A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia.

BACKGROUND: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing's syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20-50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene. CASE PRESENTATION: A 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation. CONCLUSIONS: In conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.

Nasopharyngeal Swabs Are More Sensitive Than Oropharyngeal Swabs for COVID-19 Diagnosis and Monitoring the SARS-CoV-2 Load.

Objective: Detection of SARS-CoV-2 by oropharyngeal swabs (OPS) and nasopharyngeal swabs (NPS) is an essential method for coronavirus disease 2019 (COVID-19) management. It is not clear how detection rate, sensitivity, and the risk of exposure for medical providers differ in two sampling methods. Methods: In this prospective study, 120 paired NPS and OPS specimens were collected from 120 inpatients with confirmed COVID-19. SARS-CoV-2 nucleic acid in swabs were detected by real-time RT-PCR. The SARS-CoV-2 detection rate, sensitivity, and viral load were analyzed with regards NPS and OPS. Sampling discomfort reported by patients was evaluated. Results: The SARS-CoV-2 detection rate was significantly higher for NPS [46.7% (56/120)] than OPS [10.0% (12/120)] (P < 0.001). The sensitivity of NPS was also significantly higher than that of OPS (P < 0.001). At the time of sampling, the time of detectable SARS-CoV-2 had a longer median duration (25.0 vs. 20.5 days, respectively) and a longer maximum duration (41 vs. 39 days, respectively) in NPS than OPS. The mean cycle threshold (Ct) value of NPS (37.8, 95% CI: 37.0-38.6) was significantly lower than that of OPS (39.4, 95% CI: 38.9-39.8) by 1.6 (95% CI 1.0-2.2, P < 0.001), indicating that the SARS-CoV-2 load was significantly higher in NPS specimens than OPS. Patient discomfort was low in both sampling methods. During NPS sampling, patients were significantly less likely to have nausea and vomit. Conclusions: NPS had significantly higher SARS-CoV-2 detection rate, sensitivity, and viral load than OPS. NPS could reduce droplets production during swabs. NPS should be recommended for diagnosing COVID-19 and monitoring SARS-CoV-2 load. Chinese Clinical Trial Registry, number: ChiCTR2000029883.

Stepwise neoadjuvant chemoradiotherapy in the management of mid-low locally advanced rectal cancer.

BACKGROUND: This study aimed to compare the treatment response, complications and prognosis in mid-low locally advanced rectal cancer (LARC) patients who underwent stepwise neoadjuvant chemoradiotherapy (SCRT) or traditional neoadjuvant chemoradiotherapy (CRT). METHODS: The medical records of patients with mid-low rectal cancer who underwent SCRT or CRT were retrospectively analyzed. Differences in the treatment response, pathologic complete response (pCR), R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation, defunctioning stoma, treatment-emergent adverse events (TEAEs), overall survival (OS) and disease-free survival (DFS) between patients who underwent SCRT and CRT were compared. RESULTS: A total of 430 medical records were investigated, including 194 patients in the SCRT group and 236 patients in the CRT group. There was no significant difference in the rates of treatment response, pCR, R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation or TEAEs between the two groups. However, the rate of defunctioning stoma in the SCRT group was significantly lower than that in the CRT group (20.1% vs. 44.1%, respectively, P < 0.01). Moreover, the median OS time of the SCRT and CRT groups was 44.0 and 50.5 months, respectively (P = 0.17). The median DFS time of the SCRT and CRT groups was 41.0 and 46.8 months, respectively (P = 0.32). CONCLUSION: Compared with the CRT group, the SCRT group had a similar treatment response, local control and long-term prognosis, and more importantly, a portion of the patients in the SCRT group were exempted from excessive radiation.

[Accordion operation for the bone transport in treating tibial bone defect].

OBJECTIVE: To discuss clinical outcomes of accordion operation for the Ilizarov technique in treating tibial bone defects. METHODS: From January 2014 to June 2016, 22 patients with tibial bone defects were treated by Ilizarov bone-transport technique, including 19 males and 3 females with an average age of 44.04 years old ranging from 23 to 60 years old;the length of the bone defects before the bone transport was 5 to 11 cm with an average 7.68 cm; Cause of injury invlved traffic accidents in 14 cases, fall injury in 3, smashing injury in 4, high drop injury in 1; 6 cases were on the left and 16 cases were on the right. The patients were divided into two groups: 11 cases in accordion group were treated by "accordion operation" after bone transport was completed;11 cases in control group were treated by the external fixator locked waiting for bone consolidation after bone transport was completed. All patients were followed up for 18 to 36 months with an average time of 27.9 months. There was no statistical significance between two groups, such as sex, age, length of bone defect(P>0.05). Analysis of healing time, healing index and other indicators, and Paley's criterion was used to evaluate the healing effect of bone healing and function recovery of the limb. RESULTS: The result of X-ray evaluation was all patients achieved bone healing. In accordion group, the bone healing time was (365±91) days, the bone healing index was (46.2±3.5) d/cm; in control group, the bone healing time was(435±108) days, the bone healing index was (57.8±3.5) d/cm. There was no statistical significance in the bone healing time between the two groups(t=1.648, P=0.115);There was statistical significance in the bone healing index between the two groups(t=7.754, P=0.000). At the final follow-up, according to Paley's criterion, the result in accordion group was excellent in 9 cases, good in 2 cases; in control group, excellent in 8 cases, good in 3 cases. Score was not statistically significant(z=-0.479, P=0.619). Complications involved nail infection (9 cases in accordion group, 10 cases in control group);local traction pain (2 cases in accordion group, 1 case in control group); axial malalignment>10°(4 cases in accordion group, 3 cases in control group);location difference of the junction of bone defects (3 cases in accordion group, 2 cases in control group);Complications were not statistically significant(P>0.05). CONCLUSIONS: Accordion operation for the Ilizarov technique in treating tibial bone defects can shorten the treatment time and consolidation time, and improve the healing index.

Numerical study on the lubrication performance of compression ring-cylinder liner system with spherical dimples.

The effects of surface texture on the lubrication performance of a compression ring-cylinder liner system are studied in this paper. By considering the surface roughness of the compression ring and cylinder liner, a mixed lubrication model is presented to investigate the tribological behaviors of a barrel-shaped compression ring-cylinder liner system with spherical dimples on the liner. In order to determine the rupture and reformulation positions of fluid film accurately, the Jacoboson-Floberg-Olsson (JFO) cavitation boundary condition is applied to the mixed lubrication model for ensuring the mass-conservative law. On this basis, the minimum oil film thickness and average friction forces in the compression ring-cylinder liner system are investigated under the engine-like conditions by changing the dimple area density, radius, and depth. The wear load, average friction forces, and power loss of the compression ring-cylinder liner system with and without dimples are also compared for different compression ring face profiles. The results show that the spherical dimples can produce a larger reduction of friction in mixed lubrication region, and reduce power loss significantly in the middle of the strokes. In addition, higher reduction percentages of average friction forces and wear are obtained for smaller crown height or larger axial width.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway (AU)

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Meta-analysis Reveals the Prognostic Value of Circulating Tumour Cells Detected in the Peripheral Blood in Patients with Non-Metastatic Colorectal Cancer.

Detecting circulating tumour cells (CTCs) is considered as effective and minimally invasive technique to predict the prognosis of patients with metastatic colorectal cancer (CRC), but its clinical validity is still conflicting in patients without metastasis. We performed this meta-analysis to evaluate whether detection of CTCs in the peripheral blood can be used as a prognostic marker for patients with non-metastatic CRC. We performed a comprehensive search of the EMBASE, PubMed, and Web of Science databases (up to September 2016). Meta-analyses were conducted using a random-effects model with the hazard ratio (HR) and 95% confidence interval (95% CI) as the effect measures. Twenty studies including 3,687 patients were eligible for inclusion. Overall analyses demonstrated that the presence of CTCs was significantly associated with aggressive disease progression (HR = 2.57, 95% CI = 1.64-4.02, P heterogeneity < 0.001, I 2 = 81.0%) and reduced disease survival (HR = 2.41, 95% CI = 1.66-3.51, P heterogeneity = 0.002, I 2 = 59.7%). Subgroup analyses further supported the prognostic effect of CTCs based on different subsets, including sampling time, detection method and cancer type. Our findings suggest that detection of CTCs in the peripheral blood has the clinical utility to indicate poor prognosis in patients with non-metastatic CRC.

Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways.

The effects of Bone morphogenetic protein 2 (BMP-2) on the angiogenesis of hepatocellular carcinoma have not yet been observed and its molecular mechanisms is not clear. We first constructed the recombinant lentivirus vectors expressing small hairpin RNA against BMP-2 gene (LV-SH-BMP2) and the recombinant lentivirus vectors over-expressing BMP-2 (overexpression-LV-BMP2), and then the two recombinant lentivirus vectors were respectively transfected into Hep G2 cells. The Hep G2 cells transfected with LV-SH-BMP2 or overexpression-LV-BMP2 were respectively co-cultured with human umbilical vein endothelial cells (HUVECs) to observe the effects of BMP-2 on HUVECs. The effect of BMP-2 on tumor microvessel density (MVD) was examined. The abilities of proliferation, migration and angiogenesis were significantly inhibited in the HUVECs co-cultured with BMP-2 knockdown Hep G2 (all P < 0.05), but significantly enhanced in the HUVECs co-cultured with BMP-2 overexpression Hep G2 (all P < 0.05). MVD was significantly increased in overexpression-LV-BMP2-transfected Hep G2 tumor, but decreased in LV-SH-BMP2-transfected Hep G2 tumors. The protein expressions of VEGF, p-P38, p-ERK, p-AKT, p-m-TOR were significantly increased after BMP-2 over-expression, or significantly decreased after BMP-2 knockdown (all P < 0.05). These results reveal that BMP-2 can enhance HUVEC proliferation, migration and angiogenesis through P38, ERK and Akt/m-TOR pathway.

Design and Hardware Implementation of a New Chaotic Secure Communication Technique.

In this paper, a scheme for chaotic modulation secure communication is proposed based on chaotic synchronization of an improved Lorenz system. For the first time, the intensity limit and stability of the transmitted signal, the characteristics of broadband and the requirements for accuracy of electronic components are presented by Multisim simulation. In addition, some improvements are made on the measurement method and the proposed experimental circuit in order to facilitate the experiments of chaotic synchronization, chaotic non-synchronization, experiment without signal and experiment with signal. To illustrate the effectiveness of the proposed scheme, some numerical simulations are presented. Then, the proposed chaotic secure communication circuit is implemented through analog electronic circuit, which is characterized by its high accuracy and good robustness.

The significant prognostic value of circulating tumor cells in triple-negative breast cancer: a meta-analysis.

BACKGROUND: The clinical validity of circulating tumor cells (CTCs) is still controversial in patients with triple-negative breast cancer (TNBC). METHODS: A comprehensive literature search was performed to identify relevant articles in the PubMed, Web of Science, MEDLINE, and Embase databases through September 2015. The outcomes of interest were disease progression and overall survival. The hazard ratio (HR) and 95% confidence interval (95% CI) were considered the effect indicators and were pooled in meta-analyses under a fixed- or random-effect model according to heterogeneity. RESULTS: Ten of the eligible studies were included for a total of 642 enrolled TNBC patients. Overall analyses revealed that the presence of CTCs predicted aggressive disease progression (HR = 2.18, 95% CI = 1.59-2.99, Pheterogeneity = 0.010, I2 = 52.2%) and reduced overall survival (HR = 2.02, 95% CI = 1.59-2.57, Pheterogeneity = 0.169, I2 = 26.6%). Further subgroup analyses demonstrated that CTC-positive patients also had poor disease progression and overall survival in different subsets, including cancer stage. CONCLUSIONS: Our meta-analysis provides strong evidence that detection of CTC in the peripheral blood is an independent prognosticator of poor survival outcomes for TNBC patients.

Genetic variant in CLPTM1L confers reduced risk of lung cancer: a replication study in Chinese and a meta-analysis.

BACKGROUND: Rs31489 in the cleft lip and palate transmembrane1-like gene (CLPTM1L) has been identified to be associated with lung cancer through genome-wide association studies (GWAS). However, some recent replication studies yielded inconclusive results. Thus, we undertook this study to investigate the precise effect of rs31489 on lung cancer susceptibility. MATERIALS AND METHODS: A hospital-based case-control study in 1,673 Chinese subjects (611 individuals with lung cancer and 1,062 controls) and a meta-analysis among 32,199 subjects (16,364 cases and 15,835 controls) were performed in this study. RESULTS: In our case-control study, rs31489 was inversely associated with lung cancer (AC versus CC: OR=0.68, 95%CI=0.52-0.88; additive model: OR=0.68, 95%CI=0.54-0.85; dominant model: OR=0.65, 95%CI =0.51-0.84). Stratification analysis by smoking status showed a significant association and strong genetic effect in non-smokers but not in smokers. Our meta- analysis further confirmed the association, although with significant heterogeneity contributed by study design and source of controls, as shown by stratified analysis. Sensitive and cumulative analyses both indicated robust stability of our results. In addition, there was no observable publication bias in our meta-analysis. CONCLUSIONS: Overall, the findings from our replication study and meta-analysis demonstrated that CLPTM1L gene rs31489 is significantly associated with lung cancer.

P21 (waf1/cip1) is required for non-small cell lung cancer sensitive to Gefitinib treatment.

Lung cancer is the leading cause of death from cancer in the world. Gefitinib is known to its inhibition of EGFR tyrosine kinase and worldwide used for antitumor in non-small cell lung cancer (NSCLC). Here, we show that Gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities which result in impaired cell cycle progression through G1 arrest only in NSCLC cells in which it inhibits growth. We find that Gefitinib-induced p21 protein stability, rather than increased RNA accumulation, was responsible for the elevated p21 levels. More, treatment of beta-elemene, a natural plant drug extracted from Curcuma wenyujin, restored sensitivity to Gefitinib via the mechanism modulated the elevation of p21 levels in the cells which are acquired resistance to Gefitinib. These data suggest that administration of Gefitinib in combination with beta-elemene may offer great opportunities for NSCLC which are acquired resistance to Gefitinib. The p21 effect on the cells to response to Gefitinib was further confirmed by p21 over-expression and knockdown studies pointing to a requirement of p21 for the cells sensitive to Gefitinib. Thus, we propose that p21 is required for Gefitinib-sensitive NSCLC cells.

PTD4-apoptin protein and dacarbazine show a synergistic antitumor effect on B16-F1 melanoma in vitro and in vivo.

PTD4-apoptin protein enters cells and harbors tumor-selective cell death activity. Dacarbazine is the mainstay of treatment for malignant melanoma. In this study, we investigated the cytotoxic effect of PTD4-apoptin protein and/or dacarbazine in mouse B16-F1 and human A875 and SK-MEL-5 melanoma cells in vitro and by means of a mouse B16-F1 melanoma model in vivo. PTD4-apoptin protein inhibits the growth of B16-F1, A875 and SK-MEL-5 melanoma cells in a dose-dependent manner, but not in normal human cell lines WI-38 and L-02. PTD4-apoptin combined with dacarbazine revealed a synergistic cytotoxic effect (coefficient of drug interaction<1) in all three different tumor cell lines. In vivo, PTD4-apoptin protein and dacarbazine alone effectively inhibited the growth of B16-F1 melanoma in C57BL/6 mice. Strikingly, combined PTD4-apoptin/dacarbazine treatment significantly increased the antitumor effect in comparison to the single treatments. As important, a combined PTD4-apoptin/dacarbazine treatment with a 50% reduction of dacarbazine revealed similar antitumor activities, without detectable hematologic side effects. A combined PTD4-apoptin/dacarbazine treatment represents a promising novel efficient and safe anticancer strategy.

Combined treatment with TNF-alpha/gefitinib alleviates the resistance to gefitinib in PC-9 cells.

Gefitinib has been approved for the treatment of patients with non-small cell lung cancer. However, its efficiency is limited by the development of drug resistance. Additional treatments for cases of non-small cell lung cancer relapsing with treatment with gefitinib are urgently required. To investigate the mechanisms of acquired resistance to gefitinib, we established PC-9-ZD, a human lung cancer cell line resistant to gefitinib after long-term exposure to the drug. PC-9-ZD cells showed more resistance to gefitinib than their parental PC-9 cells. We show that gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities, which result in impaired cell cycle progression through G1 arrest only in parental PC-9 cells, in which it inhibits growth. Our present data suggested that after long-term exposure to gefitinib, the survival of PC-9-ZD cells with heightened levels of p-Akt and reduced levels of p21 resisted further gefitinib-induced inhibition of cell growth. To explore a new strategy to improve the efficacy of gefitinib, we treated the cells with tumor necrosis factor-alpha (TNF-alpha) and found that the cells with acquired resistance to gefitinib showed increasing sensitivity to TNF-alpha, which correlated with the low activation level of nuclear factor (NF)kappaB/p65 in PC-9-ZD cells. TNF-alpha treatment induced an elevated activated NFkappaB/p65, concomitant with induced p21 levels, which resulted in increased sensitivity to gefitinib in PC-9-ZD cells. Consistent with our earlier observation that p21 is induced in an NFkappaB/p65-dependent manner, we conclude that p21 plays an important role in mediating cell growth inhibition by gefitinib. Thus, we proposed that combined treatment with TNF-alpha/gefitinib is an efficient therapeutic strategy for tumors that develop resistance to gefitinib.

TNF-alpha promotes Doxorubicin-induced cell apoptosis and anti-cancer effect through downregulation of p21 in p53-deficient tumor cells.

p53 is a key regulator in cell apoptosis, and cancer cells deficient in p53 expression fail to respond to chemotherapy. Here we show that effective Doxorubicin (DOX)-induced apoptosis is p53-dependent. However, an alternative treatment of DOX/TNF-alpha/DOX restored sensitivity of p53-deficient cells to DOX-induced apoptosis. Treatment of cells with TNF-alpha resulted in a decrease of p21 (waf1/cip1/sdi1) expression following second dose of DOX. In previous work, we demonstrated that p21 suppressed DOX-induced apoptosis via its (cyclin-dependent kinase) CDK-binding and CDK-inhibitory activity. Thus, we propose that TNF-alpha enhances the anti-cancer effect of DOX through suppressing the anti-apoptotic activity of p21, and that a combined treatment TNF-alpha/Dox is an effective chemotherapeutic strategy for p53-deficient cancers.