Epidemiology of mental health comorbidity in patients with atopic dermatitis: An analysis of global trends from 1998 to 2022.

The prevalence rates of attention deficit hyperactivity disorder (ADHD), depression, anxiety and suicide are increasing in patients with atopic dermatitis (AD), although no research has systematically examined these trends yet. Here, we explore the prevalence of the occurrence of comorbidities, such as ADHD, depression, anxiety and suicide with AD. We searched seven electronic databases from inception to October 2022 to identify relevant studies, and the Agency for Healthcare Research and Quality (AHRQ) and Newcastle-Ottawa Scale (NOS) tools were used to assess the quality of observational studies. Statistical analysis was performed using R software. Publication bias was evaluated using Egger's and Begg's linear tests. The global prevalence rates of ADHD, depression, anxiety and suicidal ideation in patients with AD were 7%, 17%, 21% and 13%, respectively, between 1998 and October 2022. Among children (aged <18 years), North American children with AD had the highest prevalence rates of ADHD (10%), depression (13%) and anxiety (20%). Among the adult (aged ≥18 years) population, patients with AD in Africa had the highest prevalence rates of depression (36%) and anxiety (44%), while Asian adults with AD had the highest prevalence rates of ADHD (7%) and suicidal ideation (20%). These results highlight the high prevalence and comorbidity rates of mental illnesses with AD, which should be brought to the attention of patients with AD and their physicians.

Correlation Between Central Vein Smoke Ultrasonography and Thrombus Elasticity Graphy in Severe Patients.

Objective: The objective of this study was to analyze the correlation between central vein smoke ultrasonography (CVSU) and thrombus elasticity graphy (TEG). Methods: A retrospective analysis was made on 300 severe patients with smoky echo changes (SECs) in the internal jugular and femoral veins who were admitted to the hospital from January 2021 to March 2022. According to the ultrasound results, all patients were divided into Group A (n = 75), Group B (n = 75), Group C (n = 75), and Group D (n = 75). TEG examination, ultrasound examination, routine coagulation test were received. The coagulation function and TEG index were compared and analyzed in each group, and their correlation was analyzed. Results: The trends of R value and K value of TEG index of patients in different groups were the same. The R value and K value in group D were the highest, followed by group C, and the lowest in group A; while those in groups C and D exhibited great differences with P < .05 to those in groups A and B. The PT, TT, APTT, and FIB of patients in groups C and D were much higher based on the values in groups A and B. R-value was positively correlated with APACHEII (0.678), TT (0.198), and APTT (0.187), and negatively associated with PT (-0.008), D-D (-0.315), and FDP (-0.298). K value presented a positive correlation with APACHEII (0.692) and TT (0.342) but a negative correlation with PT (-0.187), APTT (-0.053), D-D (-0.497), and FDP (-0.453). Positive correlations were observed between α and PT (0.198), APTT (0.046), D-D (0.602), and FDP (0.532), while negative correlations were found between α and APACHEII (-0.398) and TT (-0.315). MA was positively correlated with PT, D-D, and FDP but negatively with APACHEII, TT, and APTT. Conclusion: TEG parameters had an obvious correlation with the coagulation function test, which can effectively evaluate the CVSU in severe patients. The ultrasonic signs can be undertaken as clinical hypercoagulability detection indicators in severe patients and intervention indicators for early thrombosis prevention in the future, they can guide clinicians to make the best treatment plan for severe patients.

Neoadjuvant chemotherapy with weekly cisplatin and paclitaxel followed by chemoradiation for locally advanced cervical cancer.

BACKGROUND: Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). Forty percent of patients present with disease recurrence. This study aims to investigate the feasibility, safety and efficacy of neoadjuvant chemotherapy (NACT) with weekly cisplatin and paclitaxel (TP) followed by CCRT. METHODS: We are conducting a phase III trial comparing the efficacy and side effects of patients with cervical cancer (FIGO 2018 stage IIB to IVA) who were assigned to four cycles of NACT with cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly followed by CCRT or CCRT alone. In this report, we studied the medium-term effect of 50 patients enrolled in the NACT + CCRT arm. The primary endpoints were the response rate post-NACT and 12 weeks post-CCRT evaluated by MR/CT based on RECIST v 1.1. The secondary endpoints were 3-year OS (overall survival) and PFS (progression-free survival) measured by the Kaplan-Meier method. RESULTS: Among 50 patients enrolled in the NACT + CCRT arm, the complete and partial response rates were 10.4% and 68.8%, post-NACT. Twelve weeks after treatment completion, the complete response rate was 72.0%, whereas the total response rate (complete and partial response) was 90.0%. After a median follow-up of 28 months, the 3-year OS rate was 83.9%, and the 3-year PFS rate was 73.6%. NACT response was related to superior PFS and OS compared with NACT nonresponse (P < 0.01). Late AEs were exiguous, while early AEs mainly included myelosuppression and gastrointestinal AEs. CONCLUSIONS: This study showed a good response rate achieved by dose-dense weekly cisplatin and paclitaxel followed by standard CCRT. The treatment regimen is feasible, as evidenced by the acceptable toxicity of NACT and by the high compliance with radiotherapy. TRIAL REGISTRATION: Protocol version number and date. Chinese clinical trial registry, ChiCTR1900025327; http://www.chictr.org.cn . Registered 24 August 2019. Retrospectively registered, medresman.org.cn/ChiCTR1900025326. The date recruitment began 01-01-2019.

Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity.

Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.

[Study on perceived fatigue evaluating model during simulated load carriage].

OBJECTIVE: To establish a perceived fatigue evaluating model during simulated load carriage that is based on objective variables through analyzing the characteristics and trends of shoulder force, shoulder pressure, waist pressure, back pressure, and perceived fatigue, and to provide an analytical technique for research on load carriage. METHODS: A 50-min simulated walking (at a speed of 5 km/h and a slope of 0%) experiment including 14 healthy male adults was conducted under four levels of backpack payloads (25, 29, 34, 37 kg). Shoulder force and trunk pressure were sampled simultaneously and analyzed with time- and frequency- domain methods. Multivariable linear regression was used to build a perceived fatigue evaluating model during load carriage. RESULTS: The perceived fatigue evaluating model based on shoulder force, trunk pressure distribution ratio, load, and body mass index (BMI) was established. Its adjusted determination coefficient (aR2) was 0.709 and the absolute percentage error (APE) at the end of the experiment was less than 20%. The goodness of fit of the model based on frequency-domain independent variables was much higher compared with the model based on time-domain independent variables. The addition of BMI that represents the individual differences to the model obviously improved the goodness of fit. CONCLUSION: The perceived fatigue evaluating model established in this study does not rely on the physiological changes of individuals, and thus can be used to establish an evaluation system for human load carriage with dummy as a substitution for human in experiments and to provide a scientific basis for efficient human load carriage.

Development and influencing factors of compliance behaviors of investigators in clinical trials.

The development and influencing factors of compliance behavior of investigators in clinical trials were explored. According to literature review, a hypothetical model of development of compliance behavior of investigators in clinical trials was established, and the influencing factors of compliance behavior of investigators and their interrelationships were studied based on questionnaire survey of five hundred investigators sampled randomly from one hundred clinical trial institutions in China. Cronbach's alpha coefficient and structural equation modeling were adopted to empirically analyze the results. Six variables in the hypothetical model were included: compliance behavior of investigators, credibility of clinical trial, capability of government regulation, quality control of sponsor, quality control of clinical institution and compliance intention of investigators. Empirical analysis showed that the compliance behavior of investigators in clinical trial was directly affected by compliance intention of investigators, quality control of sponsor and quality control of clinical institution. In addition, credibility of clinical trial and capability of government regulation indirectly affected the compliance behavior of investigators in clinical trial through influencing the compliance intention of investigators, quality control of sponsor and quality control of clinical institution. Quality control of sponsor was affected by credibility of clinical trial and capability of government regulation while quality control of clinical institution was only influenced by capability of government regulation.

The impact of Paclitaxel-based hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer patients - interim analysis of safety and immediate efficacy of a randomized control trial (C-HOC trial).

OBJECTIVE: This study evaluates the potential superiority of combining paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) with sequential intravenous neoadjuvant chemotherapy over intravenous neoadjuvant chemotherapy alone in Chinese patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC, IVA and IVB high-grade serous ovarian/fallopian tube carcinoma (HGSOC). This interim analysis focuses on the safety and immediate efficacy of both regimens to determine the feasibility of the planned trial (C-HOC Trial). METHODS: In a single-center, open-label, randomized control trial, FIGO stage IIIC, IVA, and IVB HGSOC patients (FAGOTTI score ≥ 8 during laparoscopic exploration) unsuitable for optimal cytoreduction in primary debulking surgery (PDS) were randomized 2:1 during laparoscopic exploration. The Experiment Group (HIPEC Group) received one cycle of intraperitoneal neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (paclitaxel) followed by three cycles of intravenous chemotherapy (paclitaxel plus carboplatin), while the Control Group received only three cycles of intravenous chemotherapy. Both groups subsequently underwent interval debulking surgery (IDS). The adverse effects of chemotherapy, postoperative complications, and pathological chemotherapy response scores (CRS) after IDS were compared. RESULTS: Among 65 enrolled patients, 39 HIPEC Group and 21 Control Group patients underwent IDS. Grade 3-4 chemotherapy-related adverse effects were primarily hematological with no significant differences between the two groups. The HIPEC Group exhibited a higher proportion of CRS 3 (20.5% vs. 4.8%; P = 0.000). R0 resection rates in IDS were 69.2% (HIPEC Group) and 66.7% (Control Group). R2 resection occurred in 2.6% (HIPEC Group) and 14.3% (Control Group) cases. No reoperations or postoperative deaths were reported, and complications were managed conservatively. CONCLUSIONS: Combining HIPEC with IV NACT in treating ovarian cancer demonstrated safety and feasibility, with no increased chemotherapy-related adverse effects or postoperative complications. HIPEC improved tumor response to neoadjuvant chemotherapy, potentially enhancing progression-free survival (PFS). However, the final overall survival results are pending, determining if HIPEC combined with IV NACT is superior to IV NACT alone.

Anlotinib Inhibits Ovarian Cancer and Enhances Cisplatinum Sensitivity via Suppressing NOTCH2 Expression and Stemness.

BACKGROUND/AIM: The prognosis of ovarian cancer (OC) patients is especially poor for patients with chemotherapy resistance. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor, has shown encouraging clinical efficacy in several tumor types. The aim of the present study was to examine the inhibitory efficacy and mechanism of anlotinib on the proliferation and chemosensitivity of OC cells. MATERIALS AND METHODS: The inhibitory effects of Anlotinib on SKOV3 and OVCAR3 OC cells were examined using CCK-8 cell-viability, colony-formation, flow-cytometry, transwell-migration and sphere-formation assays. A xenograft mouse model was used for in vivo studies. RT-qPCR and western blotting were used to detect gene expression. RESULTS: Molecular targets of anlotinib were elevated in OC patient tumors. Anlotinib significantly inhibited ovarian cancer cell proliferation and migration in vitro. Anlotinib enhanced the sensitivity of ovarian cancer cells to cisplatinum both in vitro and in vivo. Anlotinib suppressed sphere formation and the stemness phenotype of OC cells by inhibiting NOTCH2 expression. CONCLUSION: Anlotinib inhibits ovarian cancer and enhances cisplatinum sensitivity, suggesting its future clinical promise.

TPE-embedded butterfly bis-crown ether with controllable conformation and supramolecular chiroptical property.

Understanding how subtle structural differences between macrocyclic conformational isomers impact their properties and separation has garnered increasing attention in the field of supramolecular synthetic chemistry. In this work, a series of tetraphenylene (TPE)-embedded butterfly bis-crown ether macrocycles (BCE[n], n = 4-7), comprising two crown ether side rings and a TPE core, are synthesized through intramolecular McMurry coupling. Unexpectedly, the presence of flexible oligoethylene chains with varying lengths are found to influence molecular conformation via multiple intramolecular interactions, resulting in the formation of two stabilized conformers with specific semi-rigid symmetric/asymmetric structures (sym-BCE[n] and asym-BCE[n], n = 5, 6). Moreover, it is noteworthy that neither symmetric nor asymmetric conformers are present in the more rigid BCE[4] or the more flexible BCE[7]. Interestingly, these conformers display distinct fluorescence properties and host-guest binding abilities, and only sym-BCE[5] can serve as a host for chiral polymer binding, resulting in the formation of chiral supramolecular assemblies through host-guest interaction induced chirality. Moreover, both circular dichroism and circularly polarized luminescence signals of the obtained assemblies can be switched off by the addition of sodium ion, suggesting potential applications in the field of dynamic chiral materials.

[Study on real-time wearable monitoring system for human heat and cold stresses].

In order to study the way of evaluating human performance under heat and cold stresses, we developed a wearable physiological monitoring system-intelligent belt system, capable of providing real-time, continuous and dynamic monitoring of multiple physiological parameters. The system has following features: multiuser communication, high integration, strong environment adaptability, dynamic features and real time physiological monitoring ability. The system uses sensing belts and elastic belts to acquire physiological parameters, uses WIFI to build wireless network monitoring for multiuser, and uses Delphi to develop data processing software capable of real-time viewing, storagng, processing, and alerting. With four different intensity-activity trials on six subjects and compared with standard laboratory human physiological acquisition instruments, the system was proved to be able to acquire accu-rate physiological parameters such as ECG, respiration, multi-point body temperatures, and body movement. The system worked steadily and reliably. This wearable real-time monitoring system for human heat and cold stresses can solve the problem facing our country that human heat stress and cold stress monitoring technology is insufficient, provide new methods and new ways for monitoring and evaluation of human heat and cold stresses under real task or stress environment, and provide technical platform for the study on human ergonomics.

Information Monitoring of Animal Husbandry Industry Based on the Internet of Things and Wireless Communication System.

This paper was aimed at discussing the information monitoring of animal husbandry based on the Internet of Things and wireless communication system. The breeding and health of animals in the breeding industry has always been a topic that people talk about. The advent of the wireless communication system has made monitoring and positioning technologies more and more simple. The wireless communication network technology is applied to the environmental monitoring of animal breeding farms, and a real-time reporting system is designed to pay attention to animal health in real time. This article focuses on the connection between the two. First, this article briefly describes the state of the wireless communication network and the aquaculture industry, furthermore explains the research methods, such as the livestock breeding environment monitoring system model, which needs to have the characteristics of humanization, fast and simple, easy to maintain, high reliability, compatibility, scalability, and intelligence, and designs related monitoring systems and hardware systems to integrate carbon dioxide, ammonia, and other gas sensors with temperature and humidity sensors to sense the environment. Next, this article shows the wireless communication network monitoring and positioning algorithm, namely, the TOA-based wireless communication positioning algorithm and the LTE prediction algorithm. The predicted time is used as the link weight, and the weight within the wide link cluster is defined according to the time threshold, making the link maintain stability for a short time to enhance the network topology. Then, this article conducts experiments based on ZigBee wireless communication network sensor combined with improved genetic algorithm in the temperature and humidity test of farms, designs the environmental monitoring system, improves the algorithm, and cooperates with experiments and analysis to verify the feasibility and apply it to the temperature and humidity test of the livestock farm. The results are good, and the temperature and humidity errors are reduced by 88.28% and 84.21%, respectively. It has a certain degree of guidance. Finally, it is discussed and summarized. It can be seen that the system and algorithm designed in this paper have a good prospect in the development of animal husbandry. However, this algorithm takes a long time and has a broader research space.

BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer.

Background: The frequent emergence of drug resistance to chemotherapy is a major obstacle for the treatment of ovarian cancer. There is a need for novel drugs to fulfill this challenge. Pyroptosis-inducing drugs can inhibit tumor growth. However, their roles in ovarian cancer have not been demonstrated. Methods: We tested the effectiveness of a novel drug, BI 2536, which we found in colorectal cancer. Cell proliferation, cell cycle, and drug-induced apoptosis and pyroptosis were tested. In vivo treatments were performed using a cell-derived xenograft model. Results: BI 2536 significantly inhibited the proliferation of ovarian cancer cells and induced cell cycle arrest at the G2/M phases. After BI 2536 treatment, DNA fragmentation and PS exposure on the outside of apoptotic cells were detected. Moreover, the pyroptotic phenotype of ovarian cancer cells along with the release of LDH and HMGB1 were observed, indicating the leakage of cells. Western blot analysis verified that BI 2536 induced GSDME-mediated pyroptosis. Pyroptosis was abolished after additional treatment with Z-DEVD-FMK, a caspase-3 inhibitor. Thus, BI 2536 induced pyroptosis in ovarian cancer through the caspase-3/GSDME pathway. In vivo experiments further demonstrated the antitumoral effect and ability of BI 2536 to accumulate CD8+ T cells in ovarian cancer. Conclusion: In this study, we identified BI 2536 as an effective anti-ovarian cancer drug that inhibits proliferation, arrests the cell cycle, induces apoptosis and pyroptosis, and leads to the accumulation of CD8+ T cells in tumor sites. Drug-induced pyroptosis may have promising prospects for reducing side effects and activating immune responses.

Association between long-term static postures exposure and musculoskeletal disorders among university employees: A viewpoint of inflammatory pathways.

Background: Musculoskeletal disorders (MSDs) are critical occupational and social problems. With the improvement of production mechanization and automation, and the widespread application of computers, more occupations are exposed to static postures and load. This study explored the role of inflammation in the association between static postures exposure and MSDs. Methods: This study adopted a prospective nested case-control design in which 66 lower back MSDs cases and 66 healthy controls were selected from a cohort study of university employees. The personal information, postural load, musculoskeletal symptoms, pressure pain thresholds (PPTs), and inflammatory cytokines were collected. Logistic and linear regressions were used to investigate the association among postural load, inflammatory cytokines, and lower back MSDs. Mediation analysis was used to calculate the mediation effect. Results: The results of logistic and linear regressions showed that postural load and inflammatory cytokines were positively associated with lower back MSDs (P < 0.05), and postural load was positively associated with inflammatory cytokines (P < 0.05). Further, mediation analysis showed that the mediation effect of postural load on the lower back MSDs through TNF-α was 0.073 (95%CI: 0.025-0.128), and the mediation effect of posture load on the lower back MSDs through IL-6 was 0.098 (95%CI: 0.041-0.179), respectively. Conclusion: Static postures were associated with the occurrence of MSDs through inflammatory cytokines, and low-level inflammation may be a critical early event in the generation of MSDs. This study may help bridge the gap of potential mechanisms linking static postures to increased risks of MSDs, and provide new evidence for targeted protection against the global increasing MSDs.

A Lightweight, Elastic, and Thermally Insulating Stealth Foam With High Infrared-Radar Compatibility.

The development of infrared-radar compatible materials/devices is challenging because the requirements of material properties between infrared and radar stealth are contradictory. Herein, a composite of poly(3, 4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) coated melamine foam is designed to integrate the advantages of the dual materials and the created heterogeneous interface between them. The as-designed PEDOT:PSS@melamine composite shows excellent mechanical properties, outstanding thermal insulation, and improved thermal infrared stealth performance. The relevant superb radar stealth performance including the minimum reflection loss value of -57.57 dB, the optimum ultra-wide bandwidth of 10.52 GHz, and the simulation of radar cross section reduction value of 17.68 dB m2 , can be achieved. The optimal specific electromagnetic wave absorption performance can reach up as high as 3263.02 dB·cm3 g-1 . The average electromagnetic interference shielding effectiveness value can be 30.80 dB. This study provides an approach for the design of high-performance stealth materials with infrared-radar compatibility.

Tetraphenylethylene-embedded [15]paracyclophanes: AIEgen and macrocycle merged novel supramolecular hosts used for sensing Ni2+ ions.

Transformation of [15]paracyclophanes ([15]PCP) into fluorophores has been achieved by embedding tetraphenylethene (TPE) units into their skeletons at the meso-positions. The obtained two hosts demonstrated distinct aggregation-induced emission (AIE) properties and their fluorescence could be selectively quenched by Ni2+ ions.

Influence of water-soluble pillararene hosts on Kemp elimination.

Since pillar[5]arene was first discovered in 2008, it has developed into a multifunctional supramolecular host. Its application covers many fields from drug delivery and chemical sensing to the construction of molecular machines, and so on. Supramolecular catalysis based on pillar[n]arenes is one of the hot research topics that has emerged in recent years. In this paper, we have synthesized two water-soluble pillar[5]arenes with peripheral rims bearing opposite charges and investigated their influence on Kemp elimination reaction of 1,2-phenylisoxazole derivatives. It is found that both hosts have a moderate rate acceleration effect on the reaction, and the positively charged host H1 has a greater impact on the reaction rate than the negatively charged host H2.

Reduction of Stat3 activity attenuates HIV-induced kidney injury.

HIV-1 Nef induces podocyte proliferation and dedifferentiation by activating the Stat3 and MAPK1,2 pathways. Activation of Stat3 also occurs in human kidneys affected by HIV-associated nephropathy (HIVAN), but its contribution to the development of HIVAN is unknown. Here, we generated HIV-1 transgenic mice (Tg26) with either 75% Stat3 activity (Tg26-SA/+) or 25% Stat3 activity (Tg26-SA/-). The kidneys of Tg26-SA/+ mice, but not Tg26-SA/- mice, showed increased Stat3 phosphorylation. The Tg26-SA/+ phenotype was not different from Tg26 mice, but Tg26-SA/- mice developed significantly less proteinuria, glomerulosclerosis, and tubulointerstitial injury. Tg26-SA/+ mice exhibited reduced expression of podocyte differentiation markers and increased expression of VEGF and proliferation markers as compared to Tg26-SA/- mice. Primary podocytes isolated from Tg26-SA/+ mice showed increased Stat3 phosphorylation and reduced expression of podocyte differentiation markers. The tubulointerstitial compartment and isolated tubules of Tg26-SA/+ mice also had increased Stat3 phosphorylation and expression of Stat3 target genes. We confirmed that the expression of the HIV-1 transgene and reduction of Stat3 activity did not affect T and B cell development. In conclusion, Stat3 plays a critical role in the pathogenesis of HIVAN.

Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy.

Recent studies suggest that Stat3, a transcription factor that mediates cytokine signaling, plays a critical role in the pathogenesis of diabetic nephropathy. Complete Stat3 gene knockout is embryonic lethal; therefore, we crossed Stat3+/- mice with Stat3 mutant mice (SA/SA) that lack full Stat3 activity. This strategy generated Stat3SA/- mice (25% activity) and Stat3SA/+ mice (75% activity), which were made diabetic using streptozotocin in order to define the role of Stat3 in diabetic kidney disease. While the glomerular number was not different between these two groups of mice, the diabetic SA/- mice had significantly less proteinuria, mesangial expansion, glomerular cell proliferation, and macrophage infiltration than the diabetic SA/+ mice. The reduction in Stat3 activity did not affect glomerular hyperfiltration seen after the induction of diabetes, as it was increased to the same degree in both groups of mice. Phosphorylation of Stat3 was markedly increased in the glomeruli of diabetic SA/+ mice compared to diabetic SA/- mice. The expression of inflammatory markers, IL-6, MCP-1, and activated NF-kappaB; type IV collagen, TGF-beta, and ICAM-1 mRNA; or type IV collagen and TGF-beta protein, were all found to be significantly less in glomeruli isolated from diabetic SA/- mice, as compared with diabetic SA/+ mice. Our study shows that Stat3 plays a critical role in the regulation of inflammation and abnormal matrix synthesis at an early stage of DN.

Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation.

A large number of extracellular polypeptides bound to their cognate receptors activate the transcription factor STAT3 by phosphorylation of tyrosine 705. Supplemental activation occurs when serine 727 is also phosphorylated. STAT3 deletion in mice leads to embryonic lethality. We have produced mice with alanine substituted for serine 727 in STAT3 (the SA allele) to examine the function of serine 727 phosphorylation in vivo. Embryonic fibroblasts from SA/SA mice had approximately 50% of the transcriptional response of wild-type cells. However, SA/SA mice were viable and grossly normal. STAT3 wild-type/null (+/-) animals were also normal and were interbred with SA/SA mice to study SA/- mice. The SA/- mice progressed through gestation, showing 10 to 15% reduced birth weight, three-fourths died soon after birth, and the SA/- survivors reached only 50 to 60% of normal size at 1 week of age. The lethality and decreased growth were accompanied by altered insulin-like growth factor 1 (IGF-1) levels in serum, establishing a role for the STAT3 serine phosphorylation acting through IGF-1 in embryonic and perinatal growth. The SA/- survivors have decreased thymocyte number associated with increased apoptosis, but unexpectedly normal STAT3-dependent liver acute phase response. These animals offer the opportunity to study defined reductions in the transcriptional capacity of a widely used signaling pathway.

Cytokeratin 15 is an Effective Indicator for Progression and Malignancy of Esophageal Squamous Cell Carcinomas.

PURPOSE: To compare the expression level of CK 15 in normal esophageal and esophageal squamous-cell carcinoma (ESCC) tissues and analyse possible functions of CK15 in occurrence and development. MATERIALS AND METHODS: Immunohistochemistry was used to compare CK14, CK15 and proliferating cell nuclear antigen (PCNA) expression levels in ESCCs . Expression level of CK15 was also assessed by Western blotting. In addition, levels of CK15, cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) and PCNA were detected in serum by enzyme-linked immunosorbent assay (ELISA) and chemiluminescence methods. Relationships between clinicopathological parameters and CK14 and CK15 expression were then analyzed. RESULTS: According to immunohistochemistry, in esophageal and intraepithelial neoplasia (SIN) tissues, the expression of CK14, CK15 and PCNA localized to basal layer of the epithelium. CK14 and CK15 levels were higher in normal esophageal squamous epithelial tissue than in SIN and ESCC, and greater in highly differentiated than poorly differentiated carcinoma tissue. By Western blotting, we found more pronounced expression of CK15 in normal esophageal tissue, compared with carcinoma tissue. The specificity of changed CK15 and CYFRA21-1 expression was respectively 90.0% and 96.7% in serum of ESCC patients. Joint detection could improve the sensitivity of esophageal carcinoma diagnosis. Relationships between CK14, CK15 expression and clinical parameters were not statistically significant (P>0.05). Postoperative survival in patients of CK14, CK15 positive expression was longer than with negative expression (χ²=4.352, P=0.037; χ²=9.852, P=0.002). CONCLUSIONS: CK15 expression decreased in esophageal squamous cell carcinoma tissue and serum of esophageal squamous carcinoma patients. We infer that CK15 may play an important role for the occurrence and development of esophageal squamous-cell carcinoma. In the future, CK15 may be used for the diagnosis, treatment and prognostic evaluation of esophageal squamous-cell carcinoma.