation and invasion. Bioinformatics analysis revealed that runt‑related transcription factor 3 (RUNX3) may be a target of miR‑301a‑3p, which was confirmed by Dual‑luciferase reporter assay. Western blot analysis also demonstrated that miR‑301a‑3p regulated the protein expression levels of RUNX3. In addition, the results indicated that miR‑301a‑3p may regulate the Wnt signaling pathway, and rescue experiments indicated that RUNX3 contributed to the effects of miR‑301a‑3p on cell proliferation and invasion through Wnt signaling. In conclusion, these findings suggested that miR‑301a‑3p may promote prostate cancer cell invasion and proliferation by targeting RUNX3, and provided insight into understanding prostate cancer pathogenesis. miR‑301a‑3p may be a potential therapeutic candidate to treat prostate cancer.

A variety of medications and procedures are available for the treatment of warts, but it appeared the treatment response in systemic lupus erythematosus (SLE) patients is poor. It is necessary to investigate the feasibility, safety and efficacy of local thermotherapy for extensive viral warts.A SLE patient on systemic steroid developed extensive viral warts on both her hands and feet for months. She had a high score of SLE Disease Activity Index (SLEDAI), up to 30, and was extensively treated with high and prolonged dosage of corticosteroid and intermittent use of cyclophosphamide. We applied local hyperthermia at 44 °C on a target lesion for 30 min on days 1, 2, 3, 17, 18, a protocol which has been successfully used in treating viral warts. There was no sign of clinical response in a 3-month follow-up. Then we treated the patient on a once-a-week protocol.All the lesions cleared in ten weeks and there was no sign of recurrence.This observation suggests that more intensive local hyperthermia is required for clearing viral warts in SLE.

To investigate the distributions of HLA-B alleles and estimate their associations with idiopathic male infertility in Chinese Han population.Polymerase chain reaction-sequence-based typing (PCR-SBT) method was used for DNA typing at HLA-B locus in 109 patients with idiopathic male infertility and 152 healthy controls in male Han population of Shaanxi Province, situated in northwestern China.In total, we detected 45 HLA-B alleles in idiopathic infertile patients, 48 HLA-B alleles in control subjects. However, no significant differences of these allelic frequencies were found between the infertile patients and the controls.HLA-B gene was unlikely a major risk factor of idiopathic male infertility in this sample population. As different populations have different HLA polymorphisms, investigation of the relationship of other HLA genes and idiopathic male infertility with larger sample size, is warranted in the future.

There have been anecdotal reports that local hyperthermia was effective in the treatment of viral warts. We conducted a randomized, patient-blinded, placebo-controlled trial to test the effect of local hyperthermia (44 degrees C for 30 min a day for 3 consecutive days plus 2 additional days 2 weeks later) on plantar warts. By the end of 3 months, 53.57% of patients (15/28) in the treatment group and 11.54% of patients (3/26) in the control group were cured (P < .01). The effect was not influenced by patient age, duration of disease, or number or size of lesions.

Hyperthermia has shown clinical potency as a single agent or as adjuvant to other therapies in cancer treatment. However, thermotolerance induced by thermosensitive genes such as the heat shock proteins can limit the efficacy of hyperthermic treatment. In the present study, we identified HSPB1 (HSP27) is hyperthermically inducible or endogenously highly expressed in both murine and human melanoma cell lines. We used a siRNA strategy to reduce HSPB1 levels and showed increased intolerance to hyperthermia via reduced cell viability and/or proliferation of cells. In the investigation of underlying mechanisms, we found knock down of HSPB1 further increased the proportion of apoptotic cells in hyperthermic treated melanoma cells when compared with either single agent alone, and both agents leaded to cell cycle arrest at G0/G1 or G2/M phases. We concluded that hyperthermia combined with silencing of HSPB1 enhanced cell death and resulted in failure to thrive in melanoma cell lines, implying the potential clinical utility of hyperthermia in combination with HSPB1 inhibition in cancer treatment.

Facial common wart is a disfiguring condition caused by human papilloma virus infection. Choices to treat facial warts should be cautious, in consideration of adverse cosmetic consequences. Two cases of facial common warts were treated by local hyperthermia at 44 °C for 30 minutes, once a day for three consecutive days (the first session), and similarly treated a week later for more 2 days (second session). The warts completely disappeared in 10 and 12 weeks, respectively in the two patients. Adverse effect was tolerable burning sensation in the two patients and a temporary heat-induced blistering in one of them. This pioneer trial suggested that mild hyperthermia is a safe and effective method in treating facial common warts.

Background Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin disease in children characterized by dermatitis and pruritus. MicroRNAs (miRNAs) have been shown as great potential biomarkers for disease fingerprints to predict prognostics. We aimed to identify miRNA signature from serum and urine for the prognosis of AD patient by genome-wide miRNA profiling analysis. Methods Serum and urine from 30 children with AD and 28 healthy children were collected and their genome-wide miRNA expression profiles were measured by TaqMan-based array and confirmed by quantitative real-time PCR. Inflammatory factors in serum were detected by Antibody Array System. Results miR-203 and miR-483-5p were significantly up-regulated in serum of children with AD compared with healthy children. The level of miR-483-5p in serum was significantly associated with other atopic conditions, such as rhinitis and/or asthma. However, miR-203 was markedly decreased in urine of children with AD compared with healthy children. Down-regulated miR-203 in urine was significant associated with abnormal level of serum IgE in AD patients. 7 inflammatory factors in serum were altered in children with AD compared with healthy children. Up-regulated miR-203 in serum was significantly associated with increased sTNFRI and sTNFRII. Conclusions Up-regulated miR-483-5p in serum may be indicative of other atopic conditions in children with AD. Down-regulated miR-203 in urine may serve as a biomarker for the severity of inflammation in children with AD.

A 37-year-old man complained of dozens of gray or skin-colored papules on his scalp for 6 years. Six years ago, he noticed two gray papules about 2-to-3 mm in diameter on his scalp. Since then, the number and sizes of the papules increased gradually. He was diagnosed with viral warts in his local hospital and was treated with CO2 ablative laser about 10 times. Some of the warty lesions cleared while leaving atrophic scars over the treated area. However, there was continuing growth of old lesions [...]

The case of a 21-year-old woman presenting with macronodular multi-organs tuberculoma is reported. She was examined for pulmonary tuberculosis on a chest X-ray film in January, 1995, and admitted with a cough, anorexia, and abdominal pain in July, 1996. Computed tomography revealed multiple calcified nodules with peripheral hypodense areas in the brain, and calcified hypodense masses in the liver and spleen. Magnetic resonance (MR) imaging showed hypointense masses in the liver and spleen on T1-weighted spin echo images and a hypointense mass with a hyperintense area on T2-weighted spin echo images. On contrast-enhanced dynamic MR images, the liver and spleen masses were unenhanced and hypointense with slight rim enhancement. T2-weighted spin echo images showed a round hypointense nodule in the right kidney and hydronephrosis and enlargement in the left kidney. Antituber-culous treatment was started with a gradual improvement in her signs and symptoms. Her temperature became normal. However, she was systemically treated with antituberculous chemotherapy 10 months later, her condition worsened again. She died from increased intracranial pressure in August, 1997.

Prostate carcinoma is the most common cancer for men and among the leading cancer-related causes. Many evidences have shown that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) potently induces apoptosis in cancer cells, and thus, is a promising biologic agent for prostate carcinoma therapy. However, TRAIL expression mediated by the current vectors lacks tumor specificity, thereby exerting cytotoxicity to normal cells. To solve this problem, we inserted miRNA response elements (MREs), miR-143 and miR-145, expression levels of which were reduced in prostate carcinoma, as well as that of miR-122, which is specifically expressed in hepatic cells, into adenoviral vectors to control TRAIL expression (Ad-TRAIL-M3). qPCR data confirmed that miR-143, miR-145, and miR-122 levels were all decreased in prostate carcinoma cell lines and prostate cancer samples from patients. Luciferase assays showed that MREs-regulated luciferase expression was potently suppressed in normal cells, but not in prostate cancer cells. Ad-TRAIL-M3, which expresses TRAIL in a MREs-regulated manner, produced high level of TRAIL and suppressed the survival of prostate cancer cells by inducing apoptosis, while Ad-TRAIL-M3 had no TRAIL expression in normal cells and thus exerted no cytotoxicity to them. The studies on PC-3 tumor xenograft in mice further confirmed that Ad-TRAIL-M3 was able to inhibit the growth of tumors and possessed high biosafety. In conclusion, we successfully generated an adenoviral vector that expresses TRAIL in miRNA-regulated mechanism. This miRNA-based gene therapy may be promising for prostate carcinoma treatment.

X-ray repair cross-complementing group 1 (XRCC1) is a scaffold protein that plays a critical role in DNA base excision repair. To explore the association between XRCC1 single-nucleotide polymorphisms and infertility with idiopathic azoospermia in a northern Chinese Han population, PCR restriction fragment length polymorphism was used to genotype a SNP locus (rs25487) of XRCC1 in 112 patients with idiopathic azoospermia and 156 healthy controls. Furthermore, nucleotide sequences were sequenced. The results showed that, compared with GG genotype, the GA and GA+AA genotypes showed a significant association with an increased risk of idiopathic azoospermia (OR 2.119, 95% CI 1.245–3.606, P =0.005), (OR 2.052, 95% CI 1.227–3.431, P =0.006) respectively. Meanwhile, the A allele frequency was significantly higher in azoospermic patients than that in controls (OR 1.472, 95% CI 1.029–2.105, P =0.034). The substitutions bring about an amino acid alteration: G→A changes the arginine residue into glutamine. In conclusion, the SNP locus rs25487 of XRCC1 could be a marker for genetic susceptibility to idiopathic azoospermia and the A allele might be a risk gene of idiopathic azoospermia in the northern Chinese Han population. The current study is to investigate the XRCC1 (X-ray repair cross-complementing group 1) gene single nucleotide polymorphisms and estimate their associations with idiopathic azoospermia in Northern Chinese Han population by using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method. This study reveals that SNP loci (rs25487) of XRCC1 gene could be a marker for genetic susceptibility to idiopathic azoospermia and the A allele might be a risk gene of idiopathic azoospermia in Northern Chinese Han population. Further research on this issue is still necessary.

We report here a Chinese family with erythrokeratodermia variabilis which had 30 affected members. The patients had characteristic clinical features of stationary and migratory lesions. Some of the patients had adult onset of the disease. Five out of 30 patients noted episodes of pustule-like lesions during their disease course. Histological examination of the proband showed granular cell vacuolation and upper-epidermal neutrophil aggregates. Mitochondria vacuolation was noted in keratinocytes by electron microscopic examination. No GJB3 and GJB4 pathogenic mutation was detected. These unusual presentations suggested a new phenotypic and genetic correlation in this Chinese pedigree of erythrokeratodermia variabilis.

Aim: To study the incidence of single nucleotide polymorphisms in ubiquitin-specific protease 26 (USP26) gene and its involvement in idiopathic male infertility in China. Methods: Routine semen analysis was performed. Infertility factors such as immunological, infectious and biochemical disorders were examined to select patients with idiopathic infertility. DNA was isolated from peripheral blood of the selected patients and control population, which were examined for mutations using polymerase chain reaction-single strand conformation polymorphism analysis. Furthermore, nucleotide sequences were sequenced in some patients and controls. Results: Of 41 infertile men, 9 (22.0%, P = 0.01) had changes in USP26 gene on the X chromosome. A compound mutation (364insACA; 460G→A) was detected in 8 patients (19.5%, P = 0.01) and a 1044T→A substitution was found in 1 patient (2.4%, P > 0.05). All three variations led to changes in the coding amino acids. Two substitutions predict some changes: 460G → A changes a valine into an isoleucine, and 1044T → A substitutes a leucine for a phenylalanine. Another insertion of three nucleotides ACA causes an insertion of threonine. No other changes were found in the remaining patients and fertile controls. Conclusion: The USP26 gene might be of importance in male reproduction. Mutations in this gene might be associated with male infertility, and might negatively affect testicular function. Further research on this issue is in progress. (Asian J Androl 2007 Nov; 9: 809–814)

AIM: To assess the hepatic microvascular parameters in patients with liver cirrhosis by perfusion computed tomography (CT). METHODS: Perfusion CT was performed in 29 patients without liver disease (control subjects) and 39 patients with liver cirrhosis, including 22 patients with compensated cirrhosis and 17 patients with decompensated cirrhosis, proved by clinical and laboratory parameters. CT cine-scans were obtained over 50 s beginning with the injection of 50 mL of contrast agent. Hepatic microvascular parameters, mean transit time (MTT) and permeability surface area product (PS) were obtained with the Perfusion 3 software (General Electric, ADW 4.2). RESULTS: The overall differences of MTT and PS between control subjects, patients with compensated cirrhosis and those with decompensated cirrhosis were statistically significant (P = 0.010 and P = 0.002, respectively). MTT values were 15.613 ± 4.1746 s, 12.592 ± 4.7518 s, and 11.721 ± 4.5681 s for the three groups, respectively, while PS were 18.945 ± 7.2347 mL/min per 100 mL, 22.767 ± 8.3936 mL/min per 100 mL, and 28.735 ± 13.0654 mL/min per 100 mL. MTT in decompensated cirrhotic patients were significantly decreased compared to controls (P = 0.017), whereas PS values were remarkably increased (P = 0.001). CONCLUSION: The hepatic microvascular changes in patients with liver cirrhosis can be quantitatively assessed by perfusion CT. Hepatic microvascular parameters (MTT and PS), as measured by perfusion CT, were significantly altered in decompensated cirrhosis.