Dysregulated Ribosome Biogenesis Is a Targetable Vulnerability in Triple-Negative Breast Cancer: MRPS27 as a Key Mediator of the Stemness-inhibitory Effect of Lovastatin.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.

Associations of bisphenol A exposure with metabolic syndrome and its components: A systematic review and meta-analysis.

Mounting evidence shows that bisphenol A (BPA) is associated with metabolic risk factors. The aim of this study was to review related epidemiologic studies and conduct a meta-analysis to quantitatively estimate the association between BPA and metabolic syndrome. Four electronic databases were systematically searched to identify suitable articles. A total of 47 published studies were finally included. Two studies involved metabolic syndrome. Of the 17, 17, 14, and 13 studies on the relationship between BPA with abdominal obesity, blood pressure, fasting plasma glucose, and dyslipidemia, 10, 6, 3, and 4 studies were included in the meta-analysis, respectively. The results showed that the risk of abdominal obesity increased with the increase of BPA exposure, especially in the group with higher BPA exposure levels (Quartile 2 vs. Quartile 1, pooled OR = 1.16, 95%CI: 1.01, 1.33; Q3 vs. Q1 , pooled OR = 1.31, 95%CI: 1.13, 1.51; Q4 vs. Q1 , pooled OR = 1.40, 95%CI: 1.21, 1.61). However, there was no significant correlation between BPA exposure and metabolic syndrome components including hypertension, abnormal fasting plasma glucose, and dyslipidemia. The present study found that BPA exposure is significantly associated with a higher risk of abdominal obesity. However, the relationship between BPA with metabolic syndrome and its other components needs further longitudinal studies to verify.

Disulfidptosis: Six Riddles Necessitating Solutions.

Disulfidptosis occurs as a result of the accumulation of intracellular cystine followed by disulfide stress in actin cytoskeleton proteins due to a reduction of NADPH produced through the pentose phosphate pathway in cells with high expression of SLC7A11. It is a cell death caused by the redox imbalance resulting from the disruption of amino acid metabolism and glucose metabolism. The discovery of disulfidptosis has sparked immense enthusiasm, but there are numerous unresolved issues that need to be addressed. Solutions to these riddles will provide insights into the detailed mechanisms and the pathophysiological relevance of disulfidptosis and utilizing disulfidptosis as an actionable therapeutic target.

Amino acids and their roles in tumor immunotherapy of breast cancer.

Breast cancer is the most commonly diagnosed cancer among women. The primary treatment options include surgery, radiotherapy, chemotherapy, targeted therapy and hormone therapy. The effectiveness of breast cancer therapy varies depending on the stage and aggressiveness of the cancer, as well as individual factors. Advances in early detection and improved treatments have significantly increased survival rates for breast cancer patients. Nevertheless, specific subtypes of breast cancer, particularly triple-negative breast cancer, still lack effective treatment strategies. Thus, novel and effective therapeutic targets for breast cancer need to be explored. As substrates of protein synthesis, amino acids are important sources of energy and nutrition, only secondly to glucose. The rich supply of amino acids enables the tumor to maintain its proliferative competence through participation in energy generation, nucleoside synthesis and maintenance of cellular redox balance. Amino acids also play an important role in immune-suppressive microenvironment formation. Thus, the biological effects of amino acids may change unexpectedly in tumor-specific or oncogene-dependent manners. In recent years, there has been significant progress in the study of amino acid metabolism, particularly in their potential application as therapeutic targets in breast cancer. In this review, we provide an update on amino acid metabolism and discuss the therapeutic implications of amino acids in breast cancer.

Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in TNBC but still encounters low overall response. Neutrophils, the most abundant leukocytes in the body, are increasingly recognized as an active cancer-modulating entity. In the bloodstream, neutrophils escort circulating tumor cells to promote their survival and stimulate their proliferation and metastasis. In the tumor microenvironment, neutrophils modulate the immune milieu through polarization between the anti-tumor and the pro-tumor phenotypes. Through a comprehensive review of recently published literature, it is evident that neutrophils are an important player in TNBC immunobiology and can be used as an important prognostic marker of TNBC. Particularly, in their pro-tumor form, neutrophils facilitate TNBC metastasis through formation of neutrophil extracellular traps and the pre-metastatic niche. These findings will help advance the potential utilization of neutrophils as a therapeutic target in TNBC.

Exoskeleton-Assisted Anthropomorphic Movement Training for the Upper Limb After Stroke: The EAMT Randomized Trial.

BACKGROUND: Robot-assisted arm training is generally delivered in the robot-like manner of planar or mechanical 3-dimensional movements. It remains unclear whether integrating upper extremity (UE) natural coordinated patterns into a robotic exoskeleton can improve outcomes. The study aimed to compare conventional therapist-mediated training to the practice of human-like gross movements derived from 5 typical UE functional activities managed with exoskeletal assistance as needed for patients after stroke. METHODS: In this randomized, single-blind, noninferiority trial, patients with moderate-to-severe UE motor impairment due to subacute stroke were randomly assigned (1:1) to receive 20 sessions of 45-minute exoskeleton-assisted anthropomorphic movement training or conventional therapy. Treatment allocation was masked from independent assessors, but not from patients or investigators. The primary outcome was the change in the Fugl-Meyer Assessment for Upper Extremity from baseline to 4 weeks against a prespecified noninferiority margin of 4 points. Superiority would be tested if noninferiority was demonstrated. Post hoc subgroup analyses of baseline characteristics were performed for the primary outcome. RESULTS: Between June 2020 and August 2021, totally 80 inpatients (67 [83.8%] males; age, 51.9±9.9 years; days since stroke onset, 54.6±38.0) were enrolled, randomly assigned to the intervention, and included in the intention-to-treat analysis. The mean Fugl-Meyer Assessment for Upper Extremity change in exoskeleton-assisted anthropomorphic movement training (14.73 points; [95% CI, 11.43-18.02]) was higher than that of conventional therapy (9.90 points; [95% CI, 8.15-11.65]) at 4 weeks (adjusted difference, 4.51 points [95% CI, 1.13-7.90]). Moreover, post hoc analysis favored the patient subgroup (Fugl-Meyer Assessment for Upper Extremity score, 23-38 points) with moderately severe motor impairment. CONCLUSIONS: Exoskeleton-assisted anthropomorphic movement training appears to be effective for patients with subacute stroke through repetitive practice of human-like movements. Although the results indicate a positive sign for exoskeleton-assisted anthropomorphic movement training, further investigations into the long-term effects and paradigm optimization are warranted. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100044078.

Association between napping and 24-hour blood pressure variability among university students: A pilot study.

Background: Blood pressure variability (BPV) has been reported to be a predictor of cardiovascular and some cognitive diseases. However, the association between napping and BPV remains unknown. This study aimed to explore the association between napping and BPV. Materials and methods: A cross-sectional study including 105 university students was conducted. Participants' 24 h ambulatory blood pressure monitoring (24 h ABPM) were measured, and napping behaviors were investigated. BPV were measured by the 24 h ABPM, included standard deviation (SD), coefficient of variation (CV), and average real variability (ARV). Results: Among the participants, 61.9% reported daytime napping. We found that nap duration was significantly associated with daytime CV of diastolic blood pressure (DBP) (r = 0.250, P = 0.010), nighttime CV of systolic blood pressure (SBP) (r = 0.217, P = 0.026), 24 h WCV of DBP (r = 0.238, P = 0.014), 24 h ARV of SBP (r = 0.246, P = 0.011) and 24 h ARV of DBP (r = 0.291, P = 0.003). Compared with the no napping group, 24 h WCV of DBP, daytime CV of DBP, and daytime SD of DBP were significantly higher in participants with napping duration >60 min. With multiple regression analysis we found that nap duration was an independent predictor for 24 h ARV of SBP (ß = 0.859, 95% CI, 0.101-1.616, P = 0.027) and 24 h ARV of DBP (ß = 0.674, 95% CI, 0.173-1.175, P = 0.009). Conclusions: Napping durations are associated with BPV among university students. Especially those with napping durations >60 min had a significantly higher BPV than those non-nappers.

Association of BMAL1 clock gene polymorphisms with fasting glucose in children.

BACKGROUND: The brain and muscle Arnt-like protein-1 (BMAL1) gene is an important circadian clock gene and previous studies have found that certain polymorphisms are associated with type 2 diabetes in adults. However, it remains unknown if such polymorphisms can affect fasting glucose in children and if other factors modify the associations. METHODS: A school-based cross-sectional study with 947 Chinese children was conducted. A multivariable linear regression model was used to analyze the association between BMAL1 gene polymorphisms and fasting glucose level. RESULTS: After adjusting for age, sex, body mass index (BMI), physical activity, and unhealthy diet, GG genotype carriers of BMAL1 rs3789327 had higher fasting glucose than AA/GA genotype carriers (b = 0.101, SE = 0.050, P = 0.045). Adjusting for the same confounders, rs3816358 was shown to be significantly associated with fasting glucose (b = 0.060, SE = 0.028, P = 0.032). Furthermore, a significant interaction between rs3789327 and nutritional status on fasting glucose was identified (Pinteraction = 0.009); rs3789327 was associated with fasting glucose in the overweight/obese subgroup (b = 0.353, SE = 0.126, P = 0.006), but not in non-overweight/non-obese children. CONCLUSIONS: BMAL1 polymorphisms were significantly associated with the fasting glucose level in children. Additionally, the observed interaction between nutritional status and BMAL1 supports promoting an optimal BMI in children genetically predisposed to higher glucose level. IMPACT: Polymorphisms in the essential circadian clock gene BMAL1 were associated with fasting blood glucose levels in children. Additionally, there was a significant interaction between nutritional status and BMAL1 affecting fasting glucose levels. BMAL1 rs3789327 was associated with fasting glucose only in overweight/obese children. This finding could bring novel insights into mechanisms by which nutritional status influences fasting glucose in children.

A bibliometric analysis of 16,826 triple-negative breast cancer publications using multiple machine learning algorithms: Progress in the past 17 years.

Background: Triple-negative breast cancer (TNBC) is proposed at the beginning of this century, which is still the most challenging breast cancer subtype due to its aggressive behavior, including early relapse, metastatic spread, and poor survival. This study uses machine learning methods to explore the current research status and deficiencies from a macro perspective on TNBC publications. Methods: PubMed publications under "triple-negative breast cancer" were searched and downloaded between January 2005 and 2022. R and Python extracted MeSH terms, geographic information, and other abstracts from metadata. The Latent Dirichlet Allocation (LDA) algorithm was applied to identify specific research topics. The Louvain algorithm established a topic network, identifying the topic's relationship. Results: A total of 16,826 publications were identified, with an average annual growth rate of 74.7%. Ninety-eight countries and regions in the world participated in TNBC research. Molecular pathogenesis and medication are most studied in TNBC research. The publications mainly focused on three aspects: Therapeutic target research, Prognostic research, and Mechanism research. The algorithm and citation suggested that TNBC research is based on technology that advances TNBC subtyping, new drug development, and clinical trials. Conclusion: This study quantitatively analyzes the current status of TNBC research from a macro perspective and will aid in redirecting basic and clinical research toward a better outcome for TNBC. Therapeutic target research and Nanoparticle research are the present research focus. There may be a lack of research on TNBC from a patient perspective, health economics, and end-of-life care perspectives. The research direction of TNBC may require the intervention of new technologies.

The conserved domain database in 2023.

NLM's conserved domain database (CDD) is a collection of protein domain and protein family models constructed as multiple sequence alignments. Its main purpose is to provide annotation for protein and translated nucleotide sequences with the location of domain footprints and associated functional sites, and to define protein domain architecture as a basis for assigning gene product names and putative/predicted function. CDD has been available publicly for over 20 years and has grown substantially during that time. Maintaining an archive of pre-computed annotation continues to be a challenge and has slowed down the cadence of CDD releases. CDD curation staff builds hierarchical classifications of large protein domain families, adds models for novel domain families via surveillance of the protein 'dark matter' that currently lacks annotation, and now spends considerable effort on providing names and attribution for conserved domain architectures. CDD can be accessed at https://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml.

Trends and influencing factors of endurance performance of Han college students in Hunan Province during 1985-2019 / 中国学校卫生

Objective@#To analyze the trends and influencing factors of endurance performance of 19-22 years old college students in Hunan Province from 1985 to 2019, so as to provide objective and scientific basis for sports and health work in colleges and universities.@*Methods@#A retrospective analysis was conducted on the data of 14 490 college students aged 19-22 in Hunan Province from 8 consecutive National Student Physical Fitness and Health Surveys conducted from 1985 to 2019. The analysis indexes were 1 000 m running for boys and 800 m running for girls.@*Results@#From 1985 to 2019, the endurance running time of 19-22 years old Han college students in Hunan Province showed an obvious trend of decline. The 1 000 m running time of urban and rural male students increased by 41.9 and 45.4 s on average, and the 800 m running time of urban and rural female students increased by 29.5 and 30.6 s on average, respectively. Multiple linear regression analysis showed that age ( β =0.17), urban students (rural students as reference; β =0.44), GDP ( β =0.94) and urbanization level ( β = 0.44 ) were positively correlated with the average endurance running time of males. Urban students ( β =0.92), GDP ( β = 1.38 ) and Engel coefficient ( β =0.93) were positively correlated with the average endurance running time of females. BMI ( β =-0.47) was negatively correlated with the females mean time of endurance running ( P ＜0.05).@*Conclusion@#The endurance performance of Han college students in Hunan Province showed a declining trend from 1985 to 2019,which is associated with age, urban and rural distribution, regional GDP, Engel s coefficient, urbanization level and BMI. Effective measures should be taken to improve the physical quality of college students.

Hexokinase 2 Is a Pivot for Lovastatin-induced Glycolysis-to-Autophagy Reprogramming in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited therapeutic options available. We have recently demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, suppresses TNBC cell proliferation and stemness properties in vitro and in vivo. However, the mechanisms through which lovastatin inhibits TNBC cells are not fully understood. Here, we used 1H NMR-based metabolomic profiling to investigate lovastatin-induced metabolic changes in TNBC cell line MDA-MB-231. Among the 46 metabolites identified, lactate demonstrated the highest variable importance in projection (VIP) score. Glycolysis stress test revealed that lovastatin significantly decreased the extracellular acidification rate (ECAR) in MDA-MB-231 cells. Furthermore, lovastatin treatment down-regulated the levels of glycolysis-related proteins including GLUT1, PFK1, and PKM2 in MDA-MB-231 but not non-TNBC MDA-MB-453 cells. In addition, lovastatin induced autophagy as evidenced by increased LC3 puncta formation and LC3-II/I ratio, increased AMPK phosphorylation, and decreased Akt phosphorylation. We also revealed the interaction between the glycolytic enzyme hexokinase 2 (HK2) and the mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1), an important regulator of autophagy. Further bioinformatics analysis revealed that VDAC1 was expressed at a higher level in breast cancer than normal tissues and higher level of VDAC1 predicted poorer survival outcomes in breast cancer patients. The present study suggests that lovastatin might exert anti-tumor activity by reprogramming glycolysis toward autophagy in TNBC cells through HK2-VDAC1 interaction.

[Associations between birth outcomes with blood pressure level and risk of high blood pressure in childhood].

OBJECTIVE: To explore the associations between birth outcomes and blood pressure, and study the sex dimorphism of these associations. METHODS: With a multistage cluster random sampling method, 62 168 children were recruited in seven provinces of China in September of 2013, with 32 064 boys and 30 104 girls, median age of 10.74 years and mean birth weight of 3.3 kg, 49 843 single birth(97%), 1339 twin(2.6%), 180 triplet or more(0.4%). Questionnaire investigation and physical examination were conducted in the present study. Weight, height and blood pressure were measured in the physical examination. Demographic characteristics, birth outcomes(including birth weight and number of births), dietary behavior, physical activities were measured by questionnaire. The widely used age-, gender-and height-specific high blood pressure standard developed by American CDC was used for the present study. Multivariate linear and logistic regression analysis were conducted to study the associations between birth outcomes and blood pressure level or high blood pressure(HBP), and also sex dimorphism of these associations was explored. RESULTS: A total of 5933 children were categorized as having high blood pressure in the 62 168 participants(9.5%). With stratified analyses by birth weight category, only in the low-birth-weight strata birth weight was significantly inversely associated with systolic blood pressure(SBP) and diastolic blood pressure(DBP) with potential covariates adjusted(SBP: b=-1.628, 95%CI-2.571--0.685, P=0.001; DBP: b=-1.463, 95%CI-2.186--0.740, P<0.001). While compared with the non-low birth weight children, low birth weight was not associated with higher risk of HBP(P>0.05). Compared with those boys born as singleton, boys born as one of the twins have a 36.4% higher risk of HBP(OR=1.364, 95%CI 1.049-1.774), while in girls no such significant association was found. Additionally, compared with a term birth, overdue birth and preterm birth was not associated with higher risk of HBP(P>0.05). CONCLUSION: Birth weight and singleton or not were associated with childhood blood pressure levels and higher risk of high blood pressure, and some associations were sex specific. Gender differences should be paid attention to in the prevention and control of high blood pressure in children and adolescents in the future, and the prevention and control should be focused on low-birth weight children or twin boys.

Early life exposure to the Chinese Famine of 1959 - 1961 is an independent risk factor of adulthood elevated homocysteine, hyperuricemia, high LDL, and hypertension.

Famine exposure in early life was associated with cardiovascular diseases in later life. Whether biochemical surrogates of cardiovascular diseases, such as homocysteine and uric acid, are also associated with famine exposure is unknown so far. Data were derived from a population-based cross-sectional study in the Hunan Province of China, which was heavily affected by the Famine in 1959 - 1961. A total of 1,150 adults born between 1952 and 1964 were selected, and 5 cohorts were defined: no exposure, fetal, early childhood, mid-childhood, and late childhood exposure. Compared with the no-famine exposure group, participants exposed to famine in their fetal period had a higher risk of high homocysteine in adulthood with OR of 2.21 (95% CI: 1.01 - 4.83), whereas famine exposures in early, mid, or late childhood were not significantly associated with high homocysteine in adulthood. Similarly, participants in the fetal famine exposure group had a 1.59-fold higher risk of hyperuricemia (OR = 2.59, 95% CI: 1.07 - 5.30) and a 2.03-fold higher risk of high low-density lipoprotein cholesterol (LDL) (OR = 0.03, 95% CI: 1.35 - 6.78) in adulthood compared to those without famine exposure, respectively. We furthermore conducted a meta-analysis including 16 studies regarding the association between fetal famine exposure and adulthood hypertension, including our study. The meta-analysis, including 34,804, subjects showed that fetal famine exposure is associated with a higher risk of adulthood hypertension (OR = 1.22, 95% CI: 1.07 - 1.40). Taken together, fetal famine exposure is related to higher odds of cardio-metabolic risk factors, such as high homocysteine, hyperuricemia, and LDL as well as hypertension, suggesting that undernutrition during fetal life may affect metabolism of homocysteine, uric acid, and LDL in adulthood.

Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer.

Background: In triple-negative breast cancer (TNBC), PDL1/PD1-directed immunotherapy is effective in less than 20% of patients. In our preliminary study, we have found CSPG4 to be highly expressed together with PDL1 in TNBCs, particularly those harboring TP53 aberrations. However, the clinical implications of co-expressed CSPG4 and PDL1 in TNBCs remain elusive. Methods: A total of 85 advanced TNBC patients treated in the Hunan Cancer Hospital between January 2017 and August 2019 were recruited. The expressions of CSPG4 and PDL1 in TNBC tissues were investigated using immunohistochemistry (IHC). The RNA-seq dataset from the TCGA-BRCA project was further used to analyze the mRNA expression of CSPG4 and PDL1 in TP53-aberrant TNBCs. Cox proportional hazards model and Kaplan-Meier curves with Logrank test was used to analyze the effects of CSPG4 and PDL1 on survival. TNBC cell lines were further used to investigate the molecular mechanism that were involved. Results: TP53 aberrations occurred in more than 50% of metastatic TNBCs and were related to higher tumor mutation burden (TMB). In TCGA-BRCA RNA-seq dataset analysis, both CSPG4 and PDL1 levels were high in TNBCs, especially in TP53-aberrant TNBCs. IHC assay showed nearly 60% of advanced TNBCs to be CSPG4-positive and about 25% to be both CSPG4-positive and PDL1-positive. The levels of CSPG4 and PDL1 were high in TNBC cell lines as revealed by flow cytometry and immunoblotting compared with non-TNBC cells. Univariate Cox regression analysis indicated that CSPG4 positivity was a significant risk factor for progression-free survival in metastatic TNBCs, with a hazard ratio (HR) of 2.26 (P = 0.05). KM curves with Logrank test also identified high level of CSPG4 as a significant risk factor for overall survival in advanced breast cancers in TCGA-BRCA samples (P = 0.02). The immunoblotting assays showed that EMT-related pathways were involved in CSPG4-mediated invasion. Conclusions: CSPG4 expression level is associated with PDL1 positivity in TP53-aberrant TNBC cells. Patients with CSPG4 expression have poor treatment response and poor overall survival. Co-expressed CSPG4 and PDL1 may have an important prognostic value and provide new therapeutic targets in TNBC patients. CSPG4 might mediate tumor invasion and PDL1 overexpression through EMT-related pathway.

Nucleolar and Coiled-Body Phosphoprotein 1 Is Associated With Stemness and Represents a Potential Therapeutic Target in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks approved specific targeted therapies. One of the major reasons why TNBC is difficult to treat is the high proportion of cancer stem cells within the tumor tissue. Nucleolus is the location of ribosome biogenesis which is frequently overactivated in cancer cells and overactivation of ribosome biogenesis frequently drives the malignant transformation of cancer. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) is a nucleolar protein responsible for nucleolus organization and rRNA synthesis and plays an important role in ribosome biogenesis. However, the correlation of NOLC1 expression with patient prognosis and its value as a therapeutic target have not been evaluated in TNBC. In the current study, based on bioinformatics analysis of the online databases, we found that the expression of NOLC1 was higher in breast cancer tissues than normal tissues, and NOLC1 was expressed at a higher level in TNBC than other subtypes of breast cancer. GSEA analysis revealed that stemness-related pathways were significantly enriched in breast cancer with high NOLC1 gene expression. Further analyses using gene expression profiling interactive analysis 2 (GEPIA2), tumor immune estimation resource (TIMER) and search tool for retrieval of interacting genes/proteins (STRING) demonstrated that NOLC1 was significantly associated with stemness in both all breast cancer and basal-like breast cancer/TNBC patients at both gene and protein levels. Knockdown of NOLC1 by siRNA decreased the protein level of the key stemness regulators MYC and ALDH and inhibited the sphere-forming capacity in TNBC cell line MDA-MB-231. Univariate and multivariate Cox regression analyses demonstrated that NOLC1 was an independent risk factor for overall survival in breast cancer. PrognoScan and Kaplan-Meier plotter analyses revealed that high expression of NOLC1 was associated with poor prognosis in both all breast cancer and TNBC patients. Further immunohistochemical analysis of breast cancer patient samples revealed that TNBC cells had a lower level of NOLC1 in the nucleus compared with non-TNBC cells. These findings suggest that NOLC1 is closely associated with the stemness properties of TNBC and represents a potential therapeutic target for TNBC.

Lovastatin enhances chemosensitivity of paclitaxel-resistant prostate cancer cells through inhibition of CYP2C8.

Chemotherapy is the mainstay of treatment for prostate cancer, with paclitaxel being commonly used for hormone-resistant prostate cancer. However, drug resistance often develops and leads to treatment failure in a variety of prostate cancer patients. Therefore, it is necessary to enhance the sensitivity of prostate cancer to chemotherapy. Lovastatin (LV) is a natural compound extracted from Monascus-fermented foods and is an inhibitor of HMG-CoA reductase (HMGCR), which has been approved by the FDA for hyperlipidemia treatment. We have previously found that LV could inhibit the proliferation of refractory cancer cells. Up to now, the effect of LV on chemosensitization and the mechanisms involved have not been evaluated in drug-resistant prostate cancer. In this study, we used prostate cancer cell line PC3 and its paclitaxel-resistant counterpart PC3-TxR as the cell model. Alamar Blue cell viability assay showed that LV and paclitaxel each conferred concentration-dependent inhibition of PC3-TxR cells. When paclitaxel was combined with LV, the proliferation of PC3-TxR cells was synergistically inhibited, as demonstrated by combination index <1. Moreover, colony formation decreased while apoptosis increased in paclitaxel plus LV group compared with paclitaxel alone group. Quantitative RT-PCR showed that the combination of paclitaxel and LV could significantly reduce the expression of CYP2C8, an important drug-metabolizing enzyme. Bioinformatics analysis from the TCGA database showed that CYP2C8 expression was negatively correlated with progression-free survival (PFS) in prostate cancer patients. Our results suggest that LV might increase the sensitivity of resistant prostate cancer cells to paclitaxel through inhibition of CYP2C8 and could be utilized as a chemosensitizer for paclitaxel-resistant prostate cancer cells.

A telerehabilitation programme in post-discharge COVID-19 patients (TERECO): a randomised controlled trial.

OBJECTIVES: To investigate superiority of a telerehabilitation programme for COVID-19 (TERECO) over no rehabilitation with regard to exercise capacity, lower limb muscle strength (LMS), pulmonary function, health-related quality of life (HRQOL) and dyspnoea. DESIGN: Parallel-group randomised controlled trial with 1:1 block randomisation. SETTING: Three major hospitals from Jiangsu and Hubei provinces, China. PARTICIPANTS: 120 formerly hospitalised COVID-19 survivors with remaining dyspnoea complaints were randomised with 61 allocated to control and 59 to TERECO. INTERVENTION: Unsupervised home-based 6-week exercise programme comprising breathing control and thoracic expansion, aerobic exercise and LMS exercise, delivered via smartphone, and remotely monitored with heart rate telemetry. OUTCOMES: Primary outcome was 6 min walking distance (6MWD) in metres. Secondary outcomes were squat time in seconds; pulmonary function assessed by spirometry; HRQOL measured with Short Form Health Survey-12 (SF-12) and mMRC-dyspnoea. Outcomes were assessed at 6 weeks (post-treatment) and 28 weeks (follow-up). RESULTS: Adjusted between-group difference in change in 6MWD was 65.45 m (95% CI 43.8 to 87.1; p<0.001) at post-treatment and 68.62 m (95% CI 46.39 to 90.85; p<0.001) at follow-up. Treatment effects for LMS were 20.12 s (95% CI 12.34 to 27.9; p<0.001) post-treatment and 22.23 s (95% CI 14.24 to 30.21; p<0.001) at follow-up. No group differences were found for lung function except post-treatment maximum voluntary ventilation. Increase in SF-12 physical component was greater in the TERECO group with treatment effects estimated as 3.79 (95% CI 1.24 to 6.35; p=0.004) at post-treatment and 2.69 (95% CI 0.06 to 5.32; p=0.045) at follow-up. CONCLUSIONS: This trial demonstrated superiority of TERECO over no rehabilitation for 6MWD, LMS, and physical HRQOL. TRIAL REGISTRATION NUMBER: ChiCTR2000031834.

Bullying Victimization and Life Satisfaction Among Rural Left-Behind Children in China: A Cross-Sectional Study.

Objectives: This study aimed to evaluate the associations between bullying victimization and life satisfaction in primary school children and also investigate the interactive effects of left-behind status and bullying victimization on life satisfaction. Materials and Methods: Bullying victimization was measured using the Chinese version of the revised Olweus Bully/Victim Questionnaire. Life satisfaction was assessed using the Multidimensional Students' Life Satisfaction Scale (MSLSS). Life satisfaction is composed of five domains, namely, family, school, friends, environment, and self-satisfaction. Left-behind status of rural children was defined as one or both their parents migrating to working in cities. The data were analyzed using Mann-Whitney U tests, Chi-square tests, and multivariate linear and logistic regression analyses. Results: A total of 810 primary school children were involved, of which 8.5% reported bullying victimization, and 44.3% were left-behind children (LBC). We found that bullying victimization was negatively associated with all domains of life satisfaction (all p < 0.05). With further left-behind status-stratified analysis, we found that negative association between bullying victimization and friend satisfaction was more profound in the LBC group than in the non-LBC group [b(SE)= -0.133 (0.03) vs. -0.061 (0.026) for LBC and non-LBC, respectively, p < 0.05]. When further interaction analysis was conducted, we identified interaction effects between left-behind status and bullying victimization on friend satisfaction (p interaction = 0.048). Similar interaction effect between bullying victimization and left-behind status on school satisfaction was also found (p interaction = 0.004). Conclusions: Bullying victimization was associated with low life satisfaction (including lower family, friends, school, self, and environment satisfaction). There were significant interactions between left-behind status and bullying victimization on friend satisfaction, as well as school satisfaction. Left-behind status of children may exaggerate the impact of bullying victimization on friends/school satisfaction rating.