Concentration of polychlorinated biphenyls and risk assessment in finless porpoises from the East China Sea.

Polychlorinated biphenyls (PCBs) are bioaccumulative persistent organic pollutants with a great impact on cetaceans. To examine the content of PCBs and their risks to finless porpoises, this study determined the concentrations of seven typical PCB congeners in 56 tissue samples of East Asian finless porpoises (EAFPs) sampled in 2009-2012 from Ningbo (29.8835° N, 122.0644° E), Pingtan (25.5133° N, 119.8172° E) and Lvsi (32.1035° N, 121.6078° E). PCB138, PCB153 and PCB101 were the predominant congeners, accounting for 31.15%, 18.59% and 15.75%, respectively, of all PCBs detected. The content of PCBs increased with age in males but decreased from juveniles to adults in females due to transfer to calves by reproduction and lactation. EAFPs in Ningbo and Pingtan accumulated more PCBs than those in Lvsi Port. The trophic positions of EAFPs from Lvsi, Pingtan and Ningbo were 9.41, 8.95 and 9.43, respectively. PCB concentrations did not accumulate significantly with increasing trophic levels. The risk quotient index indicated that the risk of trichlorobiphenyl (3-PCB), tetrachlorobiphenyl (4-PCB), pentachlorobiphenyls (5-PCB), and hexachlorobiphenyls (6-PCB) to EAFPs in the East China Sea was generally low and within safe limits thus far. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00221-0.

Comparison of transoral vestibular robotic thyroidectomy with traditional low-collar incision thyroidectomy.

Transoral vestibular robotic thyroidectomy can really make the patient's body surface free of scar. This study aimed to compare the surgical and patient-related outcomes between the transoral vestibular robotic thyroidectomy and traditional low-collar incision thyroidectomy. The clinical data of 120 patients underwent transoral vestibular robotic thyroidectomy (TOVRT) or traditional low-collar incision thyroidectomy (TLCIT) were collected from May 2020 to October 2021. Propensity score matching analysis was used to minimize selection bias. All these patients were diagnosed with papillary thyroid carcinoma (PTC) through ultrasound-guided fine-needle aspiration prior to surgical intervention and surgical plan was tailored for each patient. An intraoperative recurrent laryngeal nerve (RLN) detection system was used in all patients, whose RLNs were identified and protected. We performed transoral vestibular robotic thyroidectomy with three intraoral incisions. Additional right axillary fold incisions were adopted occasionally to enhance fine reverse traction of tissue for radical tumor dissection. Clinical data including gender, age, tumor size, BMI, operation time, postoperative drainage volume and time, pain score, postoperative length of stay (LOS),number of lymph nodes removed, complications, and medical expense were observed and analyzed. Propensity score matching was used for 1:1 matching between the TOVRT group and the TLCIT group. All these patients accepted total thyroidectomy(or lobectomy) plus central lymph node dissection and all suffered from PTC confirmed by postoperative pathology. No conversion to open surgery happened in TOVRT group. The operative time of TOVRT group was longer than that of TLCIT group (P < 0.05). The postoperative drainage volume of TOVRT group was more than that of TLCIT group (P < 0.05). The drainage tube placement time of TOVRT group were longer than that of TLCIT group (P < 0.05). Significant differences were also found in intraoperative bleeding volume, pain score and medical expense between the two groups (P < 0.05). The incidence of perioperative common complications such as hypoparathyroidism and vocal cord paralysis in the two groups was almost identical (P > 0.05). However, there were some specific complications such as surgical area infection (one case), skin burn (one case), oral tear (two cases), and paresthesia of the lower lip and the chin (two cases) were found in TOVRT group. Obviously, the postoperative cosmetic effect of the TOVRT group was better than TLCIT group (P < 0.05). TOVRT is safe and feasible for low to moderate-risk PTC patients and is a potential alternative for patients who require no scar on their neck. Patients accepted TOVRT can get more satisfaction and have less psychologic injury caused by surgery.

Effort Expenditure Increases Risk-Taking for Improbable Rewards.

Previous studies have found that exerting effort can lead people to engage in risk-taking behaviors. While effort can be either cognitive or physical, risk-taking can take place in either a risky context with known outcome probabilities or an ambiguous context with unknown outcome probabilities. The goal of the current research is to investigate how effort type and decision context influence risk-taking after effort exertion. Across three experiments, we find evidence that investing effort increases risk-taking at a short timescale. Importantly, this effect is particularly noticeable when the chance of winning is low, rather than when it is uncertain. Furthermore, the increase in risk-taking happens regardless of whether the effort is cognitive or physical. These findings suggest the existence of a cost-invariant but decision context-variant mechanism for the risk-taking after-effect of effort expenditure, which helps to bring the negative emotions caused by effort exertion back to a state of emotional homeostasis.

Tertiary lymphoid structures in gynecological cancers: prognostic role, methods for evaluating, antitumor immunity, and induction for therapy.

Tertiary lymphoid structures (TLSs), referred to as tertiary lymphoid organs and lymphoid tissue neogenesis, are aggregates of immune cells that occur in nonlymphoid tissues. In recent years, it has been found that TLSs within the tumor microenvironment have been associated with local adaptive immune immunity against cancer and favorable prognosis in several human solid tumors, including gynecological cancers. The issue of the prognosis of gynecological cancers, including endometrial, cervical, and ovarian cancer, is an enormous challenge that many clinical doctors and researchers are now facing. Concerning the predictive prognostic role of TLSs, effective evaluation, and quantification of TLSs in human tissues may be used to assist gynecologists in assessing the clinical outcome of gynecological cancer patients. This review summarizes the current knowledge of TLSs in gynecological cancers, mainly focusing on the potential mechanism of TLS neogenesis, methods for evaluating TLSs, their prognostic value, and their role in antitumor immune immunity. This review also discusses the new therapeutic methods currently being explored in gynecological cancers to induce the formation of TLSs.

Dissociable neural after-effects of cognitive and physical effort expenditure during reward evaluation.

The reward after-effect of effort expenditure refers to the phenomenon that previous effort investment changes the subjective value of rewards when obtained. However, the neural mechanisms underlying the after-effects of effort exertion are still not fully understood. We investigated the modulation of reward after-effects by effort type (cognitive vs. physical) through the lens of neural dynamics. Thirty-two participants performed a physically or cognitively demanding task during an effort phase and then played a simple gambling game during a subsequent reward phase to earn monetary rewards while their electroencephalogram (EEG) was recorded. We found that previous effort expenditure decreased electrocortical activity during feedback evaluation. Importantly, this effort effect occurred in a domain-general manner during the early stage (as indexed by the reward positivity) but in a domain-specific manner during the later and more elaborative stage (as indexed by the P3 and delta oscillation) of reward evaluation. Additionally, effort expenditure enhanced P3 sensitivity to feedback valence regardless of effort type. Our findings suggest that cognitive and physical effort, although bearing some surface resemblance to each other, may have dissociable neural influences on the reward after-effects.

Nurse managers' experience during the COVID-19 pandemic in China: A qualitative study.

AIMS: The aim of the study was to explore the experiences of female new nurse managers during the COVID-19 pandemic. DESIGN: This was a phenomenological study, and qualitative descriptive analysis was used. METHODS: New nurse managers were defined as new nurse managers with less than 3 years of management experience in this study. During November and December of 2021, 18 female new nurse managers were interviewed face-to-face with a semi-structured interview guide in three municipal hospitals. The study followed the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines for evaluating qualitative research reports. Data analysis was performed using Colaizzi's seven-step method. RESULTS: Four main themes and 10 sub-themes were extracted from the collected data. The four major themes were as follows: (1) a shift in stress; (2) work-related physical and psychological discomfort; (3) reflection on the cause; (4) coping and struggles. CONCLUSIONS: New nurse managers were experiencing great stress and exhaustion in their roles. It is important that they are helped to handle situations. Providing them with readily accessible support, addressing their psychosocial needs and addressing exhaustion is necessary. Considering their short management time, the hospital should provide adequate support in human, financial and material areas and provide training to help new nurse managers better adapt to their new roles. In addition, nurse directors should create a culture of mutual respect, identify workplace bullying and create a harmonious and cooperation-oriented work environment for new nurse managers. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Reduced 2,4-dienoyl-CoA reductase 1 is served as an unfavorable biomarker and is related to immune infiltration in cervical cancer.

BACKGROUND: Worldwide, cervical cancer (CC) remains the most prevalent malignancy of the female reproductive system, posing a threat to women's life and health, and increasing the medical and economic burden on society. Therefore, the search for tumor biomarkers for CC remains an important research direction. Immunotherapy has significantly improved patient outcomes, and genes related to tumor immune infiltration have been clinically relevant and highly reproducible biomarkers that affect the prognosis and response to treatment of CC. 2,4-dienoyl-CoA reductase 1 (DECR1) was considered to be an oncogene in a previous study, but relationship between DECR1 and immune infiltration was not mentioned. Our study aimed to reveal the clinical value of DECR1 in CC and to investigate its relationship with immune infiltration. METHODS: Human Protein Atlas was used to identify the localization of DECR1. The Ualcan database, TCGA, and IHC were used to assess the prognostic value of DECR1. GSEA was used to assess the possible signaling pathways of DECR1 in CC. The TIMER database was applied to reveal the relevance between DECR1 and immune infiltration. GEPIA was conducted to detect the co-relationship among DECR1, immune markers, and typical molecules of apoptosis. RESULTS: DECR1 was mainly distributed in the cytoplasm and overlapped with the endoplasmic reticulum. DECR1 was downregulated in CC compared to adjacent tissue. Survival analysis showed that patients with lower expression of DECR1 have a worse prognosis in CC. GSEA suggested that DECR1 was closely related to apoptosis signaling. TIMER showed that DECR1 was positively correlated with CD8+ T cell and CD4+ T cell but not with B cell in CC. CONCLUSION: DECR1 may be a potential cancer suppressor in CC and may be involved in apoptotic pathways and associated with immune infiltration.

Contextual valence influences the neural dynamics of time and magnitude representation during feedback evaluation.

Contextual valence is an important dimension during value-based decision-making. Previous research has revealed behavioral and neural asymmetries between the gain context and the loss context. The present event-related potential study investigated the effects of contextual valence on neural dynamics underlying magnitude and time, two important reward dimensions, during feedback evaluation. Forty-two participants performed a simple guessing task in which they experienced both a gain context wherein high or low rewards were delivered immediately or six months later, and a loss context wherein high or low losses were delivered in the same way. Results showed that in the gain context, time and magnitude information were processed in a parallel way during the time windows of the reward positivity (RewP) and the P3. In the loss context, however, time and magnitude information were processed in a serial way such that time information was encoded during the RewP and P3 periods, whereas magnitude information was not tracked until the time window of the late positive potential. Our findings suggest that the neural dynamics underlying time and magnitude information are distinct between the gain and loss contexts, thus providing a novel perspective for the well-known gain-loss asymmetry.

Urban-rural disparities of carbon storage dynamics in China's human settlements driven by population and economic growth.

China has experienced a rapid expansion of human settlement in both urban and rural areas over the past three decades. Regarding the impacts on carbon storage, previous studies that only focus on certain ecosystems cannot reflect urban-rural disparities, resulting in the carbon storage changes in human settlement remaining unknown. In this study, we aimed to explore China's urban-rural disparities in human settlement expansion and direct impacts on carbon storage by using the big Earth data technology. The results showed that from 1990 to 2018, the total amount of China's human settlement expansion reached 175,703.80 km2, and the inner-city, peri-urban, and rural components accounted for 21.00 %, 20.18 %, and 58.82 %, respectively. Along with the general tendency of impervious surface area (ISA) growth, there was more soil organic carbon (SOC) (1254.33 TgC) being sealed beneath ISA (0-100 cm depth), compared to a huge reduction in vegetation biomass carbon (VBC) (91.44 TgC) during the study period. The results further indicated that the change density of either VBC or SOC presented a slightly rising trend along the urban-rural gradient, due to the increasingly common encroachment on vegetation and soil types with higher carbon content. We also found that socioeconomic drivers had a greater influence in urban areas than rural areas, and the related correlation exhibited a descending trajectory in both urban and rural areas. There is thus an urgent need to preserve lands with abundant carbon storage and contain the waste of land resources in rural areas. All stakeholders should pay more attention to concerted and targeted regulation policies for well-planned and eco-friendly human settlement expansion such as enhancing rural land use efficiency and promoting large-scale afforestation and continuous urban greening, which will be critical not only for guiding sustainable urbanization all over China but also for mitigating climate change for the entire world.

Design of an ultra-broadband optical filter based on a local micro-structured long period fiber grating near PMTP.

This paper presents a local micro-structured long period fiber grating (LMS-LPFG) ultra-broadband optical filter based on the wide bandwidth near the phase-matching turning point (PMTP). The structure of LMS-LPFG is obtained by dividing a LPFG into two parts of equal length and reducing the cladding radius of the second LPFG. At this time, the LMS-LPFG can be regarded as a cascade of two equal-length LPFGs with different resonance wavelengths. The cladding mode and grating period are determined to make the first LPFG work in the double-peak resonance state, and the second LPFG operates near PMTP. It is found that the transmission spectra of the two LPFGs can be superimposed to form a wide loss bandwidth. Then the cladding radii of the second LPFG and grating structure parameters are designed based on coupled-mode theory. First, the grating period corresponding to the operating wavelength is determined from the phase-matching curve of LMS-LPFG. Then, the radius of the second LPFG with a designated grating period is selected to make LPFG 2 work in PMTP by reducing its cladding radius. In addition, the grating lengths of the two LPFGs are determined by maximizing the loss of the LMS-LPFG's transmission spectrum. Finally, the two LPFGs are cascaded into a LMS-LPFG, and the optical transmission spectrum of the LMS-LPFG is calculated by the transfer matrix method. Simulation results show that the bandwidth of the transmission spectrum can reach 380 nm. In addition, the flexibility of design for the operating wave band is discussed and confirmed, and can meet different actual requirements of optical communication.

In Vitro Interactions of Antifungal Agents and Everolimus Against Aspergillus Species.

Multiple cellular activities, including protein and lipid synthesis, ribosome biogenesis, and metabolic processes, are regulated by the target of rapamycin (TOR) pathway. Recent research suggests that the TOR might play an important role in various physiological functions of pathogenic fungi, such as nutrient sensing, stress response, and cell cycle progression. Given their robust immunosuppressant and antitumor activities, TOR inhibitors are widely used in clinical settings. In the present study, a microdilution checkerboard-based approach was employed to assess the interactions between the oral mammalian target of rapamycin (mTOR) inhibitor everolimus (EVL) and antifungal agents in the treatment of Aspergillus species derived from 35 clinical isolates in vitro. The results revealed that EVL exhibited promising inhibitory synergy with itraconazole (ITC), posaconazole (POS), and amphotericin B (AMB) for 85.7%, 74.2%, and 71.4%, respectively. In contrast, EVL exhibited minimal synergistic inhibitory activity (14.3%) when applied in combination with voriconazole (VRC). Antagonistic interactions were not observed. In vivo experiments conducted in Galleria mellonella revealed that EVL in combination with antifungal agents improved the larva survival rates in the ITC, VRC, POS, and AMB groups by 18.3%, 13.3%, 26.7%, and 13.3%, respectively. These data suggest that the combination treatment with antifungal agents and antifungal agents holds promise as a means of alleviating clinical aspergillosis.

Long Non-coding RNA GAS5/miR-520-3p/SOCS3 Axis Regulates Inflammatory Response in Lipopolysaccharide-Induced Macrophages.

Sepsis is mainly caused by infection, and inflammation plays a vital role in the progression of sepsis. Increasing evidence shows the regulatory mechanism of long non-coding RNA growth arrest-specific 5 (GAS5) in inflammatory response. However, the potential role of GAS5 in sepsis was not really clear. Here, we set to investigate the role and mechanism of GAS5 in the inflammatory response of lipopolysaccharide (LPS)-induced macrophages in vitro. Levels of GAS5, microRNA-520-3p, suppressor of cytokine signaling 3 (SOCS3) and inflammatory cytokines tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and IL-1ß were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Nitric oxide (NO) release was measured through flow cytometry. The levels of TNF-α, IL-6, and IL-1ß were also detected using ELISA. Dual-luciferase reporter and RNA pull-down assays were performed to clarify the relationship between miR-520-3p and GAS5 or SOCS3. Western blot was carried out to assess SOCS3 protein expression in macrophages. GAS5 level was remarkably decreased in sepsis serum and it was inversely related to the severity of sepsis. Upregulation of GAS5 repressed inflammatory response in LPS-induced macrophages, and the inhibitory effect was returned by miR-520-3p mimics. Moreover, miR-520-3p inhibitor downregulated the levels of inflammatory factors of TNF-α, IL-6, and IL-1ß, as well as suppressed NO release. Mechanically, GAS5 functioned as a sponge of miR-520-3p and miR-520-3p directly targeted SOCS3. GAS5 regulated inflammatory response by the miR-520-3p/SOCS3 axis in LPS-induced macrophages, which furnished a novel therapeutic idea in clinical treatment of inflammation-induced sepsis.

Comparative Transcriptome Sequencing of Taro Corm Development With a Focus on the Starch and Sucrose Metabolism Pathway.

Taro (Colocasia esculenta) is an important tuber crop and staple food. Taro corms have higher nutritional value and starch contents as compared to most of the other root/tuber crops. However, the growth and development of the taro rhizome have not been critically examined in terms of transcriptomic signatures in general or specific to carbohydrates (starch and sucrose) accumulation. In current study, we have conducted a comprehensive survey of transcripts in taro corms aged 1, 2, 3, 4, 5, and 8 months. In this context, we have employed a whole transcriptome sequencing approach for identification of mRNAs, CircRNAs, and miRNAs in corms and performed functional enrichment analysis of the screened differentially expressed RNAs. A total of 11,203 mRNAs, 245 CircRNAs, and 299 miRNAs were obtained from six developmental stages. The mRNAs included 139 DEGs associated with 24 important enzymes of starch and sucrose metabolism. The expression of genes encoding key enzymes of starch and sucrose metabolism pathway (GBSS, AGPase, UGPase, SP, SSS, ßFRUCT and SuSy) demonstrated significant variations at the stage of 4 months (S4). A total of 191 CircRNAs were differentially expressed between the studied comparisons of growth stages and 99 of these were associated with those miRNA (or target genes) that were enriched in starch and sucrose metabolism pathway. We also identified 205 miRNAs including 46 miRNAs targeting DEGs enriched in starch and sucrose biosynthesis pathway. The results of current study provide valuable resources for future exploration of the molecular mechanisms involved in the starch properties of Taro.

Empagliflozin in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Purpose: The purpose of the study is to evaluate the effect of empagliflozin in patients with heart failure (HF). Method: We performed a systematic search of PubMed, EMBASE, and the Cochrane Library database through January 20, 2021. Randomized controlled trials (RCTs) were included that compared empagliflozin and placebo in patients with HF. Dichotomous variables were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Continuous variables were calculated and expressed as mean differences (MD) and standard deviation (SD). Meta-analysis was conducted using a random-effects model on outcomes with high heterogeneity. Results: Seven studies were included in our meta-analysis (n = 5,150). Significant differences were observed in a composite of cardiovascular death or hospitalization for worsening heart failure [RR: 0.77 (95% CI 0.68-0.87); I 2 = 18%; P < 0.0001), hospitalization for worsening heart failure [RR: 0.71 (95% CI 0.61-0.82); I 2 = 0%; P < 0.00001], changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) score [MD: 1.70 (95% CI 1.67-1.73); I 2 = 0%; P < 0.00001], and changes in body weight [MD: -1.43 (95% CI -2.15 to -0.72); I 2 = 84%; P < 0.0001) from baseline. However, empagliflozin did not show a better change in the 6-min walk test (6MWT) [MD: 34.06 (95% CI -29.75-97.88); I 2 = 97%; P = 0.30] or NT-proBNP [MD: -98.36 (95% CI, -225.83-29.11); I 2 = 68%; P = 0.13] from baseline. Conclusion: The findings suggest that empagliflozin was effective in reducing a composite of cardiovascular death or hospitalization for worsening heart failure. Further well-designed RCTs are needed to evaluate the long-term effect of empagliflozin in patients with HF. PROSPERO: CRD42021231712.

OLA1 is a potential prognostic molecular biomarker for endometrial cancer and promotes tumor progression.

Obg-like ATPase 1 (OLA1) is upregulated in the tumor tissues in different types of cancer. However, the function of OLA1 and its molecular mechanisms in endometrial cancer (EC) remain unknown. The present study aimed to elucidate OLA1 expression level and its biological function in endometrial cancer. The differential expression of OLA1 between EC tissues and non-cancerous tissues was analyzed using The Cancer Genome Atlas database and clinical samples. The association between clinicopathological characteristics and OLA1 expression was analyzed using bioinformatics analysis. Cell proliferation, migration and invasion were analyzed by short interfering RNA-mediated knockdown experiments, Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine incorporation, wound healing, Transwell and Boyden assays. The potential signaling pathways associated with OLA1 in endometrial cancer were evaluated by Gene Set Enrichment Analysis. The expression levels of OLA1 in EC tissues were upregulated compared with that in non-cancerous tissues (P<0.001). Furthermore, patients with worse survival were found to have higher OLA1 expression, and increased OLA1 expression in endometrial cancer associated with clinical stage (P<0.01), histological type (P<0.01), histological grade (P<0.01), menstrual status (P<0.01), cancer status (P<0.05) and distant metastasis (P<0.05). In RL95-2 and HEC-1B cell lines, decreased levels of OLA1 inhibited proliferation, invasion and migration, and the TGF-ß signaling pathway, ubiquitin-mediated proteolysis and Wnt signaling pathway may be involved in these mechanisms. The present study revealed that OLA1 could be a potential prognostic indicator and therapeutic target in endometrial cancer, and that the TGF-ß signaling, Wnt signaling and ubiquitin-mediated proteolysis pathways may be regulated by OLA1.

Galectin-3 in septic acute kidney injury: a translational study.

BACKGROUND: Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3's role and its potential utility as a therapeutic target in S-AKI. METHODS: In 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and development of AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, Interleukin-6 (IL-6), and creatinine were examined at 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group). RESULTS: Among 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1-1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1-2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both P-MCP groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP groups (400 mg: p = 0.007; 1200 mg: p = 0.007). CONCLUSIONS: This translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.

ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ß-catenin, TCF4, and ZEB1, but also repressed ß-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ß-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/ß-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

Sp1 contributes to radioresistance of cervical cancer through targeting G2/M cell cycle checkpoint CDK1.

BACKGROUND/AIMS: Radioresistance remains a significant obstacle in the therapy of cervical cancer, and the mechanism of it is still unclear. We aimed to investigate the role of specificity protein 1 (Sp1) in radioresistance of cervical cancer. METHODS: Sp1 was examined immunohistochemically on tissues from 36 human cervical cancer patients. We used RT-qPCR and Western blot to examine the expression of Sp1 in irradiated cervical cancer cell lines SiHa and HeLa. The role of Sp1 in radioresistance of cervical cancer cells was assessed by colony-formation assay and cell cycle analysis. Dual-luciferase reporter assay was performed to detect the downstream of Sp1. RESULTS: High Sp1 expression was positively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and lymphovascular space invasion (LVSI) of cervical cancer. The expression of Sp1 was dose-dependently increased in irradiated cervical cancer cell lines at both mRNA and protein levels. Colony-formation assay showed that alteration of Sp1 expression affected the survival of cervical cancer cells with radiotherapy (RT) treatment. Knockdown of Sp1 significantly strengthened the cellular response to radiation by inducing G2/M arrest in cervical cancer cells. Overexpression of Sp1 significantly decreased G2/M arrest in cervical cancer cells, which was related to upregulation of CDK1 expression. Dual-luciferase reporter assay showed the direct effect of Sp1 on the transcriptional activation of CDK1. CONCLUSION: Sp1 may contribute to radioresistance through inhibiting G2/M phase arrest by targeting CDK1, and be considered as a potential therapeutic target to promote the effect of RT for patients with cervical cancer.

T-bet Transcription Factor Promotes Antibody-Secreting Cell Differentiation by Limiting the Inflammatory Effects of IFN-γ on B Cells.

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.