The PLOD2/succinate axis regulates the epithelial-mesenchymal plasticity and cancer cell stemness.

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.

Experimental Characteristics of Patients with Newly Diagnosed Multiple Myeloma.

Background: Multiple myeloma (MM), a malignant plasma cell proliferative disease, makes up to 1% of all cancers and somewhat exceeds 10% of all hematological cancers. Since it affects many organs, the signs and symptoms of myeloma vary greatly. This investigation was carried out to identify the clinical and laboratory characteristics of MM. Method: From January 1, 2014, to June 30, 2020, 169 in-patients who received a MM diagnosis for the first time at China-Japan Friendship Hospital in Beijing had their medical information examined. Results: Among 169 newly diagnosed patients, the median age was 60 years (26-84 years). Seven patients were younger than 40 years, and 16.0% (27/169) were 70 years or older. 40.8% (69/169) had IgG M-protein and 27.2% (46/169) had IgA. 84% (142/169) of patients were in the Durie Salmon stage 3. The major sign and symptoms at diagnosis were fatigue (100/169, 59.2%), bone pain (96/169, 56.8%), and weight loss (34/169, 20.1%). Anemia was present initially in 94.0% (159/169), high erythrocyte sedimentation rate in 92.7% (101/109), and thrombocytopenia in 26.6% (45/169). Similarly, hypercalcemia, renal insufficiency, and hypoalbuminemia were observed in 19.3% (31/161), 27.8%, and 75.7% respectively. Immunoparesis was found in 94% (110/117) of IgG, IgA, or IgM patients, and in 87% (33/38) of light chain myeloma patients. A localized band was found in 78.3% (123/157) of patients upon serum protein electrophoresis while monoclonal protein was detected by immunofixation in 91.5% (139/152) of patients. 4.1% (7/169) of the patients had non-secretory myeloma. The prevalence of light chain myeloma was 22.5% (38/169), and these individuals were more likely than other myeloma patients to have renal insufficiency (50% versus 21%, P < .05). In 84.8% of patients, the bone marrow had 10% or more plasma cells. Conclusion: The notable features that can be concluded from this study are the early onset of myeloma in the Chinese population and an advanced disease stage at the time of diagnosis with most of them accompanying anemia, hypoalbuminemia, and immunoparesis.

Increased ROS production in non-polarized mammary epithelial cells induces monocyte infiltration in 3D culture.

Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor κB (NF-κB) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is a crucial regulator that links cell polarity and ROS generation. We also linked monocyte infiltration with disruption of polarized acinar structure using a 3D co-culture system. Gain- and loss-of-function experiments demonstrated that increased ROS in non-polarized cells is necessary and sufficient to enhance monocyte recruitment. ROS also induced cytokine expression and NF-κB activity. These results suggest that increased ROS production in mammary epithelial cell leads to disruption of cell polarity and promotes monocyte infiltration.

Cassie-Baxter Surfaces for Reversible, Barrier-Free Integration of Microfluidics and 3D Cell Culture.

3D cell culture and microfluidics both represent powerful tools for replicating critical components of the cell microenvironment; however, challenges involved in the integration of the two and compatibility with standard tissue culture protocols still represent a steep barrier to widespread adoption. Here we demonstrate the use of engineered surface roughness in the form of microfluidic channels to integrate 3D cell-laden hydrogels and microfluidic fluid delivery. When a liquid hydrogel precursor solution is pipetted onto a surface containing open microfluidic channels, the solid/liquid/air interface becomes pinned at sharp edges such that the hydrogel forms the "fourth wall" of the channels upon solidification. We designed Cassie-Baxter microfluidic surfaces that leverage this phenomenon, making it possible to have barrier-free diffusion between the channels and the hydrogel; in addition, sealing is robust enough to prevent leakage between the two components during fluid flow, but the sealing can also be reversed to facilitate recovery of the cell/hydrogel material after culture. This method was used to culture MDA-MB-231 cells in collagen, which remained viable and proliferated while receiving media exclusively through the microfluidic channels over the course of several days.

Ameliorative effect of sevoflurane on endoplasmic reticulum stress mediates cardioprotection against ischemia-reperfusion injury 1.

We aimed to investigate whether the cardioprotection of sevoflurane against ischemia-reperfusion (IR) injury is via inhibiting endoplasmic reticulum stress. The rat in vivo model of myocardial IR injury was induced by ligation of the left anterior descending coronary artery. Sevoflurane significantly ameliorated the reduced cardiac function, increased infarct size, and elevated troponin I level and lactate dehydrogenase activity in plasma induced by IR injury. Sevoflurane suppressed the IR-induced myocardial apoptosis. The increased protein levels of glucose-regulated protein 78 and C/EBP homologous protein (CHOP) after myocardial IR were significantly reduced by sevoflurane. The protein levels of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2 (eIF2α), and activating transcription factor 4 (ATF4) were significantly increased in rats with IR and attenuated by sevoflurane treatment. The phosphorylation of Akt was further activated by sevoflurane. The cardioprotection of sevoflurane could be blocked by wortmannin, a PI3K/Akt inhibitor. Our results suggest that the cardioprotection of sevoflurane against IR injury might be mediated by suppressing PERK/eIF2a/ATF4/CHOP signaling via activating the Akt pathway, which helps in understanding the novel mechanism of the cardioprotection of sevoflurane.

Effects of early enteral nutrition in patients with severe burns: A systematic review.

BACKGROUND: Nutritional problems in the early stages of severe burns are prominent and seriously affect the clinical outcomes of patients. Our aim is to analyze the effects of early enteral nutrition (EEN) in patients with severe burns. METHODS: In this study, relevant articles were searched in 8 English and Chinese data, with a time limit from the creation of the database to June 2023. Two researchers independently completed the search, screening and quality assessment of the articles. We conducted a systematic review and meta-analysis of randomized controlled trials that examined EEN therapy in people with severe burns. We compared the effects of EEN and non-EEN therapy in severely burned patients. The outcomes were mortality, gastrointestinal complications, nutritional indicators, gastrointestinal hormones, sepsis, length of hospital stay and wound healing time. Categorical variables were expressed as OR and 95% CI was calculated, and continuous variables were expressed as MD and 95% CI was calculated. The protocol for this systematic review was registered in PROSPERO on May 12, 2023 (identifier CRD42023422895). RESULTS: Nineteen studies with a total of 1066 participants met the inclusion criteria. When comparing EEN therapy with non-EEN therapy, the experiment group had significantly lower mortality [OR = 0.39, 95% CI (0.20, 0.74), P = .004], lower wound healing time [MD = -10.77, 95% CI (-13.66,-7.88), P < .00001], fewer gastrointestinal complications [OR = 0.18, 95% CI (0.09, 0.36), P < .00001], lower rates of gastrointestinal hemorrhage [OR = 0.12, 95% CI (0.04, 0.36), P = .0001], lower rates of sepsis [OR = 0.40, 95% CI (0.24, 0.66), P = .0005], shorter length of hospital stay [MD = -12.08, 95% CI (-13.61, 9.19-10.56), P < .00001], and higher prealbumin levels [MD = 29.04, 95% CI (21.98, 36.10), P < .00001], higher total albumin levels [MD = 6.74, 95% CI (4.29, 9.19), P < .00001], and gastrin levels [MD = 15.93, 95% CI (10.12, 21.73), P < .00001]. However, there was no significant difference in albumin between the 2 groups [MD = 2.62, 95% CI (-0.30, 5.55), P = .08] or motilin levels [MD = 12.48, 95% CI (-43.59, 68.56), P = .66]. CONCLUSIONS: EEN plays an important role in the rehabilitation of patients with severe burns. EEN is beneficial to reduce complications and the length of hospital stay, maintain organ function, optimize the nutritional status of patients, promote wound healing, and improve the survival rate of patients.

Research hotspots and trends of the tele-rehabilitation for stroke survivors based on CiteSpace: A review.

Our first goal is to understand the research status and popularity of telerehabilitation research for stroke survivors since 2012; the second goal is to analyze the research trends and frontiers in this field, and provide a scientific basis for the future application of telerehabilitation technology in patients with poststroke functional defects. We searched the Web of Science Core Collection (WoSCC) for literature on telerehabilitation for stroke survivors published from 2012 to 2022. The included articles were visually analyzed using CiteSpace6.1.6R (64-bit). In total, 968 eligible articles were included in this study. In the past 10 years, the number of papers published on telerehabilitation after stroke has been increasing annually, with the largest number of papers published in the United States and Australia, with 101 papers published by Chinese scholars. Some subsets of cooperative networks have been formed among major research institutions and their authors, but the scale remains small, and academic exchanges and cooperation need to be strengthened further. Research on virtual reality (VR) technology and rehabilitation robot technology is popular, and the choice of time and intensity of rehabilitation exercises, patients' participation in rehabilitation exercises, and care are also worth attention. In the last 10 years, research on telerehabilitation technology in the field of rehabilitation for stroke survivors has steadily developed, and is characterized by multidisciplinary joint development. Countries around the world can combine their own characteristics and advantages, strengthen academic exchanges and cooperation with mature research institutions or authors, and explore suitable poststroke remote rehabilitation technologies and service models in different environments.

Severe autoimmune hemolytic anemia complicating hereditary spherocytosis treated successfully with glucocorticoids and cyclosporine: a case report.

BACKGROUND: Severe autoimmune hemolytic anemia complicating hereditary spherocytosis is life threatening and has not been described in a case report. Here, we report a case in which this intractable disease was treated successfully with glucocorticoids and cyclosporine. CASE PRESENTATION: A 25-year-old female patient with hereditary spherocytosis developed severe autoimmune hemolytic anemia after respiratory syncytial virus infection. Her hemoglobin level was 26 g/L and various anti-red blood cell antibodies were detected in her serum, making blood matching difficult. Glucocorticoid monotherapy was ineffective. With the addition of cyclosporine (50 mg/12 h), the patient's hemoglobin level increased significantly and the symptoms associated with anemia were greatly relieved. CONCLUSION: In patients with severe autoimmune hemolytic anemia, especially when the presence of multiple anti-red blood cell antibodies and alloantibodies interferes with blood matching, a glucocorticoid-cyclosporine regimen may be tried.

A scientometric analysis and visualization of kinesiophobia research from 2002 to 2022: A review.

Kinesiophobia is an excessive, irrational, debilitating fear of physical movement and activity caused by a sense of vulnerability to pain or re-injury, which can have a direct impact on physical functioning and mental well-being of patients. This paper aims to provide reliable support for future in-depth research on kinesiophobia through scientometrics and historical review. Studies on kinesiophobia published from 2002 to 2022 were retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer were used to conduct bibliometric analysis of the included studies and map knowledge domains. Keywords were manually clustered, and the results were analyzed and summarized in combination with a literature review. A total of 4157 original research articles and reviews were included. Research on kinesiophobia is developing steadily and has received more attention from scholars in recent years. There are regional differences in the distribution of research. Chronic pain is the focus of research in this field. A multidisciplinary model of pain neuroscience education combined with physical therapy based on cognitive-behavioral therapy and the introduction and development of virtual reality may be the frontier of research. There is a large space for the study of kinesiophobia. In the future, to improve regional academic exchanges and cooperation, more attention should be given to the clinical applicability and translation of scientific work, which will be conducive to improving the quality of life and physical and mental health outcomes of kinesiophobia patients.

Research trends and hotspots in exercise rehabilitation for coronary heart disease: A bibliometric analysis.

Exercise rehabilitation can improve the prognosis of patients with coronary heart disease. However, a bibliometric analysis of the global exercise rehabilitation for coronary heart disease (CHD) research topic is lacking. This study investigated the development trends and research hotspots in the field of coronary heart disease and exercise rehabilitation. CiteSpace software was used to analyze the literature on exercise therapy for CHD in the Web of Science Core Collection database. We analyzed the data of countries/institutions, journals, authors, keywords, and cited references. A total of 3485 peer-reviewed papers were found, and the number of publications on the topic has steadily increased. The most productive country is the USA (1125), followed by China (477) and England (399). The top 3 active academic institutions are Research Libraries UK (RLUK) (236), Harvard University (152), and the University of California System (118). The most commonly cited journals are Circulation (2596), The most commonly cited references are "Exercise-based cardiac rehabilitation for coronary heart disease" (75), Lavie CJ had published the most papers (48). World Health Organization was the most influential author (334 citations). The research frontier trends in this field are body composition, participation, and function. Research on the effects of physical activity or exercise on patients with CHD is a focus of continuous exploration in this field. This study provides a new scientific perspective for exercise rehabilitation and CHD research and gives researchers valuable information for detecting the current research status, hotspots, and emerging trends for further research.

Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis.

PURPOSE: This study aims to determine the influence of targeting araC-resistant acute myeloid leukemia by dual inhibition cyclin-dependent protein kinase (CDK9) and B-cell lymphoma-2 （Bcl-2). METHOD: The c-Myc inhibitor 10058-F4 and the CDK9 inhibitor AZD4573 were used to determine the cell cycle arrest and apoptosis. RESULTS: 10058-F4 reduces c-Myc protein levels and suppresses HepG2 cell proliferation, possibly by upregulating cyclin-dependent kinase (CDK) inhibitors, p21WAF1, and reducing intracellular alpha-fetal protein (AFP) levels. CONCLUSION: The combination of AZD4573 and 10058-F4 has a synergistic anti-araC-resistant AML activity, providing a solid database for the aforementioned scientific hypothesis.

HIV-1 diversity and drug-resistant mutations in infected individuals in Changchun, China.

OBJECTIVES: Human immunodeficiency virus type 1 (HIV-1) infection has been detected in all provinces of China. Although epidemiological and phylogenetic studies have been conducted in many regions, such analyses are lacking from Jilin province in northeastern China. METHOD: Epidemiological and phylogenetic analyses, as well as detection of drug-resistant mutations, were conducted on 57 HIV-1 infected patients from Changchun city identified and confirmed through annual surveillance by local Centers for Disease Control in Jilin province of northeastern China in 2012. RESULTS: Sexual contact was determined to be the major pathway for HIV-1 transmission in Jilin, where hetero- and homosexual activities contributed almost equally. Phylogenetic analyses detected multiple subtypes of HIV-1 including subtype G circulating in Jilin, with multiple origins for each of them. Both subtype B and CRF01_AE were dominant, and evidence of subtype B transmitting between different high-risk groups was observed. Mutations in the viral protease at position 71 indicated the presence of a selective pressure. Several drug-resistant mutations were detected, although they were predicted with low-level resistance to antiviral treatments. CONCLUSIONS: Information from this study fills the gap in knowledge of HIV-1 transmission in Changchun city, Jilin province, China. By revealing the origin and evolutionary status of local HIV-1 strains, this work contributes to ongoing efforts in the control and prevention of AIDS.

Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1.

Long interspersed elements 1 (LINE-1) occupy at least 17% of the human genome and are its only active autonomous retrotransposons. However, the host factors that regulate LINE-1 retrotransposition are not fully understood. Here, we demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) infectivity and neutralized by the viral Vpx protein, is also a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition. We also found that mutant SAMHD1s of Aicardi-Goutières syndrome patients are defective in LINE-1 inhibition. Several domains of SAMHD1 are critical for LINE-1 regulation. SAMHD1 inhibits LINE-1 retrotransposition in dividing cells. An enzymatic active site mutant SAMHD1 maintained substantial anti-LINE-1 activity. SAMHD1 inhibits ORF2p-mediated LINE-1 reverse transcription in isolated LINE-1 ribonucleoproteins by reducing ORF2p level. Thus, SAMHD1 may be a cellular regulator of LINE-1 activity that is conserved in mammals.