Pitavastatin induces autophagy-dependent ferroptosis in MDA-MB-231 cells via the mevalonate pathway.

Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The increasing potential chemoresistance of TNBC patients is mainly due to that tumor cells escape from apoptosis. In recent years, statins have demonstrated extensive anti-tumor effects. It is worth noting that statins have more effective anti-tumor effects on TNBC cells and drug-resistant breast cancer cells. Therefore, this study examines the superior cytotoxic effects of statins on TNBC cell lines and further explores their potential therapeutic mechanisms. We detected different cell phenotypes and found that statins significantly reduced the cell viability of TNBC cells. Specifically, pitavastatin showed an obvious induction in cell death, cell cycle arrest and oxidative stress in TNBC MDA-MB-231 cells. The reversal effect of iron chelator desferrioxamine (DFO) on the morphological and molecular biological changes induced by pitavastatin has revealed a new mode of cell death induced by pitavastatin: ferroptosis. This ferroptotic effect was strengthened by the decreased expression of glutathione peroxidase 4 (GPx4) as well as newly discovered ferroptosis suppressor protein 1 (FSP1). The data showed that ferroptotic death of MDA-MB-231 cells is autophagy-dependent and mediated by the mevalonate pathway. Finally, we found that therapeutic oral doses of statins can inhibit the growth of transplanted tumors, which establishes statins as a potential treatment for TNBC patients. In conclusion, we found pitavastatin could induce autophagy-dependent ferroptosis in TNBC cells via the mevalonate pathway which may become a potential adjuvant treatment option for TNBC patients.

Efficacy of exclusive enteral nutrition on the mucosal healing of different gastrointestinal segments in children with Crohn's disease.

OBJECTIVE: To investigate the association between disease location and segmental mucosal healing (SMH) following exclusive enteral nutrition (EEN) in children with Crohn's disease (CD). METHODS: Treatment-naive pediatric patients with endoscopically active CD treated with EEN alone as induction therapy were retrospectively enrolled from January 1, 2017 to June 30, 2022. The simple endoscopic score for CD (SES-CD) was employed to score disease activity in the upper gastrointestinal (GI) tract (esophagus, stomach, duodenum), rectum, left colon, transverse colon, right colon, and terminal ileum. While the Lewis score assessed that of the small bowel from the jejunum to the proximal ileum (except the terminal ileum). The variation in the total scores for each segment and SES-CD subscores for each ileocolonic segment from baseline to 1 year after EEN therapy and the segmental endoscopic outcomes and potential predictors associated with SMH for the segments scored by SES-CD were evaluated. RESULTS: Overall, 82 children with CD were enrolled. Except for the upper GI segment, scores in other segments declined significantly from baseline to EEN completion (all P < 0.001). We analyzed 486 segments (79, 80, 81, 82, 82 and 82 from upper GI tract, terminal ileum, right colon, transverse colon, left colon, and rectum) and found that the segmental SES-CD at baseline (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.55-0.70, P < 0.001) and upper GI location (OR 0.25, 95% CI 0.11-0.55, P = 0.001) were associated with SMH at EEN completion. CONCLUSION: Disease location of the upper GI segment in pediatric CD was associated with SMH following EEN therapy.

Whole-brain CT Perfusion at Admission and During Delayed Time-window Detects the Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To evaluate the utility of computed tomography perfusion (CTP) both at admission and during delayed cerebral ischemia time-window (DCITW) in the detection of delayed cerebral ischemia (DCI) and the change in CTP parameters from admission to DCITW following aneurysmal subarachnoid hemorrhage. METHODS: Eighty patients underwent CTP at admission and during DCITW. The mean and extreme values of all CTP parameters at admission and during DCITW were compared between the DCI group and non-DCI group, and comparisons were also made between admission and DCITW within each group. The qualitative color-coded perfusion maps were recorded. Finally, the relationship between CTP parameters and DCI was assessed by receiver operating characteristic (ROC) analyses. RESULTS: With the exception of cerebral blood volume (P=0.295, admission; P=0.682, DCITW), there were significant differences in the mean quantitative CTP parameters between DCI and non-DCI patients both at admission and during DCITW. In the DCI group, the extreme parameters were significantly different between admission and DCITW. The DCI group also showed a deteriorative trend in the qualitative color-coded perfusion maps. For the detection of DCI, mean transit time to the center of the impulse response function (Tmax) at admission and mean time to start (TTS) during DCITW had the largest area under curve (AUC), 0.698 and 0.789, respectively. CONCLUSION: Whole-brain CTP can predict the occurrence of DCI at admission and diagnose DCI during DCITW. The extreme quantitative parameters and qualitative color-coded perfusion maps can better reflect the perfusion changes of patients with DCI from admission to DCITW.

Potential values of circulating tumor cell for detection of recurrence in patients of thyroid cancer: a diagnostic meta-analysis.

BACKGROUND: Several studies have reported that circulating tumor cells (CTCs) are a promising marker for the diagnosis of thyroid cancer (TC) with recurrence or distant metastasis (DMs). However, some studies emerged with conflicting results. Therefore, we provide a meta-analysis to evaluate the diagnostic performance of CTC for detection of recurrence in patients of TC. METHODS: We searched PubMed, Web of Science, Cochrane library with the keywords "thyroid cancer" and "circulating tumor cells". Data extraction and risk of bias assessment were performed independently by two reviewers. The summary receiver operating characteristic curve (SROC) and other parameters were adopted to summarize the overall test performance. The sensitivity of CTCs in the detection of recurrent TC was reviewed. All analyses were performed by STATA 12.0 and Meta-disc software. RESULTS: For CTCs expressing epithelial cell adhesion molecule (EpCAM), seven studies were included in our meta-analysis. Pooled sensitivity, specificity, and diagnostic odds ratio were 0.71 (95% CI: 0.63-0.78), 0.89 (95% CI: 0.84-0.94), and 26.75 (95% CI: 9.11-78.53); 0.78 (95% CI: 0.65-0.89), 0.88 (95% CI: 0.76-0.96), and 40.01 (95% CI: 10.49-152.63) for CTCs expressing thyroid stimulating hormone receptor (TSHR). The area under the SROC for EpCAM and TSHR were both 0.91. CONCLUSION: CTC was a reliable marker for the diagnosis of TC patients with recurrence and DMs, and the sensitivity of CTCs expressing TSHR was higher than that of EpCAM. Additional research is warranted in order to establish uniformity in international guidelines, make up the drawbacks of conventional diagnostic methods and to prevent futile surgery.

Roles and mechanisms of miR-195-5p in human solid cancers.

Cancer persists as a worldwide disease that contributes to high morbidity and mortality rates. As a class of non-coding RNA, microRNAs (miRNAs) are one kind of important regulators in cancer and frequently implicated in tumor development and progression. Emerging experiments have suggested that miRNA-195-5p (miR-195-5p) can regulate neoplastic processes in many pathways. For instance, miR-195-5p can not only regulate proliferation, migration and invasion of tumor cells but also promote tumor cell apoptosis. Furthermore, low expression of miR-195-5p could induce drug resistance. Our review focuses on the expression of miR-195-5p in various tumors and elucidates the related mechanisms of which miR-195-5p participates in tumor biology, as well as summarizes the roles of miR-195-5p in tumor progression. We believe that miR-195-5p might have potential utility as a novel diagnostic biomarker and therapeutic target for cancer.

Hyperthermia promotes exosome secretion by regulating Rab7b while increasing drug sensitivity in adriamycin-resistant breast cancer.

PURPOSE: To investigate the mechanism through which hyperthermia promotes exosome secretion and drug sensitivity in adriamycin-resistant breast cancer. MATERIALS AND METHODS: We first evaluated the effect of hyperthermia on adriamycin-resistant breast cancer viability and used transmission electron microscopy, nanoparticle tracking analysis, and a bicinchoninic acid kit to validate the effect of hyperthermia on exosome secretion. The effective targeting molecules and pathways changed by hyperthermia were explored by RNA microarray and verified in vitro. The adriamycin-resistant MCF-7/ADR cells co-incubated with the exosomes produced by MCF-7/ADR cells after hyperthermia were assessed. The uptake of exosomes by MCF-7/ADR cells after hyperthermia treatment was evaluated by confocal microscopy. Finally, the mechanism through which hyperthermia promotes exosome secretion by hyperthermia was determined. RESULTS: Hyperthermia significantly suppressed the growth of adriamycin-resistant breast cancer cells and increased drug sensitivity by upregulating FOS and CREB5, genes related to longer overall survival in breast cancer patients. Moreover, hyperthermia promoted exosome secretion through Rab7b, a small GTPase that controls endosome transport. The upregulated FOS and CREB5 antioncogenes can be transferred to MCF-7/ADR cells by hyperthermia-treated MCF-7/ADR cell-secreted exosomes. CONCLUSIONS: Our results demonstrated a novel function of hyperthermia in promoting exosome secretion in adriamycin-resistant breast cancer cells and revealed the effects of hyperthermia on tumor cell biology. These hyperthermia-triggered exosomes can carry antitumor genes to the residual tumor and tumor microenvironment, which may be more beneficial to the effects of hyperthermia. These results represent an exploration of the relationship between therapeutic strategies and exosome biology.

Potential protein-phenotype correlation in three lipopolysaccharide-responsive beige-like anchor protein-deficient patients.

BACKGROUND: Patients with lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency have a variety of clinical symptoms, but there is no apparent genotype-phenotype correlation, and patients carrying the same mutations may have different phenotypes. Therefore, it is not easy for doctors to make a decision regarding hematopoietic stem cell transplantation (HSCT) for LRBA-deficient patients. We hypothesized that there may be a protein-phenotype correlation to indicate HSCT for LRBA-deficient patients. AIM: To report on three Chinese LRBA-deficient patients and determine the correlation between residual protein expression and disease phenotypes. METHODS: Clinical data of three Chinese LRBA-deficient patients were collected, and protein levels were detected by Western blot analysis. In addition, LRBA mutation information of another 83 previously reported patients was summarized. RESULTS: All the major clinical findings indicated enteropathy, but patients 1 and 3 presented with more severe symptoms than patient 2. Endoscopy and histology indicated nonspecific colitis for patients 1 and 3 but Crohn's disease-like colitis for patient 2. Compound heterozygous mutations in LRBA were found in patient 1, and homozygous mutations in LRBA were found in patient 2 and patient 3. Only patient 2 responded well to traditional immunosuppressive treatment. Residual expression of the LRBA protein in patients 1 and 3 was very low, but in patient 2, a more than 0.5-fold in expression of the LRBA protein was found compared to that in the control. After HSCT, patient 1 had increased LRBA protein expression. We summarized the genetic information of 86 patients, and the mutations in patients 1 and 3 were novel mutations. CONCLUSION: We described three Chinese LRBA-deficient patients, two of whom carried novel mutations. These patients had no genotype-phenotype correlations, but their residual LRBA protein expression might be associated with disease outcome and could be an indicator for HSCT.

Lignans intake and enterolactone concentration and prognosis of breast cancer: a systematic review and meta-analysis.

Background: Some literature has studied the relationship between lignans intake and its metabolite, enterolactone, and breast cancer survival, but the results are far from consistent and conclusive. Therefore, we conducted a systematic review and meta-analysis in this situation. Methods: From its inception to August 2020, we conducted a comprehensive search of PubMed, Embase, Web of Science, and Cochrane Library databases. This study reported the correlation between lignans intake and serum enterolactone concentrations and prognosis of breast carcinoma. The total hazard ratios (HRs) and 95% confidence interval (95% CI) were estimated, comparing the highest versus the lowest category of lignans intake and serum enterolactone concentrations, using a fixed or random-effects effect model. Results: A total of 6 articles were included in reporting the all-cause mortality (ACM), breast cancer-specific mortality (BCSM), and recurrence of 2668, 1516, and 474 breast cancer patients in 18053 breast cancer patients. In postmenopausal women with breast cancer, lignans intake or enterolactone concentrations were associated with a reduced risk of all-cause mortality (maximum and minimum) (pooled HR = 0.73, 95% CI, 0.58-0.91), as was the association with breast cancer-specific mortality (maximum and minimum) (pooled HR = 0.72, 95% CI, 0.60, 0.87). Stratified analysis showed that exposure type and diagnosis time might be the sources of heterogeneity. In premenopausal women, the relationship seemed to be the opposite, showing an increased risk of all-cause mortality (maximum and minimum) in breast cancer patients (pooled HR = 1.57, 95% CI, 1.11-2.23). No significant association was found between lignans intake or enterolactone concentrations and breast cancer recurrence (pooled HR = 0.91, 95% CI, 0.69, 1.20). Conclusion: This study provides limited evidence that lignans intake and higher serum enterolactone concentrations in postmenopausal women are beneficial to breast cancer patients' prognosis. In premenopausal women, however, the relationship may be reversed.

Special clinical characteristics and outcomes in Chinese pediatric patients with early-onset Crohn's disease.

OBJECTIVE: To study the clinical and nutritional characteristics of early-onset Crohn's disease (EO-CD) in China. METHODS: Patients were defined as having EO-CD (age at diagnosis <10 y) or late-onset Crohn's disease (LO-CD; age at diagnosis of 10-17 y). Their characteristics, clinical, and nutritional data were collected at baseline and at each follow-up visit. Statistical analyses were used to compare differences in both groups. RESULTS: From July 1993 to February 2017, of the 137 children enrolled, 68 (49.6%) had EO-CD and 69 (50.4%) had LO-CD. More patients with EO-CD than those with LO-CD presented with diarrhea, hematochezia, growth delay, anemia and skin disease, and had higher pediatric Crohn's disease activity index scores at diagnosis (all P < 0.05). Fewer patients with EO-CD achieved their first remission (42.6% vs 76.8%, P < 0.0001) during follow-up. Patients with EO-CD required a longer treatment time to reach remission (P = 0.0049) and had a higher mortality rate (P = 0.0133), as well as lower height and weight percentiles (P = 0.0200 and 0.0288, respectively), hemoglobin (P = 0.0185) and albumin levels (P = 0.0002), zinc (P = 0.0024) and iron (P = 0.0110) concentrations in blood at diagnosis. CONCLUSION: The EO-CD group had worse clinical outcomes and nutritional status than the LO-CD group.

Diagnostic Value of 128-slice Spiral CT Combined with Virtual Colonoscopy for Colorectal Cancer.

The objective of this study was to evaluate the diagnostic value of 128-slice spiral CT combined with virtual colonoscopy in diagnosis of colorectal cancer. We retrospectively analyzed 45 patients of colorectal diseases who underwent definition AS+128-slice spiral CT combined with virtual colonoscopy after bowel preparation and gas injection to evaluate the clinical diagnostic value of this technology. All the patients received electronic colonoscopy and were confirmed by pathology. In total, colorectal cancer was confirmed in 42 cases and inflammation in 3 cases. Diagnostic results shows: there were 17 cases of lump, 10 cases of infiltration, 6 cases of ulcer, 9 cases of mixed type, 4 cases of liver metastases, and 36 cases of lymph node metastasis. There was no significant difference between 128-slice spiral CT combined with virtual colonoscopy and electronic colonoscopy in detection, localization and characterization of colorectal tumors. CT virtual endoscopy has great advantages in observing the invasion around the lesion and the presence or absence of metastasis in distant organs and lymph node metastasis. It is also possible to understand the shape of the lesion in the intestinal lumen and the length of the lesion involving the lumen of the intestine.

MicroRNA-15a - cell division cycle 42 signaling pathway in pathogenesis of pediatric inflammatory bowel disease.

AIM: To determine whether cell division cycle (Cdc)42 is regulated by microRNA (miR)-15a in the development of pediatric inflammatory bowel disease (IBD). METHODS: We cultured 293T cells, used plasmids and performed dual-luciferase assay to determine whether Cdc42 is a miR-15a target gene. We cultured Caco-2 cells, and stimulated them with tumor necrosis factor (TNF)-α. We then employed lentiviruses to alter the expression of miR-15a and Cdc42. We performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence to determine whether Cdc42 is regulated by miR-15a in Caco-2 cells. Finally, we collected ileocecal tissue by endoscopy from patients and performed qRT-PCR to examine the expression of miR-15a and Cdc42 in pediatric IBD patients. RESULTS: Target Scan and dual-luciferase assay revealed that Cdc42 was a miR-15a target gene. MiR-15a expression increased (P = 0.0038) and Cdc42 expression decreased (P = 0.0013) in cells stimulated with TNF-α, and the expression of the epithelial junction proteins zona occludens (ZO)-1 (P < 0.05) and E-cadherin (P < 0.001) decreased. Cdc42 levels decreased in miR-15a-mimic cells (P < 0.001) and increased in miR-15a inhibitor cells (P < 0.05). ZO-1 and E-cadherin decreased in miR-15a-mimic cells (P < 0.001) but not in the miR-15a inhibitor + TNF-α cells. In Lv-Cdc42 + TNF-α cells, ZO-1 and E-cadherin expression increased compared to the Lv-Cdc42-NC + TNF-α (P < 0.05) or miR-15a-mimic cells (P < 0.05). Fifty-four pediatric IBD patients were included in this study, 21 in the control group, 19 in the Crohn's disease (CD) active (AC) group, seven in the CD remission (RE) group, and seven in the ulcerative colitis (UC) group. MiR-15a increased and Cdc42 decreased in the CD AC group compared to the control group (P < 0.05). miR-15a decreased and Cdc42 increased in the CD RE group compared to the CD AC group (P < 0.05). miR-15a was positively correlated with the Pediatric Crohn's disease Activity Index (PCDAI) (P = 0.006), while Cdc42 was negatively correlated with PCDAI (P = 0.0008). Finally, miR-15a expression negatively correlated with Cdc42 in pediatric IBD patients (P = 0.0045). CONCLUSION: MiR-15a negatively regulates epithelial junctions through Cdc42 in Caco-2 cells and pediatric IBD patients.

Ozone therapy induced sinus arrest in a hypertensive patient with chronic kidney disease: A case report.

RATIONALE: Ozone autohemotherapy as an alternative treatment method has been applied to the treatment of several diseases. Here, we report a patient used ozone autohemotherapy to treat her hypertension and diabetes. Nevertheless, the patient occurred sudden dizziness and black haze due to hyperkalemia. PATIENT CONCERNS: A 54-year-old woman who was admitted to our emergency department complaining of sudden dizziness and black haze for 5 hours. DIAGNOSES: The blood potassium test showed hyperkalemia. Upon further inquiry of her medical history, the patient received ozone autohemotherapy to treat hypertension and diabetes for 9 days prior to admission. INTERVENTIONS: The ozone therapy had been asked to stop. Insulin, sodium bicarbonate, and sodium polystyrene sulfonate were administered to the patient. OUTCOMES: After treatment, blood potassium remained in the normal range. After 3 days of treatment, the 24-hour dynamic electrocardiogram revealed sinus rhythm with an average heart rate of 82 beats/min, occasional ventricular premature beats, occasional ventricular premature beats, and no ST segment depression. LESSONS: Although ozone therapy is widely used in the treatment of several diseases, adverse reactions should be given attention in clinical practice, especially in patients with chronic kidney disease.

Draft Genome Sequence of a Phthalate Ester-Degrading Bacterium, Rhizobium sp. LMB-1, Isolated from Cultured Soil.

Rhizobium sp. LMB-1, newly isolated from greenhouse soil, can effectively degrade phthalate. Here, we present a 5.2-Mb assembly of this Rhizobium sp. genome for the first time. It may provide abundant molecular information for the transformation of phthalates.

Small intestinal tubular adenoma in a pediatric patient with Turner syndrome.

Turner syndrome (TS) is a female chromosomal disorder caused by the lack of an X chromosome. The loss of this chromosome may result in the deficiency of tumor-suppressive or DNA repair genes, leading to tumorigenesis. Recombinant human growth hormone (GH) has been popularly used for treatment in TS patients for growth promotion. Although treatment with GH has been correlated with precancerous and cancerous lesions in TS children, its associations with gastric or colonic tumors, especially ileal tubular adenomas, have not been reported frequently. We here report a case of a 16-year-old patient with TS and tubular adenoma of the small intestine. Whether the ileal adenoma was caused by TS itself or GH therapy was discussed.

[Development of safety climate measurement at workplace: validity and reliability assessment].

OBJECTIVE: To develop a measurement of safety climate at workplace and assess its validity and reliability. METHODS: According to the theory of preventive safety culture model, a scale including 7 dimensions of 27 items was developed. 342 workers were selected from among all workers of an artificial board factory and were investigated with the developed scale. Occupational accidents were recorded during the past year. Factor analysis, association validation and inter-item consistency test were applied to assess the scale validity and reliability. RESULTS: After the deletion of 6 items, 21 items composed the safety climate scale, which was loaded on 7 common factors: safety competence and consciousness, safety communication, organizational environment, management support, danger judgment, safety control measure and safety training. The cumulative contribution reached to 70.50%. All item communities (common factor variance) were above 0.6 except one item was 0.595. ANOVA showed that occupational accidents were associated with the safety climate score on total, danger judgment and safety control measure dimension (P < 0.05). There existed significant correlation between the safety climate total score and dimension scores (P < 0.01), the correlation coefficients were 0.700, 0.728, 0.705, 0.703, 0.354, 0.571 and 0.485 respectively. The safety climate scale total Cronbach's alpha coefficient, half-split Spearman-Brown coefficient, theta coefficient and omega coefficient indicated that the safety climate scale had good inter-item consistency among items. CONCLUSION: The measurement of safety climate at workplace is developed. It has good reliability and valid.