HSF1 Inhibits Antitumor Immune Activity in Breast Cancer by Suppressing CCL5 to Block CD8+ T-cell Recruitment.

Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that promotes cancer cell malignancy. To provide a better understanding of the biological processes regulated by HSF1, here we developed an HSF1 activity signature (HAS) and found that it was negatively associated with antitumor immune cells in breast tumors. Knockdown of HSF1 decreased breast tumor size and caused an influx of several antitumor immune cells, most notably CD8+ T cells. Depletion of CD8+ T cells rescued the reduction in growth of HSF1-deficient tumors, suggesting HSF1 prevents CD8+ T-cell influx to avoid immune-mediated tumor killing. HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T-cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer. SIGNIFICANCE: The stress-responsive transcription factor HSF1 reduces CD8+ T-cell infiltration in breast tumors to prevent immune-mediated killing, indicating that cellular stress responses affect tumor-immune interactions and that targeting HSF1 could improve immunotherapies.

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation.

The heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activation requires nuclear localization, trimerization, DNA binding, phosphorylation and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, MEK1 and DYRK2. Here, we observed activation of HSF1 by AKT1 independently of mTOR. AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1. Similarly, mTOR, p38, MEK1 and DYRK2 all phosphorylated S326 but AKT1 was the most potent activator. Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. Interestingly, T527 as a phosphorylated residue has not been previously shown and sits in the transactivation domain, further implying a role for this site in HSF1 gene transactivation. This study suggests that HSF1 hyperphosphorylation is targeted and these specific residues have direct function in regulating HSF1 transcriptional activity.

The interplay among ecological footprint, real income, energy consumption, and trade openness in 13 Asian countries.

This article investigates the effects of real income, trade openness, and energy consumption on the ecological footprint using a panel data of 13 Asian countries over the 1973-2014 period. The empirical findings suggest that the panel variance-ratio test confirms the existence of a long-run equilibrium relationship among ecological footprint real income, trade openness, and energy consumption. Results from panel pooled mean group estimates confirm that the long-run elasticity of real income, trade openness, and energy consumption is 0.16, -0.07, and 0.51, respectively. The real income and energy consumption have a positive impact on the ecological footprint. There are three bidirectional causal relationships that were found between ecological footprint and real income; between energy consumption and ecological footprint; and between trade openness and ecological footprint. In addition, three unidirectional causalities can be found: a unidirectional causality running from real income to trade openness; from real income to energy consumption; and from trade openness to energy consumption. Those causal relationships show that economic indicators are highly related to ecological footprint. The findings recommend that various governments should fund more in renewable energy and efficiency upgrade and continue sustaining their growth without hurting the environment.

Industrial water use, income, trade, and employment: environmental Kuznets curve evidence from 17 Taiwanese manufacturing industries.

This paper investigated the relationships between industrial water use, income, trade, and employment for 17 Taiwanese industries from 1998 to 2015. We explored cross-sectional dependent unit root, panel cointegration, and causality tests to estimate their long-term relationships and causal nexus. There existed long-term equilibrium relationships among the variables. The long-term elasticity estimates of industrial water use with respect to income, squared income, trade, and employment are 4.27, - 0.15, 0.22, and 0.92, respectively. The results do not confirm an inverted U-shaped environmental Kuznets curve. A unidirectional causal relationship is found between water use and income, and a bidirectional causal relationship is identified between water use and employment. Exports cause industrial water use. As expected, both employment and exports lead to income. Hence, policy makers should promote investment into water efficiency and water recycling. Various governments reward firms for water efficiency and lower consumption without negative long-term effects on economic growth.

The protocadherin alpha cluster is required for axon extension and myelination in the developing central nervous system.

In adult mammals, axon regeneration after central nervous system injury is very poor, resulting in persistent functional loss. Enhancing the ability of axonal outgrowth may be a potential treatment strategy because mature neurons of the adult central nervous system may retain the intrinsic ability to regrow axons after injury. The protocadherin (Pcdh) clusters are thought to function in neuronal morphogenesis and in the assembly of neural circuitry in the brain. We cultured primary hippocampal neurons from E17.5 Pcdhα deletion (del-α) mouse embryos. After culture for 1 day, axon length was obviously shorter in del-α neurons compared with wild-type neurons. RNA sequencing of hippocampal E17.5 RNA showed that expression levels of BDNF, Fmod, Nrp2, OGN, and Sema3d, which are associated with axon extension, were significantly down-regulated in the absence of the Pcdhα gene cluster. Using transmission electron microscopy, the ratio of myelinated nerve fibers in the axons of del-α hippocampal neurons was significantly decreased; myelin sheaths of P21 Pcdhα-del mice showed lamellar disorder, discrete appearance, and vacuoles. These results indicate that the Pcdhα cluster can promote the growth and myelination of axons in the neurodevelopmental stage.

Greenhouse Gas Emissions, Energy Consumption and Economic Growth: A Panel Cointegration Analysis for 16 Asian Countries.

This research investigates the co-movement and causality relationships between greenhouse gas emissions, energy consumption and economic growth for 16 Asian countries over the period 1990-2012. The empirical findings suggest that in the long run, bidirectional Granger causality between energy consumption, GDP and greenhouse gas emissions and between GDP, greenhouse gas emissions and energy consumption is established. A non-linear, quadratic relationship is revealed between greenhouse gas emissions, energy consumption and economic growth, consistent with the environmental Kuznets curve for these 16 Asian countries and a subsample of the Asian new industrial economy. Short-run relationships are regionally specific across the Asian continent. From the viewpoint of energy policy in Asia, various governments support low-carbon or renewable energy use and are reducing fossil fuel combustion to sustain economic growth, but in some countries, evidence suggests that energy conservation might only be marginal.

Renewable energy, carbon emissions, and economic growth in 24 Asian countries: evidence from panel cointegration analysis.

This article aims to investigate the relationship among renewable energy consumption, carbon dioxide (CO2) emissions, and GDP using panel data for 24 Asian countries between 1990 and 2012. Panel cross-sectional dependence tests and unit root test, which considers cross-sectional dependence across countries, are used to ensure that the empirical results are correct. Using the panel cointegration model, the vector error correction model, and the Granger causality test, this paper finds that a long-run equilibrium exists among renewable energy consumption, carbon emission, and GDP. CO2 emissions have a positive effect on renewable energy consumption in the Philippines, Pakistan, China, Iraq, Yemen, and Saudi Arabia. A 1% increase in GDP will increase renewable energy by 0.64%. Renewable energy is significantly determined by GDP in India, Sri Lanka, the Philippines, Thailand, Turkey, Malaysia, Jordan, United Arab Emirates, Saudi Arabia, and Mongolia. A unidirectional causality runs from GDP to CO2 emissions, and two bidirectional causal relationships were found between CO2 emissions and renewable energy consumption and between renewable energy consumption and GDP. The findings can assist governments in curbing pollution from air pollutants, execute energy conservation policy, and reduce unnecessary wastage of energy.

miR-31 targets ARID1A and enhances the oncogenicity and stemness of head and neck squamous cell carcinoma.

miR-31 is oncogenic for head and neck squamous cell carcinoma (HNSCC). Proteins containing the AT-rich interacting domain (ARID) modulate the accessibility of chromatin to the transcription machinery needed for gene expression. In this study, we showed that miR-31 was able to target ARID1A in HNSCC. HNSCC tumors had an inverse miR-31 and ARID1A expression. miR-31 associated oncogenicities were rescued by ARID1A expression in HNSCC cells. Furthermore, ARID1A repressed the stemness properties and transcriptional activity of Nanog/OCT4/Sox2/EpCAM via the protein's affinity for AT-rich sites within promoters. HNSCC patients with tumors having high level of miR-31 expression and high levels of Nanog/OCT4/Sox2/EpCAM expression, together with low level of ARID1A expression, were found to have the worst survival. This study provides novel mechanistic clues demonstrating that miR-31 inhibits ARID1A and that this enriches the oncogenicity and stemness of HNSCC.

[Occurrence characteristics and molecular genetic basis of pod shattering in soybean].

Pod shattering is a natural property of wild soybean (Glycine soja) for propagation and also a major cause of yield loss in cultivated soybean (Glycine max L. Merr). Thus, studies on occurrence characteristics and molecular genetic basis of pod shattering in soybean can provide insights into both molecular mechanisms and potential application in legume crop improvement. In this review, we summarize the occurrence features and phenotypic identification methods of pod shattering based on analysis of the cellular microstructure of shattering-resistant soybean pod. We also introduced the identification and breeding of shattering-resistant germplasms, the progress of molecular genetic studies on shattering-resistant phenotype in soybean as well as perspectives on future studies of pod-shattering trait and application in crop improvement.

EGF up-regulates miR-31 through the C/EBPß signal cascade in oral carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPß expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPß expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPß, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPß and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPß and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPß expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.

Horseshoe kidney with retrocaval ureter: one case report.

Horseshoe kidney and retrocaval ureter are uncommon congenital anomalies of the genitourinary system that are easily diagnosed by typical imaging features. Both anomalies presenting in one patient is a rare disease characterized by isthmus of horseshoe kidney between the abdominal aorta and inferior vena cava. The clinical diagnosis and treatment of horseshoe kidney with retrocaval ureter remain a challenge. Here, we reported a case of a 44-year-old man with the two anomalies who was preoperatively diagnosed by unenhanced computed tomography scanning immediately after retrograde pyelography. The literatures on such combined anomalies are reviewed and the diagnostic evaluation and surgical management of this rare entity are discussed.

[Influence of the interruption of arteria iliaca interna distal end on penile vascularity and erectile function in male renal transplant recipients].

OBJECTIVE: It is controversial whether unilateral interruption of the arteria iliaca interna distal end affects penile hemodynamics and erectile function. The purpose of this study was to prospectively evaluate this influence by detecting the blood flow of the penile artery before and after renal transplantation. METHODS: Thirty-three patients with chronic renal failure (CRF) on maintenance hemodialysis (MHD) received renal transplantation, the grafts revascularized by end-to-end anastomosis to the right internal iliac artery. Six months before and after the surgery, we obtained the IIEF scores of the patients, recorded their penile blood flow on color Doppler ultrasonography and the levels of serum creatinine, hemoglobin and serum cholesterol, and analyzed post-transplantation immunosuppressive medication. RESULTS: The patients ranged in age from 21 to 55 years, of whom 36% had erectile dysfunction (ED) during MHD, and 33% after renal transplantation. A total of 67% of the renal transplant recipients (RTR) complained of unchanged and 15% deteriorated ED, while 18% admitted improved erectile function. The patients showed a significantly stronger sexual desire after the transplantation than before it (6.2 +/- 1.6 vs 8.9 +/- 0.9, P < 0.01). There was a significant decrease in peak systolic velocity (PSV) in the cavernous arteries after transplantation as compared with pre-transplantation (P < 0.01). Penile arterial blood flow insufficiency was found in none of the RTRs. CONCLUSION: Unilateral interruption of the internal iliac artery decreases penile arterial blood flow, but not to such a degree as to result in ED. Unilateral interruption of the arteria iliaca interna distal end does not affect the erectile function of RTRs.

Rapamycin enhances the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to docetaxel.

BACKGROUND: Docetaxel (DOC) therapy is well tolerated and shows high response rates in patients with hormone refractory prostate cancer (HRPC). There are many reports on the effect of rapamycin (RPM) on the treatment of carcinogenesis. The goal of this study was to test whether RPM could enhance the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to DOC. METHODS: Prostate cancer (PC) cell lines (LNCap, PC3 and AILNCap) were cultured and treated with RPM and DOC alone or in combination. The effects of therapeutic agents on cells were determined by the WST-1 assay. Apoptosis induction was confirmed by flow cytometric analysis. The apopcyto caspase colorimetric assay kit was applied to measure the activities of caspases 3 and 9. The antitumor effects of RPM and DOC against PC cells were also assessed in nude mice using four randomized groups: control, RPM, DOC and combination drug therapy by measuring tumor size. All the animals tolerated both RPM and DOC without significant weight loss. RESULTS: RPM and DOC caused dosage-dependent growth suppression of PC cells. RPM could increase the susceptibility of PC cells to DOC significantly, and combined treatment with RPM and DOC caused synergistic growth suppression in all examined PC cell lines by isobolographic analysis. Both RPM and DOC significantly induced apoptosis in a dosage-dependent manner. RPM (10 nmol/L), DOC (1 nmol/L), and combined treatment induced apoptosis rate were 8%, 17% and 38%, respectively (the control was 2%). RPM could promote the apoptosis induced by DOC in PC cell lines. Both RPM and DOC significantly increased the caspase activity in a dosage-dependent manner. The relative activities of caspase 9 in control, RPM, DOC and RPM + DOC groups were 0.22 +/- 0.02, 0.36 +/- 0.06, 0.47 +/- 0.05 and 0.84 +/- 0.08, respectively. The relative activities of caspase 3 were 0.21 +/- 0.02, 0.24 +/- 0.05, 0.42 +/- 0.06 and 0.81 +/- 0.09, respectively. Either RPM or DOC alone significantly inhibited the growth of PC cells in nude mice compared to the control. The combination of RPM and DOC produced a significant reduction in tumor volume when compared to RPM or DOC alone. After 5-week treatment, the tumor sizes of LNCap in control, RPM, DOC and RPM + DOC groups were (570 +/- 56) mm(3), (412 +/- 41) mm(3), (425 +/- 46) mm(3) and (221 +/- 26) mm(3), respectively. CONCLUSIONS: RPM could significantly increase the susceptibility of both androgen-dependent and -independent PC cells to DOC; the synergy of RPM and DOC was demonstrated. RPM enhanced the DOC-induced upregulation of caspase activity, resulting in an increasing number of cells in sub-G1 phases. The synergy of the combined treatment might be observed in both androgen-dependent and -independent PC cell lines.

[Carcinoma recurrence rates after laparoscopic nephroureterectomy in patients undergoing transurethral incision of the ureteral orifice and open excision of bladder cuff].

OBJECTIVE: To compare the oncologic efficacy of transurethral incision of the ureteral orifice and open excision of bladder cuff in retroperitoneal laparoscopic nephroureterectomy (LNU) for patients with upper tract urothelium carcinoma. METHODS: The hospital records of 86 patients with upper tract urothelium carcinoma who underwent laparoscopic nephroureterectomy were reviewed retrospectively. 53 of the 86 patients, 22 males and 31 females, aged (68.6+/-14.1), underwent transurethral incision of the ureteral orifice (TUIUO), and 33, 14 males and 19 females, aged (72.4+/-15.2), underwent open excision of bladder cuff. Electric cauterization of the ureteral orifice was performed prior to resection. Follow-up was conducted for 28 (3-47) months. RESULTS: In all the specimens in the TUIUO group scar at the ureter orifice caused by electric excision could be seen. Test to check the pressure of distal ureter in 25 specimens proved that the ureters were all sealed. The distal ureter end began to leak at the water pressure of 135 cm in 1 case, at the water pressure of 167 cm in 1 case, and at 175 cm in 2 cases, but no leaking was seen even at 197 cm H2O in the other cases. Recurrence of bladder tumor was seen in 13 of the 53 patients of the TUIUO group and in 8 of the 33 patients of the open excision of bladder cuff group. Local recurrence developed in one case with the tumor at stage pT4N0M0 8 months after operation. CONCLUSION: Electric cauterization of the ureteral orifice prior to resection effectively ensures the leakproofness of the distal ureter end during LNU. As compared with open excision of bladder cuff, TUIUO does not increase the rate of neoplasm recurrence.

Prevalence and influential factors of erectile dysfunction in male renal transplant recipients: a multiple center survey.

BACKGROUND: Renal transplants can improve the quality of life for recipients, but the quality of their sexual life might not be improved. This study was conducted to research the prevalence of erectile dysfunction (ED) and the influential factors in male renal transplant recipients (RTRs). METHODS: A cross-sectional survey was conducted in three renal transplantation centers. Structured questionnaires were administrated by trained interviewers to 824 male renal transplant patients, who had active sexual lives in the last 6 months. RESULTS: Complaints of ED were reported by 75.5% of the 809 RTRs (age range 19 - 75 years, mean age (45 +/- 10) years), whose questionnaires were completed. Mild, moderate and severe ED were reported at 53.6%, 8.3% and 13.6%, respectively. The mean age and the graft duration were significantly higher in male RTRs with ED compared to potent graft recipients (P = 0.00 and 0.04, respectively). The prevalence of ED increased with the increase in age. It was 60.7%, 65.8%, 75.2%, 87.5% and 92.2% in patients with age below 30 years, 31 - 40 years, 41 - 50 years, 51 - 60 years and over 60 years, respectively (P = 0.000). Moreover, the severity of ED increased with aging. The percentage of moderate and severe cases of ED increased from 6.7% in patients below 40 years to 28.9% in those over 40 years (P = 0.000). The prevalence of ED in the RTR who had no occupation was higher than in those who were holding a position (P = 0.001). The prevalence of ED decreased with the increase in the education level. The prevalence of ED was 94.3%, 86.4%, 74.0% and 67.8% in men with elementary school or lower, middle school, high school, and college or higher degrees, respectively (P = 0.000). Patients, whose distal end of arteria iliaca interna was interrupted and underwent iterative transplantation, worried transplanted kidney function was impacted by sexual life, and received cyclosporine (CsA)-based immunosuppressive regimens, were more likely to have ED (P = 0.000, 0.001, 0.000, 0.000, respectively). After Logistic regression analysis, only five factors, age, education level, interruption of arteria iliaca interna distal end, worrying transplanted kidney function impacted by sexual life and CsA-based immunosuppressive regimens sustained their significance. CONCLUSIONS: Renal transplant has varying effects on erectile function. ED is highly prevalent among RTRs and its influential factors are multiple. Age, education level, interruption of arteria iliaca interna distal end, worrying transplanted kidney function impacted by sexual life, CsA-based immunosuppressive regimens are the main influential factors of ED in male RTRs.

[Evaluation of sexual function in men with symptomatic benign prostatic hyperplasia].

OBJECTIVE: To evaluate the degree of sexual dysfunction in an unselected population of men with benign prostatic hyperplasia (BPH) accompanied by lower urinary tract symptoms (LUTS), and to assess the correlation between sexual dysfunction and urinary symptoms and age. METHODS: A total of 88 men with symptomatic BPH were investigated using the International Prostate Symptom Score (IPSS), International Index of Erectile Function-5 (IIEF-5), Brief Sexual Function Inventory (BSFI), and the measurement of urinary flow rate, the total prostatic volume and serum testosterone. Regression analysis was used to determine the correlation among the variables. RESULTS: The mean age of the patients was (67.90 +/- 7.59) years, the mean IPSS score was (18.4 +/- 7. 79), and the mean IIEF-5 was (8.50 +/- 8.98). There were 76 cases of erectile dysfunction (86.36%). Among the BSFI scores, the mean sexual drive score was (1.92 +/- 2.21), the mean erectile function score was (4.18 +/- 4.96), the mean ejaculation score was (2.55 +/- 3.57), the mean problem assessment score was (10.44 +/- 3.57), and the mean overall satisfaction score was (1.90 +/- 1.37). Among the 88 cases, 65 (72.86%) had poor sexual drive, 70 (79.55%) erectile dysfunction, and 60 (68.18%) poor ejaculation. There was statistically significant correlation between age and sexual symptom scores for erection (gamma = -0.552, P = 0.000), IIEF-5 scores (gamma = - 0.567, P = 0.000), and IPSS (gamma = 0.213, P = 0.047) as well as between IPSS and sexual symptom scores for erection and overall satisfaction (gamma = -0.332, P = 0.002 and gamma = -0.302, P = 0.005). IIEF-5 scores were significantly correlated with sexual symptom scores for each of the three categories (sexual drive, erection and ejaculation) (P < 0.05). Serum testosterone did not correlate to age, IIEF-5 scores and sexual function (P > 0.05), nor did peak urinary flow rate and total prostatic volume to IPSS, IIEF-5 scores and sexual function (P > 0.05). CONCLUSION: Results of this study suggest that age and LUTS are risk factors of sexual function, and sexual dysfunction is closely related to the severity of LUTS.