KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation.

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

Roles of PPAR activation in cancer therapeutic resistance: Implications for combination therapy and drug development.

Therapeutic resistance is a major obstacle to successful treatment or effective containment of cancer. Peroxisome proliferator-activated receptors (PPARs) play an essential role in regulating energy homeostasis and determining cell fate. Despite of the pleiotropic roles of PPARs in cancer, numerous studies have suggested their intricate relationship with therapeutic resistance in cancer. In this review, we provided an overview of the roles of excessively activated PPARs in promoting resistance to modern anti-cancer treatments, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The mechanisms through which activated PPARs contribute to therapeutic resistance in most cases include metabolic reprogramming, anti-oxidant defense, anti-apoptosis signaling, proliferation-promoting pathways, and induction of an immunosuppressive tumor microenvironment. In addition, we discussed the mechanisms through which activated PPARs lead to multidrug resistance in cancer, including drug efflux, epithelial-to-mesenchymal transition, and acquisition and maintenance of the cancer stem cell phenotype. Preliminary studies investigating the effect of combination therapies with PPAR antagonists have suggested the potential of these antagonists in reversing resistance and facilitating sustained cancer management. These findings will provide a valuable reference for further research on and clinical translation of PPAR-targeting treatment strategies.

[Protective effect of oleanolic acid liposomes on cisplatin-induced oligoasthenospermia in mice].

OBJECTIVE: To study the protective effect of oleanolic acid liposomes (OA-Lips) on cisplatin-induced oligoasthenospermia (COAS) in mice. METHODS: Sixty ICR mice were randomly divided into a normal control, a COAS model control, a positive control and a low-, a medium- and a high-dose OA-Lips group. The animals in the low-, medium- and high-dose OA-Lips and positive control groups were given intragastrically OA-Lips solution at 25, 50, and 100 mg/kg/d and vitamin E at 50 mg/kg/d, respectively. On the 28th day, the mice in the COAS model control, positive control and OA-Lips groups were injected intraperitoneally with cisplatin solution at 10 mg/kg, while those in the normal control group with the same dose of normal saline. Three days after administration, all the mice were sacrificed and their testis tissues collected for detection of the semen parameters and observation of the testicular morphology. RESULTS: Both the percentage of motile sperm and sperm concentration were significantly increased in the high-dose OA-Lips group (P < 0.05). HE staining showed that OA-Lips remarkably improved the damaged testis tissue (P < 0.05) and protected the seminiferous tubules and interstitial cells. The percentage of progressively motile sperm (PMS) and the curvilinear velocity (VCL), straight line velocity (VSL), average path velocity (VAP), linearity (LIN), straightness (STR), wobble (WOB), amplitude of lateral head displacement (ALH) and beat-cross frequency (BCF) of sperm were gradually increased in a dose-dependent manner in the OA-Lips groups. The serum T level was significantly higher (P < 0.05) in the OA-Lips-treated mice than in the COAS model controls while the percentage of morphologically abnormal sperm (MAS) markedly lower in the high-dose OA-Lips group than in the model control, positive control and low-dose OA-Lips groups (P < 0.05). CONCLUSION: OA-Lips can relieve oligoaspermia and improve the productive ability of mice.

Temporal trends of carbon monoxide poisoning mortality at the global, regional and national levels: a cross-sectional study from the Global Burden of Disease study, 1990 and 2017.

OBJECTIVES: Carbon monoxide (CO) poisoning is one of the most frequent causes of fatal poisoning worldwide. Few studies have explored the mortality trends of CO poisoning grouped by age and gender, at the regional, national and global levels. We therefore aimed to determine the pattern of CO poisoning mortality, as well as temporal trends at all levels. DESIGN: A cross-sectional survey design was used in this study. SETTING: CO poisoning data collected from the Global Burden of Diseases (GBDs), from 1990 to 2017, was arranged by sex, age, region and country. In addition, we used human development index data at the national level from the World Bank. PARTICIPANTS: We collected over 100 000 information on CO poisoning mortality between 1990 and 2017, derived from the GBD study in 2017. MAIN OUTCOMES AND MEASURES: We have calculated the estimated annual percentage changes in CO poisoning age-standardised mortality rate (ASR), by sex and age at different regions and countries to quantify the temporal trends in CO poisoning ASR. RESULTS: Globally, death cases of CO poisoning decreased 7.2% from 38 210 in 1990 to 35 480 in 2017. The overall ASR decreased by an average of 1.83% (95% CI 2.10% to 1.56%) per year in this period. This decreasing pattern was heterogeneous across ages, regions and countries. The most pronounced decreases were generally observed in countries with a high sociodemographic index, including Estonia, South Korea and Puerto Rico. CONCLUSIONS: Current prevention strategies should be reoriented, and much more targeted and specific strategies should be established in some countries to forestall CO poisoning.

Association between acute severe mercury poisoning and multiple organ failure.

Acute mercury poisoning, involving a number of organs, leads to severe dysfunctions, such as acute renal failure (ARF), and even threatens patients' lives. A case of acute severe mercuric chloride (HgCl2) poisoning with multiple organ failure was reported in this study. A 38-year-old woman orally took about 50 g HgCl2 powder in 2015, and showed nausea, emesis, clouding of consciousness, lip and nail cyanosis, and dark red bloody fluid from bilateral nostrils. Based on chest and abdominal CT examinations, gastroscopy, and colonoscopy, the patient was found to suffer oral mucosal hyperemia and ulceration, gastrointestinal bleeding (haematemesis and hemafecia), ARF, metabolic acidosis, collapse and shock. Despite assisted respiration and relevant active treatments, the patient's condition deteriorated gradually and she was dead eventually. The study suggests that the best treatments for acute HgCl2 poisoning accompanied with ARF are early blood purification and mercury elimination on the basis of conventional therapy.

[Efficacy analysis of prussian blue or its combination with hemoperfusion in the treatment of acute thallium poisoning].

OBJECTIVE: To investigate the efficacy of prussian blue (PB) or its combination with hemoperfusion (HP) in the treatment of acute thallium poisoning. METHODS: Forty-seven patients with acute thallium poisoning with complete data hospitalized in the 307th Hospital of PLA from September 2002 to December 2017 were enrolled, and they were divided into mild poisoning group (blood thallium < 150 µg/L, urinary thallium < 1 000 µg/L) and moderate-severe poisoning group (blood thallium ≥ 150 µg/L, urinary thallium ≥ 1 000 µg/L) according to the toxic degrees. All patients were given symptomatic supportive treatments such as potassium supplementation, catharsis, vital organ protections, neurotrophic drugs, and circulation support. The mild poisoning patients were given PB with an oral dose of 250 mg×kg-1×d-1, while moderate-severe poisoning patients were given PB combined HP continued 2-4 hours each time. The PB dose or frequency of HP application was adjusted according to the monitoring results of blood and urine thallium. Data of gender, age, pain grading (numeric rating scale NRS), clinical manifestations, blood and urine thallium before and after treatment, length of hospitalization and prognosis were collected. RESULTS: Of the 47 patients, patients with incomplete blood and urine test results, and used non-single HP treatment such as plasmapheresis and hemodialysis for treatment were excluded, and a total of 29 patients were enrolled in the analysis. (1) Among 29 patients, there were 20 males and 9 females, median age of 40.0 (34.0, 49.0) years old; the main clinical manifestations were nervous system and alopecia, some patients had digestive system symptoms. There were 13 patients (44.8%) in the mild poisoning group with painless (grade 0) or mild pain (grade 1-3) with mild clinical symptoms, the length of hospitalization was 17.0 (14.2, 21.5) days. There were 16 patients (55.2%) in the moderate-severe poisoning group with moderate pain (grade 4-6) or severe pain (grade 7-10) with severe clinical symptoms, the length of hospitalization was 24.0 (18.0, 29.0) days. (2) After treatment, the thallium concentrations in blood and urine in the mild poisoning group were significantly lower than those before treatment [µg/L: blood thallium was 0.80 (0, 8.83) vs. 60.00 (40.00, 120.00), urine thallium was 11.30 (0, 70.10) vs. 370.00 (168.30, 610.00), both P < 0.01], the thallium concentrations in blood and urine in the moderate-severe poisoning group were also significantly lower than those before treatment [µg/L: blood thallium was 6.95 (0, 50.50) vs. 614.50 (245.00, 922.00), urinary thallium was 20.70 (1.95, 283.00) vs. 5 434.00 (4 077.20, 10 273.00), both P < 0.01]. None of the 29 patients died, and their clinical symptoms were improved significantly. All the 27 patients had good prognosis without sequela in half a year follow-up, and 2 patients with severe acute thallium poisoning suffered from nervous system injury. CONCLUSIONS: In the acute thallium poisoning patients, on the basis of general treatment, additional PB in mild poisoning group and PB combined with HP in moderate-severe poisoning group can obtain satisfactory curative effects.