Mechanism of the apoptosis of bone marrow erythroblasts in rats under hypobaric hypoxia.

This study aimed to investigate the mechanism of the apoptosis of erythroblasts in rat bone marrow after the exposure to hypobaric hypoxia. Male SD rats were randomly divided into three groups. The hypoxic group was kept in a hypobaric hypoxia chamber at a simulated altitude of 5000 m for 7 and 28 days, respectively. The control group was kept at an altitude of 2260 m. We found that myeloid: erythroid (M:E) ratio was significantly lower after hypoxia exposure and the proportions of polychromatic erythroblasts and orthochromatic erythroblasts significantly increased compared to control group, along with significant increase in the proportion of CD71+ cells and apoptosis rate. The expression levels of caspase-3, Bax, and Cyt-C in CD71+ cells were higher after hypoxia exposure than those in control group, while there was no significant difference in the expression levels of TNFR and Fas. In conclusion, after exposure to hypobaric hypoxia the proliferation of peripheral blood and bone marrow erythroblasts in rats increased, and apoptosis also increased, indicating that bone marrow erythroblasts in rats is regulated by both proliferation and apoptosis, and the mitochondrial pathway is one of the important pathways for apoptosis.

Prevalence, associated factors, and gene polymorphisms of obesity in Tibetan adults in Qinghai, China.

OBJECTIVES: To explore the prevalence and associated factors of obesity in Tibetan adults in Qinghai, China, and to determine the association between the FTO (rs1121980 and rs17817449) and MC4R gene (rs17782313 and rs12970134) polymorphisms with obesity. METHODS: A cross-sectional survey was conducted in 2015 in Qinghai to selected Tibetan adults aged 20 to 80 years. Prevalence of obesity (BMI ≥ 28 kg/m2) and overweight (BMI 24 ~ 27.9 kg/m2) were evaluated. Multivariable logistic models were used to determine the associated factors. Pair-matched subjects of obesity cases and normal-weight controls were selected for the gene polymorphism analyses. Conditional logistic models were used to assess the association between gene polymorphisms with obesity. Additive and multiplicative gene-environment interactions were tested. RESULTS: A total of 1741 Tibetan adults were enrolled. The age- and sex- standardized prevalence of obesity and overweight was 18.09% and 31.71%, respectively. Male sex, older age, heavy level of leisure-time exercise, current smoke, and heavy level of occupational physical activity were associated with both obesity and overweight. MC4R gene polymorphisms were associated with obesity in Tibetan adults. No significant gene-environment interaction was detected. CONCLUSION: The prevalence of obesity and overweight in Tibetan adults was high. Both environmental and genetic factors contributed to the obesity prevalent.

Plasma exosomal microRNA expression profiles in patients with high-altitude polycythemia.

High-altitude polycythemia (HAPC) is a chronic mountain sickness characterized by multiple severe ill-effects. Its pathogenesis is still unclear, and till date, no study has been conducted to investigate the plasma exome profile of Tibetan patients with HAPC. In this study, we aimed to elucidate the pathogenesis of HAPC by determining the microRNA (miRNA) signatures. We compared the plasma exosome miRNA expression profiles of eight patients with HAPC and eight healthy controls using next-generation miRNA sequencing. Further, we extracted and identified plasma exosomes using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. We used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to validate differentially expressed plasma exosomal miRNAs. Finally, we analyzed the diagnostic values of the differentially expressed miRNAs for HAPC using receiver operating characteristic (ROC) curves. We detected 2007 miRNAs from confirmed plasma exosomes, including 1342 known miRNAs and 665 newly predicted miRNAs. We verified the expression of the top 10 differentially expressed miRNAs via qRT-PCR. Patients with HAPC showed significantly upregulated hsa-miR-122-5p, hsa-miR-423-5p, hsa-miR-4433b-3p, hsa-miR-1291, and hsa-miR-106b-5p expression levels, while hsa-miR-200c-3p expression was downregulated. This study may provide background knowledge for future studies on HAPC studies, which may further facilitate the development of novel therapies against this common disease.

Apoptosis is one cause of thrombocytopenia in patients with high-altitude polycythemia.

High-altitude polycythemia (HAPC) can occur in individuals who are intolerant to high-altitude hypoxia. In patients with HAPC, erythrocytosis is often accompanied by a decrease in platelet count. Chronic hypoxia can increase the incidence of arteriovenous thrombosis and the risk of bleeding during antithrombotic treatment due to thrombocytopenia; therefore, understanding the cause of thrombocytopenia can reduce the risk of treatment-related bleeding. In this study, we examined platelet production and apoptosis to understand the cause of thrombocytopenia in patients with HAPC. The classification of myeloid-derived megakaryocytes (MKs) in HAPC patients was mainly granular MKs rather than mature MKs, suggesting impaired differentiation and maturation. However, the total number of MKs and newly generated reticulated platelets in the peripheral blood increased, indicating sufficient platelet generation in HAPC thrombocytopenia. Increased platelet apoptosis may be one of the causes of thrombocytopenia. Platelet activation and GP1bα pathway activation induced by thrombin and von Willebrand factor can lead to platelet apoptosis. Platelet production was not reduced in patients with HAPC, whereas platelet apoptosis was associated with thrombocytopenia. These findings provide a rationale for considering the bleeding risk in HAPC patient while treating thrombotic diseases.

What is the context?Platelets are essential in the process of blood clotting; hence, low platelet count increases the risk of bleeding. Thrombocytopenia is present in patients with high-altitude polycythemiaHypoxia can lead to platelet activation and increase in procoagulant factors, while at the same time increase the risk of thrombosis due to erythrocytosis and blood stasis.Antithrombotic therapy should be administered when thrombosis occurs in patients with high altitude polycythemia; however, due to the low platelet count, risk of bleeding must be considered.What is new?In this study, we found that platelet production was not decreased in patients with high-altitude polycythemia.One cause of thrombocytopenia is apoptosis, which is associated with platelet activation, especially GP1bα activation.Inhibition of GP1bα binding to ligand decreased the level of platelet apoptosis.What is the impact?This study provides novel insights into antithrombotic therapy for patients with high-altitude polycythemia complicated by thrombosis.Thrombocytopenia is associated with excessive apoptosis.Interfering with GP1bα targets may have a dual benefit, both in inhibiting thrombosis and avoiding thrombocytopenia.

Correlation of platelet-derived growth factor and thromboxane A2 expression with platelet parameters and coagulation indices in chronic altitude sickness patients.

NEW FINDINGS: What is the central question of this study? Is the expression of platelet-derived growth factor (PDGF) and thromboxane A2 (TXA2) elevated in chronic altitude patients, and are they related to thrombosis in chronic mountain sickness? What is the main finding and its importance? The expression of PDGF and TXA2 in both the bone marrow and the peripheral blood of patients with chronic mountain sickness is elevated, and they are considered to be correlated in the mechanism of thrombosis in the chronic mountain sickness. ABSTRACT: The purpose of this study was to evaluate the expression of platelet-derived growth factor (PDGF) and thromboxane A2 (TXA2) along with platelet parameters and coagulation indices in chronic mountain sickness (CMS) patients and healthy individuals on the Qinghai-Tibet Plateau. The levels of PDGF and TXA2 were examined in 22 CMS patients (age, 52.77 ± 9.92 years, haemoglobin, 219 ± 13 g/l) and 25 healthy individuals (age, 47.80 ± 9.78 years, haemoglobin, 146 ± 18 g/l), and the association between platelet parameters and coagulation indices was investigated. Mean platelet volume and fibrinogen degradation product were higher in the CMS compared to the control group (10.58 ± 0.83 vs. 8.92 ± 1.61, 7.50 ± 2.15 vs. 4.40 ± 2.51), platelet count and plateletcrit were lower in the CMS compared to the control group (0.13 (0.80, 0.16) vs. 0.23 (0.18, 0.24), 109 ± 46 vs. 204 ± 86). The levels of PDGF and TXA2 in the bone marrow and peripheral blood of CMS patients were higher (P < 0.01) in comparison to the control group. The two factors had no statistically significant relationship with platelet parameters or coagulation indices (P > 0.159). According to the current findings, platelets in CMS patients were activated, resulting in aberrant coagulation and PDGF and TXA2 expression, which could be due to physiological adjustments to the plateau's high altitude. To summarize, PDGF and TXA2 levels in CMS patients were not correlated with coagulation or platelet parameters, implying that the mechanism behind their increased expression warrants additional investigation.

Prevalence and risk factors of refractive error in Qinghai, China: a cross-sectional study in Han and Tibetan adults in Xining and surrounding areas.

BACKGROUND: Our study aimed to explore the prevalence and risk factors of refractive error (RE) in Han and Tibetan population aged 50-79 years in Xining and surrounding areas in Qinghai Province on Qinghai-Tibet Plateau. METHODS: As part of the China National Health Survey, our cross-sectional study compared the age-adjusted prevalence of RE in Han and Tibetan older adults aged 50-79 years in Xining and surrounding areas. A multivariate logistic regression model was used to identify risk factors for myopia and hyperopia. RESULTS: Among 769 Han participants and 476 Tibetan participants, the age-adjusted prevalence of myopia (spherical equivalent (SE) < - 0.5D), hyperopia (SE > + 0.5D), high myopia (SE < -6.0D) and astigmatism (cylindrical equivalent > = 0.5D) is 28.56, 22.82, 2.80, and 69.38%. Han participants have higher age-adjusted prevalence of myopia (32.93% vs 21.64%, p < 0.001), high myopia (3.93% vs 1.02%, p = 0.001) and astigmatism (72.14% vs 64.94%, p = 0.021) compared to Tibetan participants. Being Tibetan is the protective factor of myopia compared to being Han (OR 0.58, 95%CI 0.42-0.79, p < 0.001). Older age (p = 0.032), longer time length in rural area (p = 0.048), undergraduate/graduate education level (p = 0.031), lighter active level (p = 0.007) and lower BMI (p = 0.015) are risk factors for myopia. Older age (all p < 0.001) and pterygium status of the same eye (p = 0.013) also increase the hyperopia risk. CONCLUSIONS: Our study found an overall prevalence of myopia of 28.56% in Xining and surrounding areas in adults older than 50 years. Han population has higher myopia risk than Tibetan population. More medical and social resources should be allocated to improve the vision and life quality of older adults.

EPAS1 regulates proliferation of erythroblasts in chronic mountain sickness.

Excessive erythrocytosis (EE) is a characteristic of chronic mountain sickness (CMS). Currently, the pathogenesis of CMS remains unclear. This study was intended to investigate the role of EPAS1 in the proliferation of erythroblasts in CMS. Changes of HIF-1α and EPAS1/HIF-2α in the bone marrow erythroblasts of 21 patients with CMS and 14 control subjects residing at the same altitudes were determined by RT-qPCR and western blotting. We also developed a lentiviral vector, Lv-EPAS1/sh-EPAS1, to over-express/silence EPAS1 in K562 cells. Cells cycle and proliferation were detected by flow cytometry. Transcriptome analyses were carried out on Illumina. CMS patients showed a higher expression of EPAS1/HIF-2α in the bone marrow erythroblasts than those of controls. Variations in EPAS1 expression in CMS patients were positively correlated with RBC levels, and negatively correlated with SaO2. Over-expressing of EPAS1 in K562 cells accelerated the erythroid cells cycle progression and promoted the erythroid cells proliferation-and vice versa. Transcriptome data indicated that proliferation-related DEGs were significantly enriched in EPAS1 overexpression/silencing K562 cells. Our results suggest that EPAS1 might participate in the pathogenesis of EE by regulating the proliferation of erythroblasts.

MiR-9-5p inhibits mitochondrial damage and oxidative stress in AD cell models by targeting GSK-3ß.

This study aims to investigate the effects and underlying mechanisms of overexpression microRNA-9-5p (miR-9-5p) on the Aß-induced mouse hippocampal neuron cell line HT22. Different concentrations of Aß25-35 (10, 20, 40, 80, and 160 µM) treatment were used to establish AD model in HT22 cells. The CCK-8 assay was used to measure the cell viability. The mRNA expression levels of miR-9-5p and glycogen synthase kinase-3ß (GSK-3ß) were determined by RT-qPCR. HT22 cell apoptosis was analyzed flow cytometry. MiR-9-5p was down-regulated in Aß25-35-induced HT22 cells. GSK-3ß is a functional target for miR-9-5p. MiR-9-5p overexpression inhibited Aß25-35-induced mitochondrial dysfunction, cell apoptosis, and oxidative stress by regulating GSK-3ß expression in HT22 cells. Furthermore, through targeting GSK-3ß, overexpression of miR-9-5p partly activated nuclear factor Nrf2/Keap1 signaling, including part increases of Nrf2, HO-1, SOD-1, GCLC expression and slight decrease of Keap1 expression. Our results showed miR-9-5p may play a powerful role in the pathogenesis of AD.

Downregulation of intrinsic apoptosis pathway in erythroblasts contributes to excessive erythrocytosis of chronic mountain sickness.

Chronic mountain sickness (CMS) has a higher incidence in the plateau region and is characterized by excessive erythrocytosis and hypoxemia. Bcl-2 family plays an important role in the process of erythropoiesis and the regulation of apoptosis. This study aimed to examine the change in apoptosis of erythroblasts in CMS patients and explore the involvement of Bcl-2 family. Bone marrow mononuclear cells (BMMNCs) were isolated by density gradient centrifugation from 18 CMS patients and 17 control participants. The apoptotic rate, mitochondrial membrane potential (MMP), the protein expression of caspase-3, TNFR, Fas, Bcl-2, Bax and Cyt-C were examined by flow cytometry, and mRNA expression was determined by real-time PCR. The results showed that apoptotic rate of erythroblasts was lower and MMP was higher in CMS group than in control group. The mRNA and protein expression levels of Bcl-2 were higher while Bax level was lower in CMS group than in control group. In CMS group, the apoptosis rate of CD71+ erythroblasts was negatively correlated with the ratio of CD71+ cells in BMMNCs and positively correlated with hemoglobin level. In conclusion, erythroblasts apoptosis is decreased due to the regulation of the expression of Bcl-2 family members in the erythroblasts of CMS patients.

PI3K-Akt Signal Transduction Molecules Maybe Involved in Downregulation of Erythroblasts Apoptosis and Perifosine Increased Its Apoptosis in Chronic Mountain Sickness.

BACKGROUND Chronic mountain sickness (CMS) has a higher incidence in the plateau region. The one of its principal characters is excessive erythrocytosis. The PI3K-Akt pathway plays an important role in the process of erythropoiesis, and could downregulate apoptosis by regulating apoptosis-related molecules. In this paper, we explored the change in apoptosis of erythroblasts and the effect of the PI3K-Akt signal pathway on erythroblasts apoptosis in CMS. MATERIAL AND METHODS A total of 22 CMS and 20 non-CMS participants were involved in this study. Bone marrow mononuclear cells were cultured and treated with celecoxib and perifosine in vitro for 72 hours. The apoptotic rate, the mRNA expressions of Akt, Bcl-xl, and caspase-9, and the protein expressions of Akt, p-Akt, Bcl-xl, and caspase-9 were determined by flow cytometry, quantitative RT-PCR, and western-blot technique. RESULTS The apoptotic rate of cultured erythroblasts was lower in the CMS group than in the non-CMS group. It was increased after perifosine intervention. The mRNA and protein expressions of Akt and Bcl-xl were higher and caspase-9 was lower in the CMS group than the non-CMS group. Perifosine induced decreased Bcl-xl mRNA and proteins and p-Akt proteins, and increased caspase-9 mRNA and proteins in vitro. In the CMS group, the hemoglobin concentration was correlated with apoptotic rate negatively and with Bcl-xl mRNA positively in erythroblasts; the erythroblasts apoptotic rate was negatively associated with the Akt mRNA and Bcl-xl mRNA. CONCLUSIONS The erythroblasts apoptosis was downregulated and the PI3K-Akt signal pathway appeared to be involved in the mechanism of decreased erythroblasts apoptosis in CMS.

The combination of crocin with cisplatin suppresses growth of gastric carcinoma cell line BGC-823 and promotes cell apoptosis.

This study aimed to investigate the efficacy of crocin alone and in combination with cisplatin in the therapy of gastric carcinoma cells. In this study, human gastric carcinoma cell line BGC-823 was purchased and maintained in standard condition. Crocin, cisplatin and crocin plus cisplatin diluted to different concentrations were added into medium, respectively. MTT assay and flow cytometry were performed to test the anti-proliferation effects and apoptosis rates of cells, respectively. In addition, quantitative RT-PCR was used to detect the mRNA expression of apoptosis-related genes, such as p53, Bax and Bcl-2. After treated with different concentrations of crocin, the inhibition ratio and apoptosis rate of BGC-823 cells were not significantly changed. However, the tumor cell inhibition ratio and apoptosis rate in crocin plus cisplatin group were significantly higher than that in cisplatin, crocin and control group (p<0.05). The treatment of crocin plus cisplatin significantly increased the expression of p53 and Bax (p< 0.05), and significantly decreased the Bcl-2 expression (p<0.05). Collectively, our data demonstrated for the first time that crocin plus cisplatin may be used as a new anticancer drug for the treatment of gastric cancer.

Effects of the aqueous extract of a Tibetan herb, Rhodiola algida var. tangutica on proliferation and HIF-1α, HIF-2α expression in MCF-7 cells under hypoxic condition in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola algida var. tangutica is a traditional Tibetan herb. Its root and rhizome have been successfully used as an effective clinical remedy for the prevention and treatment of cancer and high-altitude sickness. This study aimed to investigate the effect of Rhodiola algida var. tangutica on hypoxic MCF-7 breast cancer cells and the underlying mechanisms. MATERIALS AND METHODS: The antiproliferative effects of R. algida on MCF-7 breast cancer cells were compared in vitro under hypoxic and normal conditions by using MTT analysis. The influence of R. algida on cancer cell apoptosis was determined by flow cytometry. The expression levels of hypoxia-inducible factor (HIF)-1α and HIF-2α were evaluated by western blot analysis. RESULTS: R. algida inhibited the proliferation of MCF-7 breast cancer cells in a dose- and time-dependent manner. The results of flow cytometry indicated that the antiproliferative effect of R. algida was mediated by apoptosis induction. Pretreatment with R. algida significantly suppressed the hypoxia-induced proliferation and expression of HIF-1α and HIF-2α in MCF-7 breast cancer cells. CONCLUSIONS: R. algida might exert an anti-carcinogenic effect on MCF-7 breast cancer cells by decreasing the protein levels of HIF-1α and HIF-2α, which are overexpressed under hypoxic conditions. This effect might be elicited by inhibiting the hypoxia-induced proliferation of MCF-7 breast cancer cells.

Impact of high-altitude hypoxia on Helicobacter pylori-induced gastritis pathological manifestations and inflammatory responses.

BACKGROUND: Chronic gastritis caused by Helicobacter pylori (Hp) infection is a common gastrointestinal disorder. Despite the high prevalence of Hp infection and chronic gastritis in the Tibetan Plateau, there is a lack of studies elucidating the influence of plateau hypoxia on Hp-induced gastritis. This study aimed to investigate the impact of high-altitude hypoxia on Hp-induced gastritis, particularly focusing on pathological manifestations and inflammatory responses. METHODS: This study was conducted from July 2023 to March 2024 at the Department of Gastroenterology, Affiliated Hospital of Qinghai University. Ninety patients diagnosed with chronic gastritis were enrolled in the study and divided into four groups based on their residential altitude and Hp infection status. Data on endoscopic and pathological characteristics were collected, along with serum oxidative stress and inflammatory markers. RESULTS: Patients with Hp gastritis exhibit distinctive features in the gastric mucosa, including diffuse erythema, enlarged folds, and white turbid mucus during endoscopy. Notably, individuals with Hp gastritis at high altitudes show a higher prevalence of diffuse erythema and enlarged folds. Pathological analysis reveals that these patients have elevated gastric mucosal inflammation scores and increased chronic and active inflammation. Furthermore, individuals with Hp gastritis at high altitudes demonstrate elevated levels of serum TNF-α, IL-1ß, IL-6, and MDA, as well as reduced serum SOD and GSH-Px activities. CONCLUSIONS: High-altitude hypoxia may exacerbate gastric mucosal damage by enhancing oxidative stress and inflammatory response induced by Hp infection.

Microstructure and Mechanical Properties of Dual Scaled NbC/Ti2AlC Reinforced Titanium-Aluminum Composite.

A TiAl composite containing hybrid particles and whisker reinforcements is fabricated by vacuum melting. The results of this study show that the comprehensive mechanical properties and refining effect of the material are best when the content of reinforcement is 1 wt.%, and then the mechanical properties begin to deteriorate as the content increases further. Finely dispersed NbC particles and uniformly dispersed Ti2AlC whiskers are the ideal second phases. The synergistic strengthening effect of NbC particles and in situ Ti2AlC whiskers are key to the improvement of mechanical properties. Compared with the TiAlNb matrix, the fracture stress/strain of the composite at 1073 K is improved from 612 MPa/19.4% to 836 MPa/26.6%; the fracture toughness at room temperature is improved from 18.8 MPa/m2 to 27.4 MPa/m2.

Bipartite Ranking Fairness Through a Model Agnostic Ordering Adjustment.

Recently, with the applications of algorithms in various risky scenarios, algorithmic fairness has been a serious concern and received lots of interest in machine learning community. In this article, we focus on the bipartite ranking scenario, where the instances come from either the positive or negative class and the goal is to learn a ranking function that ranks positive instances higher than negative ones. We are interested in whether the learned ranking function can cause systematic disparity across different protected groups defined by sensitive attributes. While there could be a trade-off between fairness and performance, we propose a model agnostic post-processing framework xOrder for achieving fairness in bipartite ranking and maintaining the algorithm classification performance. In particular, we optimize a weighted sum of the utility as identifying an optimal warping path across different protected groups and solve it through a dynamic programming process. xOrder is compatible with various classification models and ranking fairness metrics, including supervised and unsupervised fairness metrics. In addition to binary groups, xOrder can be applied to multiple protected groups. We evaluate our proposed algorithm on four benchmark data sets and two real-world patient electronic health record repositories. xOrder consistently achieves a better balance between the algorithm utility and ranking fairness on a variety of datasets with different metrics. From the visualization of the calibrated ranking scores, xOrder mitigates the score distribution shifts of different groups compared with baselines. Moreover, additional analytical results verify that xOrder achieves a robust performance when faced with fewer samples and a bigger difference between training and testing ranking score distributions.

Weighted gene co-expression network analysis reveals the hub genes associated with pulmonary hypertension.

Pulmonary hypertension (PH) is a cardiopulmonary vascular disease that acutely endangers human health and can be fatal. It progresses rapidly and has a high mortality rate. Its pathophysiology is complicated and still not completely elucidated; therefore, achieving treatment breakthroughs are difficult. In this study, data from 58 normal controls and 135 patients with PH were extracted from the GSE24988, GSE113439, and GSE117261 datasets in the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs). In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Weighted gene co-expression network analysis (WGCNA) was used to identify the key modules and hub genes associated with PH. Eight PH-associated hub genes were identified. Furthermore, correlation analysis between immune cell infiltration and hub genes was performed, and the receiver operating characteristic (ROC) curves showed that TARDBP had the best diagnostic efficacy. Moreover, a rat hypoxic pulmonary hypertension (HPH) model was generated, and the expression of hub genes in the lungs and pulmonary arteries of HPH rats was verified using western blotting assays. Our results showed that mTOR, PSMD2, RBM8A, SMARCA4, TARDBP, and UBXN7 were highly expressed in the lungs. In addition, EFTUD2, mTOR, RBM8A, SMARCA4, TARDBP, and UBXN7 were significantly upregulated, whereas DDB1 was significantly downregulated in the pulmonary arteries of HPH rats compared with those of controls. In conclusion, we identified PH hub genes with diagnostic and predictive value by performing WGCNA on data from the GEO database. Furthermore, we provided novel insights of PH that might be utilized to evaluate potential biomarker genes and therapeutic targets.

Infiltrating ductal breast carcinoma with monoclonal gammopathy of undetermined significance: A case report.

BACKGROUND: Infiltrating ductal breast carcinoma with monoclonal gammopathy of undetermined significance (MGUS) is rare and easily misdiagnosed. Most patients are first diagnosed with MGUS. We report a rare case of MGUS secondary to infiltrating ductal breast carcinoma. We also review the literature to analyze the clinical characteristics and diagnostic methods. CASE SUMMARY: A 51-year-old woman underwent modified radical mastectomy for infiltrating ductal carcinoma of the right breast and was then treated with radiation and chemotherapy. A decreased platelet count was found on routine blood examination, and MGUS was subsequently diagnosed. This is the first report of the occurrence of MGUS after breast cancer surgery. CONCLUSION: Vigilance is required to distinguish this rare comorbidity from breast plasmacytoma.

Ureteral calculi associated with high-altitude polycythemia: A case report.

RATIONALE: High-altitude polycythemia (HAPC) is a common disease in high-altitude areas characterized by excessive erythrocyte proliferation and severe hypoxemia. Recently, the incidence of ureteral calculi has risen. However, cases of ureteral calculi associated with HAPC have not been reported. PATIENT CONCERNS: We present the cases of 2 patients (26-year-old female, Case 1; 31-year-old male, Case 2) with HAPC who were born in the lowlands and worked in areas of high altitudes. Both patients were admitted to the hospital with acute severe pain in the ureter as the first symptom. DIAGNOSES: Urological examinations confirmed the presence of a ureteral stone. Interestingly, the biochemical tests showed elevated serum uric acid levels, and the calculous component analysis suggested anhydrous uric acid. INTERVENTIONS: In the first case, the patient underwent extracorporeal shock wave lithotripsy. In the second case, the patient underwent right ureteroscopy and right ureteral stenting. The patient received postoperative anti-inflammatory, hemostatic, and rehydration therapy. OUTCOMES: Both patients recovered well with no recurrences observed upon regular re-examinations. LESSONS: Recently, extensive research has demonstrated a significant correlation between hyperuricemia and HAPC. Therefore, we speculated that the occurrence of ureteral calculi among immigrants to the plateau might be related to hyperuricemia associated with HAPC. This case report and literature review highlights that the prevention of ureteral calculi in patients with polycythemia who immigrate to the plateaus from high-altitude areas should be considered. Additionally, the serum uric acid levels and urine pH should be monitored regularly.

VHL gene methylation contributes to excessive erythrocytosis in chronic mountain sickness rat model by upregulating the HIF-2α/EPO pathway.

AIMS: Hypoxia-inducible factors (HIFs) play important roles in the pathogenesis of erythrocytosis in chronic mountain sickness (CMS). von Hippel-Lindau (VHL) is a key regulator of hypoxia that can direct the poly-ubiquitylation and degradation of HIFs. Epigenetic mechanisms are believed to contribute toward adaption to chronic hypoxia. Here, we investigated the contribution and mechanism of VHL methylation in rats with erythrocytosis in CMS. MAIN METHODS: The methylation status of VHL was measured via bisulfite sequencing PCR, while VHL, DNMT1, DNMT3α, and DNMT3ß expression were assessed using real-time reverse transcription PCR and western blotting. HIF-2α and EPO expression levels in bone marrow were determined via immunohistochemical staining, and erythroid hyperplasia in bone marrow sections were observed with hematoxylin and eosin staining. KEY FINDINGS: We found that chronic hypoxia triggered erythroid hyperplasia in the bone marrow and increased the quantity of peripheral red blood cells in CMS rats. Chronic hypoxia significantly induced methylation at the CpG site in the VHL promoter, decreased VHL expression, and increased HIF-2α and EPO expression. Chronic hypoxia increased DNMT3α and DNMT3ß expression, consistent with the decrease in VHL expression. The DNA methyltransferase inhibitor 5-azacytidine reduced chronic hypoxia-induced erythroid proliferation in the bone marrow of rats with CMS by suppressing VHL methylation and DNMTs expression. SIGNIFICANCE: Our study suggests that VHL methylation contributes toward excessive erythrocytosis in CMS by upregulating the HIF-2α/EPO pathway in the bone marrow of rats. We demonstrated that the DNMT inhibitor 5-azacytidine can attenuate erythroid hyperplasia in the bone marrow by demethylating the VHL promoter.

Novel insights into plasma biomarker candidates in patients with chronic mountain sickness based on proteomics.

Chronic mountain sickness (CMS) is a progressive incapacitating syndrome induced by lifelong exposure to hypoxia. In the present study, proteomic analysis was used to identify the differentially expressed proteins (DEPs) and then evaluate the potential plasma biomarkers between CMS and non-CMS groups. A total of 145 DEPs were detected in CMS Han Chinese people who live in the plateau (CMS-HPu), among which 89 were significantly up-regulated and 56 were significantly down-regulated. GO enrichment analysis showed that various biological processes were enriched, including the hydrogen peroxide metabolic/catabolic process, reactive oxygen species (ROS) metabolic, and acute inflammatory response. Protein-protein interaction analysis showed that antioxidant activity, the hydrogen peroxide catabolic process and peroxidase activity were primarily mapped in interaction proteins. Nine modules showed significantly clustering based on WGCNA analysis, with two being the most significant, and GO analysis showed that proteins of both modules were primarily enriched in oxidative stress-related biological processes. Four DEPs increased in CMS patients were evaluated as the candidate biomarkers, and three showed significant AUC: hemoglobin ß chain (HB-ß), thioredoxin-1 (TRX1), and phosphoglycerate kinase 1 (PGK1). The present study provides insights into the pathogenesis of CMS and further evaluates the potentially biomarkers for its prevention and treatment of it.