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Objective To analyze the clinical characteristics and controllable risk factors of osteoporosis in elderly men with type‐2 diabetes mellitus (T2DM). Methods A total of 250 elderly OP patients with T2DM were included in the present study. Patients with one or more common chronic diseases (including hypertension, coronary heart disease, heart failure, chronic bronchitis, chronic nephrosis, and cirrhosis), and a course of more than 3 years were defined as complicated with chronic diseases. Blood glucose, cholesterol, triglyceride, low‐density lipoprotein, high‐density lipoprotein, calcium, phosphorus, glycosylated hemoglobin, urea nitrogen, creatinine, fasting insulin, liver function, and 25‐hydroxy vitamin D3 levels were measured. Bone mineral density was also measured. Results A total of 16 patients (6.4%) had severe osteoporosis. Furthermore, 66 patients (26.4%) had blood glucose control that reached the standard, while 176 patients (70.4%) used more than two anti‐diabetic drugs. The serum testosterone level was lower than the median in 87 patients (34.8%) and in 56 smokers (22.4%). Furthermore, 138 patients (55.2%) were overweight and obese, six patients (2.4%) were underweight, 197 patients (78.8%) had chronic diseases, 88 patients (35.2%) were sticking to exercise, and 117 patients (46.8%) had less exercise. In addition, 92 patients (36.8%) were treated with osteotrophy‐protective agents, and 24 patients (9.6%) received anti‐osteoporosis therapy. Smoking, poor glycemic control, low testosterone levels, less exercise, and complications with chronic diseases were the most relevant controllable risk factors. Conclusion For elderly male osteoporosis patients with type‐2 diabetes, smoking cessation, blood sugar control up to the standard, regular exercise, active prevention and treatment of complications, and appropriate testosterone supplementation are necessary for preventing and curing osteoporosis., Technology roadmap

International audience; Objective: The prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independent factor for the prognostication of mPDAC.Design: Translational study based on two prospective collections of plasma samples of mPDAC patients naïve for chemotherapy. One used as a test series and the other as validation series coming from two randomised trials (Prodige 35 and Prodige 37). CtDNA was assessed by digital droplet PCR targeting two methylated markers (HOXD8 and POU4F1) according to a newly developed and validated method. Univariate and multivariate analyses were performed according to ctDNA status.Results: Of 372 plasma samples available, 354 patients were analyzed for survival. In the validation series, 145 of 255 patients were found ctDNA positive (56.8%), Median PFS and OS were 5.3 and 8.2 months in ctDNA-positive and 6.2 and 12.6 months in ctDNA-negative patients, respectively. ctDNA positivity was more often associated with young age, high CA19-9 level and neutrophils lymphocytes ratio. In multivariate analysis including these previous markers, ctDNA was confirmed as an independent prognostic marker for PFS (adjusted hazard ratio (HR) 1.5, CI 95% [1.03-2.18], p = 0.034) and OS (HR 1.62, CI 95% [1.05-2.5], p = 0.029).Conclusions: In this first ctDNA assessment in a large series of mPDAC derived from clinical trials, ctDNA was detectable in 56.8% of patients and confirmed as an independent prognostic marker.

Background In non-metastatic colorectal cancer (CRC), we evaluated prospectively the pertinence of longitudinal detection and quantification of circulating tumor DNA (ctDNA) as a prognostic marker of recurrence. Method The presence of ctDNA was assessed from plasma collected before and after surgery for 184 patients classified as stage II or III and at each visit during 3–4 years of follow-up. The ctDNA analysis was performed by droplet-based digital polymerase chain reaction, targeting mutation and methylation markers, blindly from the clinical outcomes. Multivariate analyses were adjusted on age, gender, stage, and adjuvant chemotherapy. Results Before surgery, 27.5% of patients were positive for ctDNA detection. The rate of recurrence was 32.7% and 11.6% in patients with or without detectable ctDNA respectively (P = 0.001). Time to recurrence (TTR) was significantly shorter in patients with detectable ctDNA before (adjusted hazard ratio [HR] = 3.58, 95% confidence interval [CI] 1.71–7.47) or immediately after surgery (adjusted HR = 3.22, 95% CI 1.32–7.89). The TTR was significantly shorter in patients with detectable ctDNA during the early postoperative follow-up (1–6 months) (adjusted HR = 5, 95% CI 1.9–12.9). Beyond this period, ctDNA remained a prognostic marker with a median anticipated diagnosis of recurrence of 13.1 weeks (interquartile range 28 weeks) when compared to imaging follow-up. The rate of ctDNA+ might be underestimated knowing that consensus pre-analytical conditions were not described at initiation of the study. Conclusion This prospective study confirms the relevance of ctDNA as a recurrence risk factor in stage II and III CRC before surgery and as a marker of minimal residual disease after surgery that may predict recurrence several months before imaging techniques.

Background Preoperative anemia is an important pillar of perioperative patient blood management. However, there was no literature comprehensively described the current situation of preoperative anemia in China. Methods We conducted a national retrospective cross-sectional study to assess the prevalence and intervention of preoperative anemia in Chinese adults. Data were from the National Preoperative Anemia Database based on hospital administration data from January 1, 2013 to December 31, 2018. Findings A total of 797,002 patients were included for analysis. Overall, 27.57% (95% CI 27.47–27.67) of patients had preoperative anemia, which varied by gender, age, regions, and type of operation. Patients who were female, age over 60 years old, from South China, from provinces with lower per capita GDP, underwent operations on the lymphatic and hematopoietic system, with laboratory abnormalities were more likely to have a high risk of preoperative anemia. Among patients with preoperative anemia, 5.16% (95% CI 5.07–5.26) received red blood cell transfusion, 7.79% (95% CI 7.67–7.91) received anemia-related medications such as iron, erythropoietin, folic acid or vitamin B12, and 12.25% (95% CI 12.10–12.40) received anemia-related therapy (red blood cell transfusion or anemia-related medications) before operation. The probability of preoperative RBC transfusion decreased by 54.92% (OR 0.46, 95% CI 0.46–0.47) as each 10-g/L increase in preoperative hemoglobin. Patients with preoperative hemoglobin less than 130 g/L was associated with longer hospital stay and more hospital costs. Patients with severe preoperative anemia given iron preoperatively had lower intra/post-operative RBC transfusion rate, shorter length of stay and less hospitalization costs, but no similar correlation was found in patients with mild and moderate preoperative anemia and patients given erythropoietin preoperatively. Interpretation Our present study shows that preoperative anemia is currently a relatively prevalent problem that has not been fully appreciated in China. More researches will be required to optimize the treatment of preoperative anemia. Funding National Natural Science Foundation of China and the Logistics Support Department of the Central Military Commission.

Aspergillus niger CJ-1 was applied to conduct fermentation process on tartary buckwheat leaves (TBL), and effect of fermentation time on antioxidant ability and chemical compositions was revealed. Antioxidant ability of TBL showed a three-stage change tendency during fermentation, which was relatively consistent with change in chemical compositions. Rutin and quercetin were identified as remarkable contributors among fermentation. Both total polyphenols, rutin and quercetin was positively being correlated with antioxidant activity of TBL. Results indicated that fermentation time influenced antioxidant activity by altering content of TBL phenolic compounds, which showed a three-stage change law: augmenting at the early stage of fermentation, declining at the medium stage of fermentation, and slightly changing during the last stage. This tendency suggested that fermentation was a potent means to promote antioxidant capacity of agro-food unless fermentation time was controlled. This study may provide a theoretical basis for producing fermented foods with high bioactivity.

Human breast cancer cells exhibit considerable diversity in the methylation status of genomic DNA CpGs that regulate metastatic transcriptome networks. In this study, we identified human Sipa1 promoter-proximal elements that contained a CpG island and demonstrated that the methylation status of the CpG island was inversely correlated with SIPA1 protein expression in cancer cells. 5-Aza-2’-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, promoted the expression of Sipa1 in the MCF7 breast cancer cells with a low level of SIPA1 expression. On the contrary, in MDA-MB-231 breast cancer cells with a high SIPA1-expression level, hypermethylation of the CpG island negatively regulated the transcription of Sipa1. In addition, the epithelial-mesenchymal transition (EMT) was reversed after knocking-down of Sipa1 in MDA-MB-231 cells. However, the EMT was promoted in MCF7 cells with over-expression of SIPA1 or treated with 5-Aza-CdR. Taken together, hypomethylation of the CpG island in Sipa1 promoter-proximal elements could enhance SIPA1 expression in breast cancer cells, which could facilitate EMT of cancer cells, possibly increasing a risk of cancer cell metastasis in patients treated with 5-Aza-CdR.

4136 Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p < 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p < 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 > 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.

The phytochemical investigation of Abies chensiensis led to the isolation and identification of nine new compounds including eight triterpenoids (1-8) and a new abietane-type diterpene (9), along with three known compounds (10-12). The absolute configuration of 9 was assigned by X-ray diffraction analysis. Compounds 1-11 were evaluated for the anti-inflammatory activity. Among the tested compounds, 1, 2, 5 and 6 exhibited potent inhibitory activity with IC50 values of 15.97, 18.73, 20.18 and 10.97μM, respectively.

The development of upper tract urothelial carcinoma (UTUC) has been associated with the ingestion of aristolochic acid (AA) in Chinese herbs. The tumors are more malignant and patients have a worse prognosis in China compared with that in Western countries. Recently, whole-genome and exome sequencing of AA-associated UTUCs found that the most frequently mutated gene was lysine demethylase 6A (KDM6A). However, its biological role and clinical significance have not yet been defined in patients with UTUC in China. A total of 108 surgically resected UTUC samples were obtained. Using immunohistochemistry, the protein expression level of KDM6A in the tumors was investigated together with the clinical and pathological characteristics of the patients, including survival times. In the present study, the expression level of KDM6A was significantly lower in UTUC specimens compared with that in samples from the normal urothelium. Lower KDM6A expression was also found to be significantly associated with a higher tumor grade and shorter cancer-specific and disease-free survival times (P=0.023 and P=0.033, respectively). In addition, using immunohistochemical analysis, no positive association was found between KDM6A expression and the expression of H3K27me3 or histone-lysine N-methyltransferase EZH2, a histone methyltransferase that generates H3K27me3. The results of the present study indicated that decreased KDM6A expression level was significantly associated with tumor grade and decreased survival time in UTUC, suggesting that KDM6A expression could be used as a prognostic marker in patients with UTUC in China.

We aimed to determine whether pretherapeutic assessment of HPV circulating tumoral DNA (HPV ctDNA) by droplet-based digital PCR (ddPCR) could constitute a predictive and prognostic biomarker for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). A mono-institutional prospective biomarker study on 66 patients with p16+/HPV16-positive oropharyngeal squamous cell carcinoma (OPSCC) was conducted in European Georges Pompidou Hospital, Paris, France. Blood samples were collected at the time of diagnosis before any treatment. Optimized digital PCR assays were used to quantify HPV16 ctDNA. Forty-seven (71%) patients showed a positive pretherapeutic HPV ctDNA at time of diagnosis. Interestingly, the quantity of HPV16 ctDNA at baseline, as assessed by ddPCR, was significantly correlated with the T/N/M status or OPSCC stages according to the 2018 new staging criteria for high-risk human papillomavirus (HR HPV) related OPSCC from American Joint Committee on Cancer (AJCC). Moreover, all recurrences and the majority (83%) of death reported events occurred in patients with positive HPV16 ctDNA at baseline. Finally, when posttreatment blood samples were available (n = 6), the kinetic of pretreatment/posttreatment HPV16 ctDNA was clearly associated with treatment success or failure. HPV ctDNA monitoring by ddPCR could constitute a useful and noninvasive dynamic biomarker to select HR HPV-related OPSCC patients eligible for potential treatment de-escalation and to monitor treatment response.

GATA binding protein 3 (GATA3) and mismatch repair (MMR) deficiency contribute to the development of urothelial carcinoma. However, the combined expression of GATA3 and microsatellite instability (MSI) in upper tract urothelial carcinoma (UTUC) and its prognostic value have not been investigated. Here, we immunohistochemically stained GATA3 and MMR proteins in 108 UTUC samples. GATA3 was positive in 74 cases, and its expression was significantly lower than in adjacent benign urothelium (P < 0.001). Loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters, such as advanced stage, lymphovascular invasion, neural invasion, lymph node metastasis, and extensive necrosis. Cancer-specific survival (CSS, P = 0.028) and disease-free survival (DFS, P = 0.024) were significantly shorter in patients with GATA3 negative tumors than in patients with GATA3 positive tumors. The absence of MMR proteins was observed in 8.3% of the cases, and focal staining was identified in 13.0%. When using “lax criteria” which resulted in counting cases as negative where MMR staining was in fact focally positive (< 5%), we found that GATA3 was inversely associated with MSI (P = 0.005). Moreover, GATA3−/microsatellite stability (MS) tumors were correlated with advanced pT stage (P < 0.001) and poor outcome (P = 0.019 for CSS, P = 0.016 for DFS) compared with GATA3+/ MSI ones. The GATA3−/MSI cases had unfavorable clinical outcomes compared with GATA3+/MSI cases (P = 0.008 for CSS, P = 0.023 for DFS). This finding raises a question as to whether GATA3 interacts with MSI through the TGF-β signaling pathway and regulates UTUC progression.

International audience; Early detection of cancers through the analysis of ctDNA could have a significant impact on morbidity and mortality of cancer patients. However, using ctDNA for early cancer diagnosis is challenging partly due to the low amount of tumor DNA released in the circulation and its dilution within DNA originating from non-tumor cells. Development of new technologies such as droplet-based digital PCR (ddPCR) or optimized next generation sequencing (NGS) has greatly improved the sensitivity, specificity and precision for the detection of rare sequences. Areas covered: This paper will focus on the potential application of ddPCR and optimized NGS to detect ctDNA for detection of cancer recurrence and minimal residual disease as well as early diagnosis of cancer patients. Expert commentary: Compared to tumor tissue biopsies, blood-based ctDNA analyses are minimally invasive and accessible for regular follow-up of cancer patients. They are also described as a better picture of patients' pathology allowing to highlight both tumor heterogeneity and multiple tumor sites. After a brief introduction on the application of the follow-up of ctDNA using genetic or epigenetic biomarkers for prognosis and surveillance of cancer patients, potential perspectives of using ctDNA for early diagnosis of cancers will be presented.

Objective This study aimed to explore the relationship between urinary metabolites and clinical chemotherapy response in breast cancer by CE-MS coupled with on-line concentration. Design and methods Urine samples were obtained from patients with advanced or locally advanced breast cancer (n = 21) before and after chemotherapy and healthy volunteers (n = 21). A rapid and sensitive hexadimethrine bromide-coating CE-MS method coupled with normal stacking is developed for the determination of organic acids in human urine. Another CE-MS method coupled with pH-mediated sample stacking is used for the analysis of amino acids and organic acids. Results After receiving chemotherapy, chemotherapy-sensitive patients showed 30% change in metabolite levels compared to healthy people, while chemotherapy-insensitive patients showed only 9% change in metabolite levels compared to healthy people showing recurrence. The extent of energy insufficiency for chemotherapy-insensitive patients was greater than that for chemotherapy-sensitive patients. Conclusions Urinary metabolic products may be new potential predictive markers for therapy efficacy. However, more studies with a larger sample size are required to confirm these conclusions.

Objective To investigate the expression of survivin gene among human normal endometrium, atypical hyperplasia of endometrium, and endometrial carcinoma. Methods Tissue samples of human normal endometrium during proliferative phase (NE, n=20), atypical hyperplasia of endometrium (AHE, n=11), and endometrial carcinoma (EC, n=9) were collected. Besides, Paraffin embedded sections of NE (n=20), AHE (n=20), and EC (n=20) were used. The expression of survivin gene was determined by immunohistochemistry and the real-time reverse transcription polymerase chain reaction. Results Survivin immunostaining appeared in the cytoplasm of endometrial epithelial cells. Both survivin staining and mRNA had higher levels in AHE or EC than those in NE (P 0.05). Conclusion High expression of survivin gene in human endometrium is associated with the risk of atypical hyperplasia progressing to endometrial carcinoma. The high level of survivin expression is useful as a predictive indicator for endometrial carcinoma.

Visfatin is a newly identified adipocytokine and recent studies indicated that visfatin may have potential proinflammatory effect. However, its pathophysiological role in the metabolic syndrome (MetS) is not fully understood. In this study we investigated whether serum visfatin levels is altered in patients with the MetS, and compared the levels of visfatin between patients with and without carotid plaques.A total of 139 patients with MetS and 105 controls were included. The patients were further divided into two groups: 40 with carotid plaques and 99 without carotid plaques. Serum visfatin was measured by using enzyme immunoassay method and carotid intimal-media thickness (IMT) was measured by ultrasound in all subjects.Serum visfatin was elevated in both MetS patients with and without carotid plaques compared to controls (log visfatin: 1.14 +/- 0.14 vs. 0.99 +/- 0.17 ng/ml vs. 0.93 +/- 0.23 ng/ml, P0.001 and P0.05 vs. control group, respectively), and in patients with carotid plaques more than in patients without carotid plaques (P0.001). Multiple stepwise regression analysis revealed that only LDL-cholesterol correlated with visfatin, and visfatin independently correlated with max IMT in the patients with MetS. A log visfatin1.08 ng/ml had 70% sensitivity and 67% specificity for detecting patients with carotid plaques.Our results showed that serum visfatin was increased in patients with MetS, especially in those with carotid plaques. Visfatin may be an inflammatory marker of MetS.

Aims. This study aimed to examine the use of a free hotline service for breastfeeding mothers in Taiwan. Specific attention was given to the accumulated consultation time and to investigate the trends and reasons that prompted people to contact the service. Background. Breastfeeding can be a difficult time for mothers, especially during the first two weeks after birth. It has been suggested that a telephone hotline service may be helpful for breastfeeding mothers. Design. In this quantitative study data, including the demographic data and the problems of consultations, were gathered from callers during August 2003 to August 2005. Results. Of the 2445 callers, 935 made subsequent calls (38·2%). Approximately 25·25 calls were answered each day by two specially-trained staff according to an answering book. The mean consultation time for single first-call was 21·82 minutes and for one subsequent-call was 15·87 minutes. Perceived insufficient milk supply (30%) and returning to work (21%) were the top two reasons for a first-call. If callers’ problems were about babies’ sickness, perceived insufficient milk supply, babies’ body weight gain and supplement issues, the accumulated consultation time would last longer. More than half (53·3%; 1303/2445) of callers made the first-call during the first month after birth, followed by 23·2% (566/2445) during babies’ age between one and three months old. Conclusion. The telephone hotline service for breastfeeding mothers in Taiwan was well used during the two year period of this study. Many mothers used the service repeatedly for a variety of reasons. Relevance to clinical practice. Recommendations for breastfeeding support strategies for the professionals include category of common breastfeeding problems by different stages after birth. This study supports the establishment of free hotline services may encourage greater empowerment in breastfeeding mothers. Future studies are required to examine client satisfaction of the telephone service.

To evaluate the effects of YC-1 on leukemia cell lines, PI incorporation was used to determine cell viability. YC-1 induced a dose- and time-dependent decrease in viability and apoptosis in YC-1-treated U937 cells. YC-1-induced apoptosis is a cyclic guanosine monophosphate (cGMP)-independent pathway. Proteomic analysis showed that the altered proteins include the significant regulation of HSP70, chaperonin, ATP synthase beta chains, and Chain F. Western blotting and immuno-cytochemistry stain showed that YC-1 treatment caused a time-dependent increase in cytosolic Cytochrome c, pro-caspase-9, Apaf-1, and the activation of caspase-9 and -3. Importantly, the in vivo antileukemia effects of YC-1 were evaluated in BALB/c mice inoculated with WEHI-3B orthotopic model. YC-1 enhanced survival rate and prevented the body weight loss in leukemia mice. The enlargement of spleen and lymph nodes were reduced in YC-1 treated than that in leukemia mice. H-E stain of spleen sections revealed that infiltration of immature myeloblastic cells into red pulp was reduced in YC-1-treated group. The apoptotic cells of splenocyte were significantly increased in YC-1 treated than that in leukemia mice by Tdt-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. Taken together, we conclude that YC-1 acted against U937 cells in vitro via a mitochondrial-dependent apoptosis pathway, and in orthotopic leukemia model, YC-1 administered antileukemia activity.

The research aimed to investigate the effectiveness of cupping therapy (CT) in changes on skin surface temperature (SST) for relieving chronic neck and shoulder pain (NSP) among community residents. A single-blind experimental design constituted of sixty subjects with self-perceived NSP. The subjects were randomly allocated to two groups. The cupping group received CT at SI 15, GB 21, and LI 15 acupuncture points, and the control group received no intervention. Pain was assessed using the SST, visual analog scale (VAS), and blood pressure (BP). The main results were SST of GB 21 acupuncture point raised from 30.6°C to 32.7°C and from 30.7°C to 30.6°C in the control group. Neck pain intensity (NPI) severity scores were reduced from 9.7 to 3.6 in the cupping group and from 9.7 to 9.5 in the control group. The SST and NPI differences between the groups were statistically significant (P < 0.001). One treatment of CT is shown to increase SST. In conjunction with the physiological effect the subjective experience of NSP is reduced in intensity. Further studies are required to improve the understanding and potential long-term effects of CT.

One of the most common head and neck cancers is laryngeal squamous cell carcinoma (LSCC). LSCC exhibits high mortality rates and has a poor prognosis. The molecular mechanisms leading to the development and progression of LSCC are not entirely clear despite genetic and therapeutic advances and increased survival rates. In this study, a total of 116 differentially expressed genes (DEGs), including 11 upregulated genes and 105 downregulated genes, were screened from LSCC samples and compared with adjacent noncancerous. Statistically significant differences (log 2-fold difference > 0.5 and adjusted P-value

Objective This study evaluates the thermographic changes associated with moxa burner moxibustion at the SP6 acupuncture point to establish an appropriate, safe distance of efficacy for moxibustion. Methods Baseline temperature changes using a moxa burner were obtained for a paper substrate at various distances and times, and the tested with volunteers in a pilot study. A single-group trial was then conducted with 36 healthy women to monitor temperature changes on the body surface at the acupuncture point (SP6). Results Based on the temperature changes seen for the paper substrate and in the pilot study, a distance of 3 cm was chosen as the intervention distance. Moxibustion significantly increased the SP6 point skin surface temperature, with a peak increase of 11°C at 4 min (p Conclusions We determined 3 cm was a safe distance between the moxa burner and acupuncture point. Moxibustion can increase the skin surface temperature at the SP6 point. This data will aid traditional Chinese medicine (TCM) practitioners in gauging safer treatment distances when using moxibustion treatments.

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL.

Background PMS2 expression loss was reported in a variety of human. However, its importance has not been fully understood in cervical carcinoma. The aim of this study was to determine the expression of PMS2 in cervical carcinoma and evaluate the significance of mismatch repair gene PMS2 regulated by glycogen synthase kinase 3β (GSK-3β) in chemosensitivity. Methods We examined PMS2 and phosphorylated GSK-3β(s9) expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we detected PMS2 expression in HeLa cells and evaluate the interaction with GSK-3β after transfection with GSK-3β by small interference RNA (siRNA), co-immunoprecipitation and immunoblotting. We also evaluated the effect of PMS2 transfection on HeLa cells' chemosensitivity to cisplatin treatment. Results We found significant downregulation of PMS2 in cervical carcinoma, which was negatively associated with phosphorylated GSK-3β (s9). Furthermore, we demonstrated GSK-3β transfection was able to interact with PMS2 and enhance PMS2 production in HeLa cells, and increased PMS2 production was responsible for enhanced chemosensitivity. Conclusions Our results provide the evidence that stabilization of PMS2 production by GSK-3β was important to improve chemosensitization, indicating the significance of GSK-3β-related PMS2 downregulation in the development of cervical carcinoma and in developing a potential strategy for chemotherapy.

BACKGROUND The Internet is rapidly becoming an accepted standard for disseminating and obtaining health information. However, health information presented on the Web frequently is neither tailored to patients' characteristics nor theoretically driven. This study used Prochaska's transtheoretical model to guide the design and evaluation of a tailored Web-based mammography educational program. PURPOSE This study used a pretest-posttest design to examine the impact of a tailored Web-based educational intervention on women's perceptions of and intentions to obtain a mammography. We hypothesized that a complete tailored intervention (CTI) would result in a significantly higher score than that of tailored message intervention (TMI) in terms of women's perceptions of mammography and intentions to receive a mammography. Both TMI and CTI have been found to have significantly higher scores in terms of women's perceptions of mammography and intentions to receive a mammography than those of the standard intervention (SI). METHODS One hundred eighty-five women were assigned randomly to one of three groups: CTI (n = 61), TMI (n = 63), or SI (n = 61). Online questionnaires were completed by participants at baseline and after completion of intervention. RESULTS Study results supported the hypothesis of perceptions of mammography. The CTI group had significantly higher scores on intention to obtain a mammogram than those of the SI group. However, the differences between CTI and TMI groups and between TMI and SI groups were not significant. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE Results of the study validated the importance of utilizing theory for tailored intervention design to enhance individuals' positive perceptions of health behaviors. Additional studies should consider the effect of various processes and activities on women at different stages of acceptance of the need to obtain a mammogram to further determine outcomes and apply such to mammography screening behavior.

Objective To investigate the root canal curvature of permanent anterior teeth from Chuang population. Methods 245 anterior teeth from Chuang population were collected and examined by X-ray radiography both from labiolingual and mesiodistal directions. For 218 type I anterior teeth, degree of root canal curvature, radius of curvature and length of the curved part of root canal were measured by a special electronic vernier caliper according to Schneider's and Schafer's method and the data obtained were analyzed. Results Root canals of anterior teeth from Chuang population were mainly of type I. The number of type II, III, IV were about 13 in mandibular central and 12 in mandibular lateral incisors. The incidence of curvature in maxillary central incisors, lateral incisors, canines and mandibular central incisors, lateral incisors, canines were 40%, 80%, 77%, 65%, 66%, 73% in mesiodistal directions, 62%, 69%, 70%, 62%, 41%, 61% in labiolingual directions respectively. The most curvature was moderate and happened in apical third. The heaviest curvature occurred in maxillary canines in mesiodistal direction and mandibular canines in labiolingual direction. The shortest radius and length of curvature occurred in maxillary lateral incisors. Conclusion Root canal curvature of anterior tooth in Guangxi Chuang population is complex. The incidence of type II, III, IV is high in mandibular incisors.

SPA-1 (signal-induced proliferation associated gene-1) functions as a suppressor of myeloid leukemia by negatively regulating Rap1 signaling in hematopoietic progenitor cells (HPCs). Herein, we showed that transplantation of HPCs expressing farnesylated C3G (C3G-F), a Rap1 guanine nucleotide exchange factor, resulted in a marked expansion of thymocytes bearing unique phenotypes (CD4/CD8 double positive [DP] CD3(-) TCRbeta(-)) in irradiated recipients. SPA-1(-/-) HPCs expressing C3G-F caused a more extensive expansion of DP thymocytes, resulting in lethal T-cell acute lymphoblastic leukemia (T-ALL) with massive invasion of clonal T-cell blasts into vital organs. The C3G-F(+) blastic thymocytes exhibited constitutive Rap1 activation and markedly enhanced expression of Notch1, 3 as well as the target genes, Hes1, pTalpha, and c-Myc. All the T-ALL cell lines from C3G-F(+) SPA-1(-/-) HPC recipients expressed high levels of Notch1 with characteristic mutations resulting in the C-terminal truncation. This proliferation was inhibited completely in the presence of a gamma-secretase inhibitor. Transplantation of Rag2(-/-) SPA-1(-/-) HPCs expressing C3G-F also resulted in a marked expansion and transformation of DP thymocytes. The results suggested that deregulated constitutive Rap1 activation caused abnormal expansion of DP thymocytes, bypassing the pre-T-cell receptor and eventually leading to Notch1 mutations and Notch-dependent T-ALL.

Uterine leiomyomas were shown to be clonal lesions, but the relationship among different tumor nodules in multiple uterine leiomyomas remains unresolved. In this study, X-chromosomal inactivation patterns of these tumor nodules were shown by allelic polymorphism analysis through polymerase-chain reaction at the phosphoglycerate kinase and androgen receptor loci following pretreatment with the methylation-sensitive restriction enzyme HpaII or HhaI. A total number of 113 cases of uterine leiomyomas were examined. Monoclonality was demonstrated in all of the 315 nodules from 76 informative cases. The inter-nodular relationship was evaluated in 55 multiple cases with 294 tumor nodules. Different inactivation patterns were observed in 20 cases, demonstrating a multicentric origin, while an identical inactivated allele was found in all or most of the nodules in the rest of the cases, indicating a common clonal origin. The occurrence of the unicentric cases appeared to be associated with an elevated mitotic activity. Seven nodules from a multi-nodular case with a morphology indicative of mitotically active leiomyoma were shown to carry the identical inactivated allele, which demonstrates their unicellular origin and malignant nature. In addition, the same androgen receptor gene alteration was identified in two discrete leiomyoma nodules from a uterus. These results approve the monoclonality of uterine leiomyomas and demonstrate the presence of unicentric multiple leiomyomas.

We previously reported that the mice deficient for SPA-1, a Rap1 GTPase-activating protein, developed hematopoietic stem cell disorders. Here, we demonstrate that SPA-1(-/-) mice show an age-dependent increase in B220(high) B1a cells producing anti-dsDNA antibody and lupus-like nephritis. SPA-1(-/-) peritoneal B1 cells revealed the altered Vkappa gene repertoire, including skewed Vkappa4 usage and the significant Igkappa/Iglambda isotype inclusion indicative of extensive receptor editing. Rap1GTP induced OcaB gene activation via p38MAPK-dependent Creb phosphorylation, and consistently, SPA-1(-/-) immature BM B cells showing high Rap1GTP exhibited the augmented expression of OcaB and Vkappa4 genes. SPA-1(-/-) BM cells could transfer the autoimmunity in association with the generation of peritoneal B220(high) B1a cells in Rag-2(-/-) recipients. Finally, a portion of SPA-1(-/-) mice developed B1 cell leukemia with hemolytic autoantibody. Present results suggest that the regulated Rap1 signal in the immature B cells plays a role in modifying the B cell receptor repertoire and in maintaining the self-tolerance.

Increased risk due to nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been observed in patients. Although diaphragm-like stricture in the small bowel and colon induced by NSAIDs therapy has been rarely reported, gastric body diaphragm-like stricture has not been reported. We describe the first case of gastric body diaphragm-like stricture due to NSAIDs in a 44-year-old male patient who was successfully treated by an endoscopic approach to avoid complicated surgery. This case highlights new insight into the disadvantages of NSAIDs and provides new data for future clinical studies.

AIM:To establish an assay for detecting serum hepatitis B virus (HBV) transcripts including the full-length (fRNA) and truncated RNA molecules (trRNA) in chronic HBV carriers, and to investigate its clinical significance. METHODS:The serum viral nucleic acids were analyzed using PCR and RT-PCR targeted to the HBV x protein-encoding region. Reaction specificity was confirmed by Southern blotting. Representative amplification products were cloned and sequenced. RESULTS:Different viral transcripts including fRNA and trRNA were identified in sera of HBV carriers. Presence of fRNA was closely correlated with seropositivity of hepatitis B e antigen and viral DNA. However, trRNA did not depend on serum e antigen, its association with circulating viral DNA was weak. Similarly, no remarkable correlation was ob-served between the levels of trRNA and the degrees of liver damage. Different age-dependent representations for fRNA and trRNA were recognized, fRNA was progressively decreased to undetectable levels and trRNA increased to high levels in the second decade of life and then remained in high level in the rest of life.The trRNA and RNA without polyadenylation at either of the two addition sites were detected even in the absence of any other conventional HBV markers such as viral DNA. They were also observed in sera from patients with cryptogenic cirrhosis or chronic hepatitis C. CONCLUSION:The viral transcripts are potential serum markers for identifying replicative and non-replicative infection stages and diagnosis of occult HBV infection.

Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.