Emerging strategy for the treatment of urothelial carcinoma: Advances in antibody-drug conjugates combination therapy.

Urothelial carcinoma (UC) is a prevalent malignant tumor involving the urinary system. Although there are various treatment modalities, including surgery, chemotherapy, and immune checkpoint inhibitor (ICI) therapy, some patients experience disease recurrence and metastasis with poor prognosis and dismal long-term survival. Antibody-drug conjugates (ADCs), which combine the targeting ability of antibody drugs with the cytotoxicity of chemotherapeutic drugs, have recently emerged as a prominent research focus in the development of individualized precision cancer therapy. Although ADCs have improved the overall response rate in patients with UC, their effectiveness remains limited. Currently, ADC-based combination therapies, particularly ADC combined with ICIs, have demonstrated promising efficacy. This combination approach has advanced the treatment of UC, exhibiting the potential to become the standard first-line therapy for advanced UC in the future. This article reviewed clinical trials involving ADC-based combination therapy for UC and discussed the possible challenges and future perspectives to provide guidance for the clinical treatment of UC.

Thermostable and nonflammable polyimide/zirconia compound separator for lithium-ion batteries with superior electrochemical and safe properties.

Separators are applied to segregate cathode and anode, and provide ion transport channels in lithium-ion batteries (LIBs). Nevertheless, present commercial polyolefin separators represent high thermal shrinkage and inferior electrolyte wettability, seriously limiting wider development of LIBs. In this work, we prepared zirconia (ZrO2) nanolayer encapsulated polyimide (PI) nanofiber compound separator through in-situ polar adsorption and hydrolysis strategy. The obtained PI/ZrO2 compound separator has superior thermal stability, electrolyte wettability and flame retardance in comparison with polypropylene (PP) separator. The shrinkage ratio of prepared PI/ZrO2 compound separator is 0 even at 300 °C, while the PP separator significantly shrank at 160 °C. Furthermore, the ionic conductivity of PI/ZrO2 separator reaches up to 1.32 mS cm-1, far higher than 0.34 mS cm-1 of PP separator. Besides, the coin batteries of LiNi0.8Co0.1Mn0.1O2 (NCM811)/electrolyte-separator/lithium (Li) assembled with PI/ZrO2 compound separator exhibit enhanced rate performance, high discharge capacity retention rate of 88.3% after 100 cycles at 1C and excellent battery safety performance even at 140 °C. Thus, combined with its advantages, such as preparation, thermostability, electrolyte wettability, electrochemical property and safety, the PI/ZrO2 compound separator exhibits promising prospect in the application of commercial LIBs.

The prevalence and characterization of self-perceived sensitive facial skin among Freshmen in Urumqi, China.

BACKGROUND: The clinical signs, symptoms, and the etiology of sensitive skin (SS) in general populations have been extensively studied over the last decades, but the characteristics of SS in Xinjiang, particularly the age-related characteristics, still remain unknown. OBJECTIVE: This study aimed to characterize the SS facial skin in normal adolescents of Xinjiang. METHODS: A questionnaire was developed based on SS and given to each participant. The clinical signs, symptoms, associated trigger factors, and DQLI of facial SS were compared in normal young Chinese males versus females. RESULTS: A total of 3584 freshmen were investigated, wherein 83 were diagnoses as self-reported facial SS (2.3%). The prevalence of SS was found to be significantly higher in females than in males. Spicy food, mood change, and skin care products are the major contributors to facial SS (p < 0.01). Moreover, family history and sun exposure are closely related to the onset of SS (p < 0.05). More SS patients were sensitive to emotional factors and had a greater difficulty with shopping or housework, dressing, socializing, or other leisure activities. The main manifestations of SS are flushing, erythema, and dry skin on buccal, frontal, and temporal sputum. The symptoms mainly include skin burning and dry itching, and two or more symptoms at the same time. The absolute value of red area and pores of SS were higher than that of normal skin (p < 0.05). CONCLUSIONS: The prevalence, symptoms, clinical characteristics, and triggering factors of facial SS in normal young of Xinjiang, especially freshmen in the 17-21 age group, were not similar with SS, which might be due to racial and regional differences.

Efficacy and safety of bipolar androgen therapy in castration-resistant prostate cancer following abiraterone or enzalutamide resistance: A systematic review.

Bipolar androgen therapy (BAT) is a new endocrinologic treatment for castration-resistant prostate cancer (CRPC) that can restore some patients' sensitivity to drugs such as abiraterone (Abi) and enzalutamide (Enz). We performed a meta-analysis using STATA16. Sensitivity analyses were performed by examining the effects of individual studies using different effect models and detecting any publication bias using the Harbord test. In a total of 108 unique records, ten studies were included in the final meta-analysis. Participants who underwent BAT achieved a PSA50 response rate of 27% (95%CI [0.22,0.31], I2=17.98%), ORR of 34% (95%CI [0.24,0.43], I2=0), and incidence of AEs (grade≥3) of 14% (95%CI [0.09,0.19], I2=0). Patients who completed BAT proceeded to AR-targeted therapy (Abi or Enz) and achieved a PSA50 response rate of 57% (95% CI [0.36,0.78], I2=0). Patients with prior Enz resistance had a stronger impact on the PSA50 of AR-target therapy rechallenge. The results of this meta-analysis indicate that BAT is a safe and effective treatment for patients who have progressed after Abi or Enz. BAT can trigger the resensitization of patients with CRPC to subsequent endocrine therapy and improve the overall survival of patients and their quality of life.

Renal cell carcinoma of different pathological types in bilateral native kidneys of a kidney transplant recipient: A case report and literature review.

Patients after kidney transplantation have a much higher risk of developing malignant tumors than the general population. And the native kidney is an organ relatively susceptible to malignant tumors after renal transplantation. However, the simultaneous development of bilateral renal tumors is very rare; especially the bilateral native kidneys harbor different pathological types of renal cell carcinoma (RCC). We report a case of a patient who developed malignant tumors in both native kidneys nearly 19 years after renal transplantation. This patient underwent bilateral laparoscopic radical nephrectomy, and postoperative pathological examination showed clear cell RCC on the left native kidney and papillary RCC on the right one. And the early detection and surgical treatment resulted in a good prognosis. The literature related to the diagnosis and treatment of bilateral RCC after renal transplantation is also reviewed.

Suppressing BCL-XL increased the high dose androgens therapeutic effect to better induce the Enzalutamide-resistant prostate cancer autophagic cell death.

Most patients with advanced prostate cancer (PCa) initially respond well to androgen deprivation therapy (ADT) with antiandrogens, but most of them eventually become resistant to ADT. Here, we found that the antiandrogen Enzalutamide-resistant (EnzR) PCa cells can be suppressed by hyper-physiological doses of the androgen DHT. Mechanism dissection indicates that while androgens/androgen receptor (AR) can decrease BCL-2 expression to induce cell death, yet they can also simultaneously increase anti-apoptosis BCL-XL protein expression via decreasing its potential E3 ubiquitin ligase, PARK2, through transcriptionally increasing the miR-493-3p expression to target PARK2. Thus, targeting the high dose DHT/AR/miR-493-3p/PARK2/BCL-XL signaling with BCL-XL-shRNA can increase high-dose-DHT effect to better suppress EnzR cell growth via increasing the autophagic cell death. A preclinical study using in vivo mouse model also validated that suppressing BCL-XL led to enhance high dose DHT effect to induce PCa cell death. The success of human clinical trials in the future may help us to develop a novel therapy using high dose androgens to better suppress CRPC progression.

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions.

Nonimmediate drug hypersensitivity reactions (niDHRs) range from mild-type maculopapular exanthema (MPE) to severe type Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with unentirely clarified pathogenesis. This study sought to explore whether complement components participated in niDHRs. The participants comprised of three groups as follows: MPE (n = 65), SJS/TEN (n = 13, contains 7 SJS, 2 SJS-TEN overlap and 4 TEN), and equal healthy controls (n = 78). Skin pathological changes were confirmed by hematoxylin and eosin staining. The mRNA and protein levels of complement components were assessed. In the MPE group, there were no alterations in complement components at the protein and mRNA levels found except for a decrease in factor H mRNA. In the SJS/TEN group, up-regulated levels of C3aR and C5aR mRNA and down-regulated factor H mRNA levels in blood were noted. A lower plasma protein level of C3, Factor H and a higher level of C3a, C5, C5a, C5b-9, Factor B (p < 0.05) were found in the SJS/TEN group compared with in the control (p < 0.05). In SJS/TEN skin lesions, indirect immunofluorescence assays showed positive specific staining for C5b-9, but not C3. Both C3aR and C5aR were positive staining in the SJS/TEN samples, while staining for C1q, mannose-binding lectin (MBL), Factor B, and Factor H were only weak or negative. The findings reported here are the first to define the expression profiles/extent of the presence of various complement components at the mRNA and protein levels in niDHRs, especially in SJS/TEN. These altered complement components might, at least in part, be integral to the mechanisms underlying the pathogeneses of SJS and TEN.

LncRNA MYCNOS facilitates proliferation and invasion in hepatocellular carcinoma by regulating miR-340.

Hepatocellular carcinoma (HCC) remains one of the most common and aggressive human cancers worldwide. Accumulating evidences indicate that non-coding RNAs are critical regulators implicated in various physiological processes including HCC development. Long non-coding RNA (lncRNA) MYCN opposite-strand (MYCNOS) was reported to be up-regulated in several human cancers, yet its role in HCC progression is still elusive. In the present study, MYCNOS was up-regulated in both HCC tissues and cell lines, and elevated MYCNOS expression was correlated to shorter survival time of HCC patients. We knocked down MYCNOS expression using short hairpin RNAs specifically targeting MYCNOS. MYCNOS knockdown significantly inhibited proliferation in HCC cells in vitro accompanied by exacerbated cell apoptosis; it also suppressed tumor growth in mouse model in vivo. Besides, the migration and invasion of HCC cells were remarkably inhibited after MYCNOS knockdown. In addition, MYCNOS acted as a negative regulator of miR-340 in HCC cells, and all effects of MYCNOS knockdown were abrogated by further miR-340 inhibition. We also discovered that oncogene phosphatidylinositol-3, 4, 5-trisphosphate-dependent Rac exchange factor 2 (PREX2) was a downstream target of miR-340, and PREX2 expression was positively correlated to that of MYCNOS in HCC tissues. In conclusion, our findings demonstrated that MYCNOS knockdown inhibited HCC progression through regulating miR-340.

Risky Sexual Behaviors and Associated Factors Among College Students in Lusaka, Zambia.

Risky sexual behaviors are important factors driving the HIV/AIDS epidemic. Although Zambia experiences a high HIV prevalence, especially among youth, there is a dearth of information regarding risky sexual behaviors among young adults. Therefore, we investigated the prevalence and associated factors of risky sexual behaviors among college students in Lusaka, Zambia. A cross-sectional study was conducted in February 2017 among 427 college students at the University of Zambia. Participants reported their sexual behaviors, sexual attitudes, and lifestyle using self-administered questionnaires. Multinomial logistic regression models were employed to assess potential determinants of risky sexual behaviors. Among the 205 students who reported ever having sex, 148 (72.2%) engaged in risky sexual behaviors in the last 12 months. Participants who were older (OR 1.30, 95% CI 1.12-1.51), engaged in low physical activity (OR 2.25, 95% CI 1.05-4.84), and reported liberal sexual attitudes (OR 1.88, 95% CI 1.02-3.47) were more likely to engage in any risky sexual behavior, while frequent alcohol use (OR 8.38, 95% CI 4.60-15.27) and suicide attempts (OR 6.42, 95% CI 2.03-20.29) predicted multiple risky sexual behaviors. In conclusion, this study indicates that Zambian college students' risky sexual behaviors are associated with multiple behavioral health risks. Future research should consider using a multiple-behavior change intervention.

Lipoblastoma of the left kidney: a case report and review of literature.

A lipoblastoma is an infrequent benign tumor derived from embryonal adipose tissue. There are few reports on kidney lipoblastomas; there are fewer than three cases, including our case. An 80-year-old female was detected to have a left renal mass during a routine medical examination. Computed tomography (CT) and magnetic resonance imaging (MRI) indicated a heterogeneous mass before surgery, and histopathological tests subsequently revealed that the mass was a rare lipoblastoma. We present this case as a reminder to consider lipoblastomas in the differential diagnoses of kidney masses.

Application of protein chip combined with SELDI-TOF-MS detection to investigate serum protein expression in patients with silicosis fibrosis.

The present study aimed to observe the identification of biomarkers of silicosis based on the differentially expressed serum proteins between normal healthy individuals and patients with silicosis fibrosis. A total number of 20 patients with clinically diagnosed silicosis were screened, which were designated as the foundation treatment group. In addition, 20 age-matched healthy patients attending a check-up at the physical examination department were selected. Serum samples were obtained and a combined protein chip with surface-enhanced laser desorption ionization flight mass spectrometry was applied to perform serum analysis. Data preprocessing, screening differences in peak, hierarchical cluster analysis, Principal Component Analysis, construction of a decision tree model, and prediction based on the differences between peaks corresponding to proteins were performed to analyze the data. The results revealed differences in the proteins in serum between the normal group and the group prior to foundation treatment prediction. The corresponding names of the protein peak, predicted protein, and gene name were as follows: M1948_00, complement c3 frag, C3; M2017_02, amyloid-ßa4 protein, APP; and M2879_56, hepcidin, HAMP. Differentially expressed serum proteins in the normal group and the basis treatment group were predicted, including M2017_02, amyloid-ßa4 protein, APP; M2879_56, hepcidin, HAMP; and M3224_97, fibrinogen-α chain frags, FGA. The differentially expressed serum proteins in the group prior to basis treatment and the group following basis treatment were predicted, including M2001_69, amyloid-ßa4 protein, APP; M2017_02, amyloid-ßa4 protein, APP, M4144_81, plasma protease c1 inhibitor frag, and SERPING1. In conclusion, there were differences in the proteins in serum between the patients with silicosis fibrosis and healthy individuals.

Long noncoding RNA TUG1 promotes renal cell carcinoma cell proliferation, migration and invasion by downregulating microRNA­196a.

Long noncoding RNA taurine upregulated gene 1 (lncRNA TUG1) and microRNA­196a (miR­196a) have been reported to serve important roles in the development of renal cell carcinoma (RCC). However, their potential mechanisms have not been completely elucidated. The aim of the present study was to clarify the biological functions of lncRNA­TUG1 and miR­196a, in addition to investigating the interaction between lncRNA­TUG1 and microRNA­196a, providing a novel insight into RCC tumorigenesis. The present study comprised two parts. In the first part, lncRNA­TUG1 was confirmed as an oncogene, via reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis, MTT assay, flow cytometry analysis, and migration and invasion assays. In the second part, the association between lncRNA­TUG1 and miR­196a, and the molecular mechanism, was illustrated via RT­qPCR analysis, MTT assay, dual luciferase reporter assay and western blotting. The results of the present study demonstrated that lncRNA­TUG1 was able to promote RCC cell proliferation, migration and invasion in vitro by suppressing miR­196a. Additionally, lncRNA­TUG1 achieved its biological functions by regulating the expression levels of RAC­α serine/threonine­protein kinase, mitogen­activated protein kinase and extracellular signal­regulated kinase via inhibition of miR­196a. In conclusion, the present findings proposed a novel potential therapeutic target, the lncRNA­TUG1­miR­196a axis, which may be applicable to the treatment of RCC.

Analysis of short-term and sub-chronic effects of ambient air pollution on preterm birth in central China.

Recently, an increasing number of studies have reported the possible linkage between maternal exposure to ambient air pollution and adverse birth outcomes. This retrospective cohort study aimed to evaluate the effect of short-term and sub-chronic exposure to air pollutants on preterm birth occurred in Shiyan and Jingzhou, Hubei province, China from 2014 to 2016. General additive models (GAM) were performed to examine the impact of the daily and cumulative weekly air pollutants exposure. The non-linear patterns between adverse birth outcomes and weather condition were assessed by including penalized smoothing splines in the model. The demographic characteristics of pregnant women were also included in the model as covariates. A total of 16,035 cases were analyzed. Significant short-term effects of air pollution exposure at lag 1 day on preterm birth were observed. In adjusted single-pollutant city-specific model, the association between acute air pollutant exposure and preterm birth was significant in Shiyan (PM2.5: OR = 1.066, 95% CI 1.027, 1.106; PM10: OR = 1.048, 95% CI 1.022, 1.076; O3: OR = 1.029, 95% CI 1.004, 1.056) and Jingzhou (PM2.5: OR = 1.037, 95% CI 1.008, 1.068; PM10: OR = 1.025, 95% CI 1.007, 1.043; SO2: OR = 1.082, 95% CI 1.023, 1.144; NO2: OR = 1.211, 95% CI 1.098, 1.335) per 10 µg/m3 increment. Also, weekly average cumulative air pollution exposure was significantly associated with preterm birth in both areas.

Viral mimic polyinosine-polycytidylic acid potentiates liver injury in trichloroethylene-sensitized mice - Viral-chemical interaction as a novel mechanism.

Occupational trichloroethylene (TCE) exposure can induce hypersensitivity dermatitis and severe liver injury. Recently, several clinical investigations indicate that viral infection, such as human herpesvirus-6, is associated with hepatic dysfunction in patients with TCE-related generalized skin disorders. However, whether viral infection potentiates TCE-induced liver injury remains unknown. This study aimed to explore the contribution of viral infection to the development of TCE-sensitization-induced liver injury in BALB/c mice. Female BALB/c mice were randomly assigned into four groups: solvent control group (n = 20), TCE group (n = 80), poly(I:C) group (n = 20) and combination of TCE and poly(I:C) (poly(I:C)+TCE) group (n = 80). Poly(I:C) (50 µg) was i.p. administrated. TCE and poly(I:C)+TCE groups were further divided into sensitization and non-sensitization subgroup. Complement 3 and C3a protein levels, and complement factors were measured. Combination treatment significantly enhanced TCE-induced liver injury, decreased complement 3, but increased C3a in serum and liver tissues in sensitization group. These changes were not correlated with the hepatic complement 3 transcription. Moreover, combination treatment specifically promoted complement factor B, but not factor D and factor H expressions. These data provide first evidence that poly(I:C) potentiates liver injury in BALB/c mouse model of TCE-sensitization. Upregulated C3a and factor B contributes to the poly(I:C) action in TCE-induced liver injury. This new mode of action may explain increased risk of chemical-sensitization induced tissue damage by viral infection.

LncRNA FLVCR1-AS1 acts as miR-513c sponge to modulate cancer cell proliferation, migration, and invasion in hepatocellular carcinoma.

In the present study, we aimed to search for dysregulated lnRNAs in Hepatocellular carcinoma (HCC) tissues, and analyze the relationship of its expression level with the clinicopathological feature and patient prognosis. The biological function of FLVCR1-AS1, the identified lncRNA, in the process of HCC development, and progression was investigated in vitro and in vivo. The underlying molecular mechanism was further explored. We determined FLVCR1-AS1 expression in HCC tissues and peri-tumor tissues by bioinformatic analysis, qRT-PCR, Northern blot and in situ hybridization. The relationship between FLVCR1-AS1 expression level and prognosis was determined by analyzing clinical samples. The effects of FLVCR1-AS1 knockdown on HCC cell proliferation, apoptosis, migration, and invasion were investigated by CCK8, FACS, and tanswell assay, respectively. Tumor xenograft model was used to determine the influence of down-regulated FLVCR1-AS1 on tumor growth and metastasis. lncRNA FLVCR1-AS1 was extremely up-regulated in HCC tissues and cell lines. FLVCR1-AS1 expression level was positively correlated with tumor severity. FLVCR1-AS1 knockdown remarkably inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo while induced cell apoptosis. In mechanism, FLVCR1-AS1 acted as a competitive endogenous RNAs to sponge miR-513c which targeted the mRNA of MET for degradation. By directly sponging miR-513c, FLVCR1-AS1 increased MET expression in HCC, and then promoted HCC progression. It was demonstrated that FLVCR1-AS1 played a positive role in HCC development and progression according to the study in its mechanism, function and clinical manifestation, so that it could be expected to become a new target in HCC prevention and treatment.

mfat-1 transgene protects cultured adult neural stem cells against cobalt chloride-mediated hypoxic injury by activating Nrf2/ARE pathways.

Ischemic stroke is a devastating neurological disorder and one of the leading causes of death and serious disability in adults. Adult neural stem cell (NSC) replacement therapy is a promising treatment for both structural and functional neurological recovery. However, for the treatment to work, adult NSCs must be protected against hypoxic-ischemic damage in the ischemic penumbra. In the present study, we aimed to investigate the neuroprotective effects of the mfat-1 transgene on cobalt chloride (CoCl2 )-induced hypoxic-ischemic injury in cultured adult NSCs as well as its underlying mechanisms. The results show that in the CoCl2 -induced hypoxic-ischemic injury model, the mfat-1 transgene enhanced the viability of adult NSCs and suppressed CoCl2 -mediated apoptosis of adult NSCs. Additionally, the mfat-1 transgene promoted the proliferation of NSCs as shown by increased bromodeoxyuridine labeling of adult NSCs. This process was related to the reduction of reactive oxygen species. Quantitative real-time polymerase chain reaction and Western blot analysis revealed a much higher expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genes (HO-1, NQO-1, GCLC). Taken together, our findings show that the mfat-1 transgene restored the CoCl2 -inhibited viability and proliferation of NSCs by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signal pathway to inhibit oxidative stress injury. Further investigation of the function of the mfat-1 transgene in adult protective mechanisms may accelerate the development of adult NSC replacement therapy for ischemic stroke.

Potential immunotoxic effects of trichloroethylene-induced IV allergic reaction in renal impairment.

Trichloroethylene (TCE) is known to induce allergic contact dermatitis and subsequent occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney, and skin injuries. However, the mechanisms underlying immune system dysfunction that result in organ injury have not yet been clearly elucidated. In the present study, we measured the levels of secreted cytokines by effect or T cells in TCE-treated guinea pigs to better understand the contribution of allergic disorders in renal injuries. We immunized guinea pigs with trichloroethylene using the Guinea Pig Maximization Test (GPMT) and scored the inflammation on the guinea pigs' skin. The kidney function and ultra-structural changes in the kidneys were detected using biochemical methods and electron microscopy. The deposition of cytokines was determined using immunohistochemistry. The sensitization rate was 63.16% in the TCE-sensitized groups. The electron microscopy results showed tubular epithelial cell mitochondrial swelling, vacuolar degeneration, and atrophy of the microvillus in the sensitized groups. A high degree of cytokine deposition was observed in the renal tubular proximal epithelial cells in the TCE-sensitized groups. As observed in this study, the variation in the level of immune system activation not only indicates that TCE can largely magnify the immune reaction but also suggests a potential role of immune dysfunction in renal impairment.