Pulmonary hypertension (PH) is a severe pulmonary vascular disease that eventually leads to right ventricular failure and death. The purpose of this study was to investigate the mechanism by which pachymic acid (PA) pretreatment affects PH and pulmonary vascular remodeling in rats.
PH was induced via hypoxia exposure and administration of PA (5 mg/kg per day) in male Sprague-Dawley rats. Hemodynamic parameters were measured using a right ventricular floating catheter and pulmonary vascular morphometry was measured by hematoxylin-eosin (HE), α-SMA and Masson staining. MTT assays and EdU staining were used to detect cell proliferation, and apoptosis was analyzed by TUNEL staining. Western blotting and immunohistochemistry were used to detect the expression of proteins related to the Nrf2-Keap1-ARE pathway.
PA significantly alleviated hypoxic PH and reversed right ventricular hypertrophy and pulmonary vascular remodeling. In addition, PA effectively inhibited proliferation and promoted apoptosis in hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). Moreover, PA pretreatment inhibited the expression of peroxy-related factor (MDA) and promoted the expression of antioxidant-related factors (GSH-PX and SOD). Furthermore, hypoxia inhibited the Nrf2-Keap1-ARE signaling pathway, while PA effectively activated this pathway. Most importantly, addition of the Nrf2 inhibitor ML385 reversed the inhibitory effects of PA on ROS generation, proliferation, and apoptosis tolerance in hypoxia-induced PASMCs.
Our study suggests that PA may reverse PH by regulating the Nrf2-Keap1-ARE signaling pathway.
Keshan disease (KD) is a mitochondrial cardiomyopathy. The present study explored the roles of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), the key regulator of mitochondrial structure and function, and its coactivators in myocardial injury in chronic KD. Furthermore, the usefulness of these molecules in the diagnosis of chronic KD was assessed.
In the present case-control study, 43 patients with chronic KD and 30 healthy individuals living in KD endemic areas were included. The myocardial injury indicators and mRNA expression levels of PGC-1α, nuclear respiratory factor 1 (NRF1), PPARα, and estrogen-related receptor alpha (ERRα) in peripheral blood were examined.
It was found that the levels of atrial natriuretic peptide, creatine kinase, and lactate dehydrogenase (LDH) were higher in patients with chronic KD, when compared to controls, while the level of bradykinin was lower. Furthermore, the PGC-1α, NRF1 and PPARα mRNA levels were higher in patients with KD. The area under the receiver operating characteristic curve and the optimal diagnostic threshold of LDH was 0.937 and 304.0 U/L, respectively. It is noteworthy that the area under the combined receiver operating characteristic curve was larger, when compared to that for LDH detection alone (Z=2.055, P=0.0399). The area under the curve for the “LDH+PPARα” combination was 0.984, with 96.7% sensitivity and 93.0% specificity.
The combined detection of LDH and the expression of PPARα can be performed to diagnose the chronic KD.
Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies world-wide. Currently, surgery, radiotherapy and chemotherapy are clinically applied as common approaches for CRC patients. Cisplatin is one of the most frequently used chemotherapy drugs for diverse cancers. Although chemotherapeutic strategies have improved the prognosis and survival of cancer patients, development of cisplatin resistance has led to cancer recurrence. Curcumin, isolated from turmeric, has been used as an effective anti-cancer agent. However, the molecular mechanisms for curcumin-mediated cisplatin sensitivity of CRC have not been elucidated. This study aimed to investigate the effects of curcumin treatment on cisplatin-resistant CRC cells.
Expression levels of miRNAs and mRNAs were determined by qRT-PCR. Protein expression levels were detected by Western blotting. Cell responses to curcumin treatments were evaluated by MTT assay, Clonogenic assay and Annexin V apoptosis assay. The glutamine metabolism of colon cancer cells was assessed by glutamine uptake and glutaminase (GLS) activity. The binding of miR-137 on 3′ UTR of GLS was validated by Western blotting and luciferase assay.
Results demonstrated that curcumin significantly synergized with cisplatin (combination index <1) to suppress proliferation of colon cancer cells compared with curcumin or cisplatin alone. Moreover, from the established cisplatin-resistant cell line (HT-29), glutamine metabolism was remarkedly elevated in cisplatin-resistant CRC cells that displayed a glutamine addictive phenotype. Furthermore, curcumin treatments attenuated glutamine metabolism in colon cancer cells. Under low glutamine supply, colon cancer cells showed less sensitivity to curcumin. Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3′ UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition.
Collectively, these results indicate that curcumin could be clinically applied as an anti-chemoresistance approach against CRC by modulating miR-137-inhibited glutamine metabolism.
An understanding of the leading causes of death in patients with head and neck squamous cell carcinoma (HNSCC) would be helpful to inform doctors, patients, and healthcare providers on disease management. This study aimed to comprehensively study the leading causes of death in these survivors.
We investigated the trends of risk factors for major causes of death in patients with HNSCC. Causes of death in HNSCC were obtained from the Surveillance, Epidemiology, and End Results registries. We characterized trends in the 5-year cumulative mortality as well as risk factors associated with the ten leading causes of death.
Among 48 297 deaths identified, the ten leading causes were as follows: HNSCC, heart disease, lung cancer, chronic obstructive pulmonary disease (COPD), cerebrovascular disease, pneumonia & influenza, accidents & adverse effects, esophagus cancer, chronic liver diseases, and septicemia. Non-HNSCC deaths surpassed HNSCC deaths 4 years after cancer diagnosis. There was a significant decline in the 5-year cumulative mortality from HNSCC, heart disease, lung cancer, COPD, cerebrovascular disease, and esophagus cancer. The risks of mortality from the ten leading causes varied with patient characteristics.
Our findings provide a useful picture of mortality patterns in HNSCC survivors, which might help when planning personalized HNSCC care.
Transcription factor GATA4 has significant roles in embryonic heart development. Mutations of GATA4 appear to be responsible for a wide variety of congenital heart defects (CHD). Despite the high prevalence of GATA4 mutations in CHD phenotypes, extensive studies have not been performed. The 3′-untranslated region (3′-UTR) of the GATA4 gene comprises regulatory motifs and microRNA binding sites that are critical for the appropriate gene expression, nuclear transportation, and regulation of translation, and stability of mRNA. This study aimed to evaluate the association between mutations in the 3′-UTR of the GATA4 gene and CHD risk among Iranian patients.
We analyzed the coding region of exon 6 and the whole 3′-UTR of GATA4 in DNA isolated from 175 blood samples of CHD patients and 115 unrelated healthy individuals. The functional importance of the observed GATA4 mutations was evaluated using a variety of bioinformatics algorithms for assessment of nonsynonymous mutations and those observed in miRNA binding sites of 3′-UTR.
Twenty-one point mutations including one missense mutation (c.511A>G: p.Ser377Gly) in exon 6 and 20 nucleotide variations in 3′-UTR of GATA4 gene were identified in 65 of the 175 CHD patients. In our patients, we identified 12 novel sequence alterations and 8 single nucleotide polymorphisms in the 3′-UTR of GATA4. Most of them had statistically significant differences between CHD patients and controls.
Our results suggest that 3′-UTR variations of the GATA4 gene probably change microRNA binding sites and present an additional molecular risk factor for the susceptibility of CHD.
Conversion of normal cells to cancer cells is often accompanied by abnormal synthesis of serum enzymes. Both alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) have been reported to have prognostic value in a variety of malignancies. The aim of this study was to investigate the effect of preoperative serum ALP and LDH levels on the prognosis of patients with periampullary carcinoma who underwent pancreatoduodenectomy (PD).
According to the preoperative ALP or LDH values, 856 cancer patients receiving PD treatment from January 2001 to January 2019 were divided into high-ALP group and low-ALP group or high-LDH group and low-LDH group. Statistical analysis was carried out to study the differences between the high-ALP and low-ALP groups or the high-LDH and low-LDH groups. Furthermore, the possibility of preoperative ALP or LDH as prognostic factor of periampullary carcinoma was investigated.
In both the high-ALP and the high-LDH groups, the prognosis of patients with periampullary carcinoma who underwent PD was worse than that of the low-ALP and low- LDH group. Even through risk factor analysis, it was found that preoperative ALP and LDH could be independent prognostic factor for patients with periampullary carcinoma who underwent PD.
Preoperative ALP or LDH is an independent risk factor for periampullary carcinoma.
To investigate the effectiveness of molding custom-made insoles for female patients with foot pain.
The study included 20 patients whose insoles were prescribed according to biomechanical evaluations and molded by repositioning the subtalar joint in its neutral position using a simple set of tools. Plantar biomechanics were measured under the following conditions: static stand, walking at self-comfortable walking speed (CWS) barefoot, walking in patient owned running shoes, and walking in running shoes plus insoles. Each patient’s upper arm isometric muscle strength and subjective feelings before and after the insole intervention were assessed.
The molded insoles increased plantar contact area both during static standing and walking at CWS compared to the barefoot condition. The insoles also had more evenly distributed plantar contact area and loading rate, with the changes in the medial arch area being most significant. Moreover, the custom-made insole intervention immediately increased maximum resistance and duration of bilateral upper arms, as well as improved foot comfort, especially at the medial arch area during single leg squat tests.
Molding custom-made insoles by repositioning the subtalar joint in its neutral position can be accomplished with a simple set of tools, making this method highly applicable for a majority of less developed regions. Insoles molded using this method are effective in immediately improving plantar biomechanics disorders and enhancing isometric upper muscle performance in female patients with foot pain.
The goal of this work is to analyze the incidence, etiology, clinical characteristics, maternal and neonatal outcomes of complete uterine rupture during pregnancy.
The information of complete uterine rupture between June 2010 and May 2020 was investigated retrospectively at a tertiary center, and included demographic data, delivery characteristics, intraoperative findings, and maternal and neonatal outcomes. The prevalence rate of uterine rupture in the early group (hospitalized from June 2010 to May 2015) and late group (June 2015 to May 2020) was compared and analyzed.
There were 37 (0.056%) cases of complete uterine rupture in 66 092 births, including 27 (0.041%) of scar uterus and 10 (0.015%) of non-scarred uterus. High-risk factors for scarred uterine rupture included: previous cesarean section (13, 48.1%), myomectomy (8, 29.6%), corneal pregnancy resection (6, 22.2%), history of uterine rupture (1, 3.7%), and uterus perforation during abortion (1, 3.7%). Compared to the early group, the number of uterine ruptures caused by previous cesarean section was significantly reduced in the late group. Of the 10 patients with non-scarred uterine rupture, 3 (30%) occurred during delivery and 7 (70%) were spontaneous. Among the 37 complete rupture patients, 3 (8.1%) died of uterine scar rupture, 19 (51.3%) cases were reported with fetal/newborn deaths, 5 (13.5%) cases underwent hysterectomy and the rest were treated with uterine repair.
Complete uterine rupture often has catastrophic effect on pregnancy outcomes. Obstetrics doctors should be vigilant to identify the risk factors and clinical presentations of uterine rupture during pregnancy. Strict prenatal management is beneficial to improve pregnancy outcomes.
The present study was designed to evaluate the effects of adjuvant chemotherapy (CT) vs. radiotherapy (RT, alone or combined with CT) on the prognosis of patients with high-risk, early-stage (stage I and stage II) endometrioid endometrial carcinoma.
This single-center retrospective clinical study was conducted in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between 2010 and 2019. In the present study, endometrioid endometrial carcinoma patients, who underwent total hysterectomy and bilateral salpingo-oophorectomy followed by postoperative adjuvant CT or RT (alone or combined with CT), and were diagnosed with stage IA grade 2/3 with lymph-vascular space invasion (LVSI), and stage IB with two or more uterine risks, including old age, histological grade 2 or 3, LVSI and stage II, were included. According to the postoperative adjuvant therapy, all eligible patients were divided into two groups: CT group and RT (RT±CT) group. The primary objective was to investigate overall survival (OS) and disease-free survival (DFS) between the CT and RT groups. Grade 3 or worse adverse events were also presented in the present study.
A total of 145 eligible patients were included. Among these patients, 97 patients underwent adjuvant CT and 48 patients underwent adjuvant RT (RT±CT). The median follow-up was 47.2 months, and the five-year OS rate was 92.7% in the CT group and 88.6 % in the RT group [hazard ratio (HR): 0.81, 95% confidence interval (CI): 0.22–2.99). The 5-year DFS rate for the two groups was 85.7% and 80.2%, respectively (HR: 0.82, 95% CI: 0.33–2.05). The cumulative incidence of local-regional disease recurrence at 60 months of follow-up was 6.2% in the CT group and 6.3% in the RT group (HR=1.11; 95%CI: 0.28–4.35). The cumulative incidence of distant recurrence at 60 months of follow-up was 5.2% in the CT group and 10.4% in the RT group (HR=0.65; 95%CI: 0.19–2.24). Both groups of patients were well-tolerant, and the only grade 3 or worse adverse events were neutropenia and thrombocytopenia.
There was no difference in efficacy for adjuvant CT or adjuvant RT (RT±CT) in high-risk, early-stage endometrioid endometrial carcinoma. CT exhibited a trend of reducing the distant relapse, although there was no significant difference, when compared with adjuvant RT (RT±CT).
To determine whether adjuvant chemotherapy improves the prognoses in women with stage IC1 epithelial ovarian cancer (EOC).
All eligible women diagnosed with stage IC1 EOC from 2003 to 2019 in Tongji Hospital were included. Patient characteristics, tumor features, surgical types, and chemotherapeutic treatments were collected. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate progression-free survival (PFS) and overall survival (OS).
Of the 140 patients (median age: 47 years old), 13 patients did not receive chemotherapy, and 127 received adjuvant chemotherapy. Kaplan-Meier analysis indicated that adjuvant chemotherapy offered no obvious improvements in PFS or OS. Subgroup analysis was conducted to adjust for the significant difference in incomplete staging surgery between the two groups, and chemotherapy still showed no benefit for survival. Cox regression analysis indicated that incomplete staging surgery was a risk factor for a worse PFS and that adjuvant chemotherapy remained unrelated to the prognosis. The patients were further divided based on the National Comprehensive Cancer Network recommendations: patients for whom observation is optional and chemotherapy would not improve the prognosis; and patients for whom chemotherapy is recommended. The results showed that postoperative chemotherapy had little correlation with survival.
Our study suggests that postoperative chemotherapy may be unnecessary for patients with stage IC1 EOC. According to our results, incomplete staging surgery is a significant risk factor for PFS.
Cytogenetic abnormalities have been proven to be the most valuable parameter for risk stratification of childhood acute lymphoblastic leukemia (ALL). However, studies on the prevalence of cytogenetic abnormalities and their correlation to clinical features in Chinese pediatric patients are limited, especially large-scale studies.
We collected the cytogenetics and clinical data of 1541 children newly diagnosed with ALL between 2001 and 2014 in four Chinese hospitals, and retrospectively analyzed their clinical features, prognosis and risk factors associated with pediatric ALL.
All of these patients had karyotyping results, and some of them were tested for fusion genes by fluorescence in situ hybridization or reverse-transcription polymerase chain reaction. Overall, 930 cases (60.4%) had abnormal cytogenetics in this study, mainly including high hyperdiploidy (HHD, n=276, 17.9%), hypodiploidy (n=74, 4.8%), t(12;21)/TEL-AML1 (n=260, 16.9%), t(1;19)/E2A-PBX1 (n=72, 4.7%), t(9;22)/BCR-ABL (n=64, 4.2%), and t(v;11q23)/MLL rearrangements (n=40, 2.6%). The distribution of each cytogenetic abnormality was correlated with gender, age, white blood cell count at diagnosis, and immunophenotype. In addition, multivariate analysis suggested that t(v;11q23)/MLL rearrangements (OR: 2.317, 95%CI: 1.219–3.748, P=0.008) and t(9;22)/BCR-ABL (OR: 2.519, 95%CI: 1.59–3.992, P<0.001) were independent risk factors for a lower event-free survival (EFS) rate in children with ALL, while HHD (OR: 0.638, 95%CI: 0.455–0.894, P=0.009) and t(12;21)/TEL-AML1 (OR: 0.486, 95%CI: 0.333–0.707, P<0.001) were independent factors of a favorable EFS.
The cytogenetic characteristics presented in our study resembled other research groups, emphasizing the important role of cytogenetic and molecular genetic classification in ALL, especially in B-ALL.