Case report: A patient with brachio-cervical inflammatory myopathy was misdiagnosed as flail arm syndrome.

Brachio-cervical inflammatory myopathy (BCIM) is a rare inflammatory myopathy characterized by dysphagia, bilateral upper limb atrophy, limb-girdle muscle weakness, and myositis-specific antibody (MSA) negativity. BCIM has a low incidence and is commonly associated with autoimmune diseases. We present a case report of a 55-year-old man with progressive upper limb weakness and atrophy, diagnosed with flail arm syndrome (FAS). The initial electromyography revealed extensive spontaneous muscle activity and increased duration of motor unit potentials (MUPs). During follow-up, evidence of myogenic damage was observed, as indicated by a decreased duration of MUPs in the right biceps muscle. Laboratory and genetic testing ruled out hereditary or acquired diseases. Negative serological antibodies for myasthenia gravis. Hereditary or acquired diseases were ruled out through laboratory and genetic testing. Whole-body muscle magnetic resonance imaging (MRI) showed extensive edema and fat replacement in the bilateral upper limbs, scapular, and central axis muscles, while the lower extremities were relatively mildly affected. Muscle biopsy revealed numerous foci of inflammatory cells distributed throughout the muscle bundle, with predominant CD20, CD138, and CD68 expression, accompanied by a light infiltration of CD3 and CD4 expression. The muscle weakness improved with the combination of oral prednisone (initially 60 mg/day, tapered) and methotrexate (5 mg/week) treatment.

CD163+ macrophage density in perimysial connective tissue associated with prognosis in IMNM.

OBJECTIVE: The pathological features of immune-mediated necrotizing myopathy (IMNM) are dominated by the infiltration of macrophages. We aimed to perform a histopathologic semiquantitative analysis to investigate the relationship between macrophage markers and prognosis. METHODS: Semiquantitative analysis of histologic features was performed in 62 samples of IMNM. Independent risk factors were identified through univariate and multivariate regression analysis. Cluster analysis was performed using the partitioning around the medoids (PAM) method. Decision tree modeling was utilized to efficiently determine cluster labels for IMNM patients. The validity of the developmental cohort was assessed by accuracy in comparison with the validation cohort. RESULTS: The most enriched groups in patients with IMNM were macrophages expressing CD206 and CD163. In the multivariate logistic regression model, the high density of CD163+ macrophages in perimysial connective tissue increased the risk of unfavorable prognosis (p = 0.025, OR = 1.463, 95% CI: 1.049-2.041). In cluster analysis, patients in Cluster 1, with lower CD163+ macrophage density and inflammatory burden, had a more favorable prognosis. Conversely, patients in Cluster 3, which were enriched for CD163+ macrophages in the perimysial connective tissue, had the most severe clinical features and the worst prognosis. Correlations were found between the density of CD163+ macrophages in connective tissue and symptom duration (R2 = 0.166, p < 0.001), dysphagia (p = 0.004), cardiac involvement (p = 0.021), CK (R2 = 0.067, p = 0.042), CRP (R2 = 0.117, p < 0.001), and ESR (R2 = 0.171, p < 0.001). CONCLUSION: The density of CD163+ macrophages in perimysial connective tissue may serve as a potential marker for the prediction of IMNM prognosis.

The Effect of Scalp Nerve Block on Postoperative Analgesia and Stress Response in Patients Undergoing Craniotomy: A Meta-Analysis.

Objective: To evaluate the effect of scalp nerve block (SNB) on postoperative analgesia and stress response in patients undergoing craniotomy by meta-analysis. Methods: PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched for randomized controlled trials involving SNB for elective craniotomy under general anesthesia from inception to August 1, 2022. Meta-analysis was performed using RevMan 5.4 and Stata MP17.0. Based on scalp block operation time (preoperative block, postoperative block), different control groups (no block, normal saline), local anesthetic types (bupivacaine, levobupivacaine, ropivacaine), the postoperative pain score at different time points was analyzed by subgroup analysis. Results: 23 studies involving 1515 patients were included. The combined results showed that SNB could significantly reduce the pain scores at all time points compared with the control group (P < .05). Subgroup analysis showed that the analgesic effect of preoperative scalp nerve block was better than that of postoperative block, and the effect of ropivacaine and levobupivacaine was better than bupivacaine. SNB could reduce morphine consumption within 48 hours after surgery (SMD = -1.51, 95% CI -2.80 -0.21, P = .02, I2 = 89%). The first rescue analgesia time was significantly longer in the SNB group than the control group (SMD = 0.57, 95% CI 0.16-0.99, P = .01, I2 = 68.76%). Compared with the control group, the levels of postoperative angiotensin, intraoperative blood glucose, and both intraoperative and postoperative cortisol levels were significantly decreased (P < .05). SNB can inhibit hemodynamic changes caused by surgical stimulation and effectively reduce the incidence of postoperative nausea and vomiting (RR = 0.71, 95% CI 0.51~0.97, P = .03). Conclusion: Scalp nerve block is an effective analgesic that reduces pain within 48 hours after craniotomy. It effectively inhibit the stress response caused by surgical stimulation, stabilize hemodynamics, and reduce the incidence of postoperative nausea and vomiting.

[Relationship between promoting effect of Zuogui Pills on angiogenesis of reproductive organs and mobilization factors GM-CSF, SDF-1, and their receptors of EPCs in early-aging rats].

This study aimed to investigate the relationship between the promoting effect of Zuogui Pills on ovarian and vaginal angiogenesis in early-aging rats and mobilization factors granulocyte-macrophage colony-stimulating factor(GM-CSF), stromal cell-derived factor-1(SDF-1), and their receptors of endothelial progenitor cells(EPCs) and explore the mechanism of Zuogui Pills in improving reproductive hypofunction in early-aging rats. Ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) was used to analyze the chemical components of the extract of Zuogui Pills. Forty 14-month-old female early-aging rats with estrous cycle disorder were randomly divided into a blank group, a conjugated estrogen group(conjugated estrogen suspension, 65 µg·kg~(-1)), and low-(11 g·kg~(-1)) and high-dose(33 g·kg~(-1)) Zuogui Pills groups, with 10 rats in each group. In addition, 10 4-month-old female rats were assigned to the youth control group. The rats in the blank group and the youth control group were treated with 20 g·kg~(-1) distilled water by gavage, while those in the groups with drug intervention were treated with corresponding drugs by gavage, once a day for 15 days. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of SDF-1 and GM-CSF in the mobilization of EPCs in serum. Hematoxylin-eosin(HE) staining was used to observe the changes in the number of ovarian follicles at all levels and corpus luteum, the number of vaginal epithelial layers, the number of vaginal folds, and the blood vessels of ovarian and vaginal tissues in the groups with drug intervention. Western blot was used to detect the expression of ER, GM-CSFR, CXCR4, and CXCR7 proteins in ovarian and vaginal tissues. As revealed by the results, the blank group showed decreased number of corpus luteum, gro-wing follicles at all levels, and blood vessels(P<0.05), decreased thickness of vaginal mucosa, the number of epithelial layers, the number of vaginal folds, and the number of vessels in the lamina propria(P<0.05), reduced content of SDF-1 and GM-CSF in the peripheral blood(P<0.05), and down-regulated levels of ER, CXCR4, CXCR7, and GM-CSFR proteins in ovarian and vaginal tissues(P<0.05). The groups with drug intervention showed increased number of growing follicles at all levels, corpus luteum, and blood vessels(P<0.05), decreased number of atresia follicles(P<0.05), increased thickness of vaginal mucosa, the number of epithelial layers, the number of vaginal mucosal folds, and the number of blood vessels in the lamina propria(P<0.05), increased content of SDF-1 and GM-CSF in the peripheral blood(P<0.05), and up-regulated levels of ER, CXCR4, CXCR7, and GM-CSFR proteins in ovarian and vaginal tissues(P<0.05). This experiment suggests that Zuogui Pills may promote ovarian and vaginal angiogenesis and improve the reproductive function of early-aging rats by up-regulating the levels of mobilization factors SDF-1, GM-CSF, and their receptors of EPCs.

Clinical-pathological features and muscle imaging findings in 36 Chinese patients with rimmed vacuolar myopathies: case series study and review of literature.

Introduction: Rimmed vacuolar myopathies (RVMs) are a group of genetically heterogeneous diseases that share histopathological characteristics on muscle biopsy, including the aberrant accumulation of autophagic vacuoles. However, the presence of non-coding sequences and structural mutations, some of which remain undetectable, confound the identification of pathogenic mutations responsible for RVMs. Therefore, we assessed the clinical profiles and muscle magnetic resonance imaging (MRI) changes in 36 Chinese patients with RVMs, emphasizing the role of muscle MRI in disease identification and differential diagnosis to propose a comprehensive literature-based imaging pattern to facilitate improved diagnostic workup. Methods: All patients presented with rimmed vacuoles with varying degrees of muscular dystrophic changes and underwent a comprehensive evaluation using clinical, morphological, muscle MRI and molecular genetic analysis. We assessed muscle changes in the Chinese RVMs and provided an overview of the RVMs, focusing on the patterns of muscle involvement on MRI. Results: A total of 36 patients, including 24 with confirmed distal myopathy and 12 with limb-girdle phenotype, had autophagic vacuoles with RVMs. Hierarchical clustering of patients according to the predominant effect of the distal or proximal lower limbs revealed that most patients with RVMs could be distinguished. GNE myopathy was the most prevalent form of RVMs observed in this study. Moreover, MRI helped identify the causative genes in some diseases (e.g., desminopathy and hereditary myopathy with early respiratory failure) and confirmed the pathogenicity of a novel mutation (e.g., adult-onset proximal rimmed vacuolar titinopathy) detected using next-generation sequencing. Discussion: Collectively, our findings expand our knowledge of the genetic spectrum of RVMs in China and suggest that muscle imaging should be an integral part of assisting genetic testing and avoiding misdiagnosis in the diagnostic workup of RVM.

Infiltrating circulating monocytes provide an important source of BMP4 at the early stage of spinal cord injury.

Bone morphogenetic protein (BMP)4 plays a critical role in regulating neuronal and glial activity in the course of spinal cord injury (SCI). The underlying cause and cellular source of BMP4 accumulation at the injured spinal cord remain unclear. Here, we observed that plasma BMP4 levels are statistically higher in SCI patients than in healthy donors. When comparing rats in the sham group (T9 laminectomy without SCI) with rats in the SCI group, we found a persistent decline in BBB scores, together with necrosis and mononuclear cell accumulation at the contusion site. Moreover, during 2 weeks after SCI both plasma and cerebrospinal fluid levels of BMP4 displayed notable elevation, and a positive correlation. Importantly, percentages of circulating BMP4-positive (BMP4+) monocytes and infiltrating MDMs were higher in the SCI group than in the sham group. Finally, in the SCI+clodronate liposome group, depletion of monocytes effectively attenuated the accumulation of both BMP4+ MDMs and BMP4 in the injured spinal cord. Our results indicated that, following SCI, infiltrating MDMs provide an important source of BMP4 in the injured spinal cord and, therefore, might serve as a potential therapeutic target.

Aberrant metabolic processes promote the immunosuppressive microenvironment in multiple myeloma.

Introduction: Multiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood. Methods: In this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis. Results: We found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy. Discussion: In summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. METHODS: The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. RESULTS: Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. CONCLUSIONS: Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM.

Nurses' practice and educational needs in oral care for postoperative patients with oral cancer in ICUs: a multicenter cross-sectional study.

BACKGROUND: Surgical incision, endotracheal intubation, structural changes in the oral cavity, and other factors lead to a divergence in oral care between patients after oral surgery and ordinary inpatients. High-quality oral care can reduce the incidence of incision infection and ventilator-associated pneumonia. However, there is a lack of guidelines or expert consensus on oral care after oral cancer surgery. Therefore, the aim of this study was to assess the practicing situation of nurses in the intensive care unit (ICU) for postoperative patients with oral cancer and their need for training. METHODS: A multicenter cross-sectional study design was conducted in 19 ICUs of 11 tertiary hospitals from Henan province in China. Data were collected from 173 nurses and 19 head nurses online using a structured questionnaire. Mann-Whitney U and Kruskal-Wallis H tests were performed to analyze the data using SPSS (Version 25.0). RESULTS: Seven ICUs (36.8%) developed evaluation regulations for the oral care of postoperative patients with oral cancer, and eight ICUs (42.1%) described the operating standards. A total of 173 nurses completed the questionnaire, and the median score was 75 (68, 78). Almost all of the examined nurses (91.2%) assessed patients' oral hygiene at a fixed time, while in 52.0% and 28.3% of nurses, the first oral care and frequency of oral care after surgery was determined based on the individual patient's situation. More than half of the nurses (55.5%) spent approximately 5-10 min conducting oral care for patients. Physiological saline solution (82.7%), swabbing (91.9%), and oral care package with cotton ball (86.1%) were the most popular oral care mouthwash, method, and tool, respectively. Nurses sought help from senior nurses (87.3%) and doctors (83.8%), mostly to solve difficulties of oral care. Moreover, 76.9% of the nurses believed that the lack of knowledge and skills surrounding oral care was the main barrier for nurses to implement oral care. The majority of participants (69.4%) had never received continuing education or training in oral care for postoperative patients with oral cancer, and almost all (98.8%) of the respondents stated their preference to receive training in standardized oral care skills. Indications and contraindications (84.4%), tools (81.5%), and mouthwash (80.9%) of oral care were the items that the respondents were most eager to learn about. Approximately three quarters of nurses preferred scenario simulation practice as the training method. CONCLUSION: Although the participants had high oral care scores for postoperative patients with oral cancer, there was great diversity in the practice. The lack of oral care knowledge was deemed the main barrier in delivering quality oral care, and the educational need was stated by almost all participants. We suggest that a standard protocol or clinical practice guidelines for oral care for postoperative patients with oral cancer should be developed, and nurses should be educated to equip them with professional knowledge and skills.

Efficacy and safety of acupuncture combined with auricular acupressure for smoking cessation: A study protocol of a multicentre, randomized, controlled clinical trial.

Background: Nicotine dependence is an addictive behavioral disease facilitated by habitually smoking cigarettes. In many countries, acupuncture and auricular acupressure have attracted growing attention as complementary or alternative treatments for smoking cessation; however, there is a lack of rigorous randomized, controlled studies evaluating the combination of these two interventions specifically for smoking cessation. The aim of this study is to evaluate the efficacy and safety of using acupuncture combined with auricular acupressure (A&AA) to increase the rates of smoking cessation and ultimately reduce the rates of relapse. Methods: This is a multicentre, prospective, parallel, randomized, controlled trial. A total of 360 patients with severe nicotine dependence will be randomized into test (A&AA) or control (nicotine replacement therapy, NRT) groups. The test group will be treated with A&AA twice weekly, while the control group will use an NRT patch daily. All treatments will be administered for 8 weeks, with a follow-up period of 4 months. The primary outcome will be the smoking abstinence rate at week 24, with a combined safety assessment. The secondary outcomes will be smoking cessation rates at other timepoints, saliva cortisone test results, and scores on the Fagerstrom Test for Nicotine Dependence, the Autonomy over Tobacco Scale, the Hamilton Anxiety Rating Scale, the Self-rating Anxiety Scale, and the Pittsburgh Sleep Quality Index. The cost of treatment will also be used to evaluate the economic effects of different smoking cessation interventions. Statistical analysis on the data collected from both the intention-to-treat (all randomly assigned patients) and per-protocol (patients who complete the trial without any protocol deviations) patients, will be performed using the statistical software package, IBM SPSS 27.0. Discussion: This study will provide rigorous clinical evidence evaluating the efficacy and safety of using A&AA as a smoking cessation therapy. Trial registration: Chinese Clinical Trial Registry (Registration number: ChiCTR1900028371).

Risk and Prognostic Factors for BRAFV600E Mutations in Papillary Thyroid Carcinoma.

Background: Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAFV600E mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAFV600E mutation potential of these lesions and new prevention strategies in PTC patients. Methods: A total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAFV600E mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021. Results: The following variables were associated with an increased risk of BRAFV600E mutation in PTC patients: age ≥ 45 years (OR = 1.39, 95%CI = 1.21-1.60, p < 0.00001), male gender (OR = 1.13, 95%CI = 0.99-1.28, p = 0.06), multifocality (OR = 1.22, 95%CI = 1.07-1.40, p = 0.004), lymph node metastasis (OR = 1.33, 95%CI = 0.79-2.23, p = 0.28), extrathyroidal extension + (OR = 1.61, 95%CI = 1.06-2.44, p = 0.03), vascular invasion + (OR = 2.04, 95%CI = 1.32-3.15, p = 0.001), and tumor node metastasis stage (OR = 1.61, 95%CI = 1.38-1.88, p < 0.00001). In addition, tumor size (>1 cm) (OR = 0.51, 95%CI = 0.32-0.81, p = 0.005) and distant metastasis (OR = 0.69, 95%CI = 0.22-2.21, p = 0.54) had no association or risk with BRAFV600E mutation in PTC patients. Conclusion: Our systematic review identified the following significant risk factors of BRAFV600E mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAFV600E mutation in PTC patients.

Indirubin-3'-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3'-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. METHODS: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. FINDINGS: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. INTERPRETATION: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. FUNDINGS: A full list of funding can be found in the acknowledgements.

Effect of resolution bandwidth and video bandwidth on the characterization of chaos in a radio-frequency spectrum analyzer.

The effect of resolution bandwidth (RBW) and video bandwidth (VBW) of a radio-frequency spectrum analyzer on the characteristics of a power spectrum for chaos generated by a semiconductor laser with external optical feedback is investigated experimentally and numerically. We describe the spectral characteristics with effective bandwidth and time-delay signature (TDS) quantificationally. The experimental results demonstrate that the ratio of VBW to RBW has a significant impact on the smoothness of the power spectrum and effective bandwidth of chaos. Meanwhile, the RBW affects the resolution of periodical peaks of the power spectrum and the TDS of chaos, which is obtained by the power spectrum. The incorrect characterization of chaos can be avoided by setting the RBW to no more than 0.1 times as much as the resonance frequency of the external cavity of chaos and setting the VBW/RBW to no more than 0.01. The simulation results qualitatively agree with the analysis of the experiment.

Acupuncture for improving a case of widespread herpes zoster after non-Hodgkin's lymphoma chemotherapy.

BACKGROUND: Herpes zoster presents as clustered blisters on one side of the body, accompanied by nerve pain. This is caused by reactivation of the varicella zoster virus, and it occurs primarily in people with weakened immunity. Tumor and chemotherapy drugs can impair the patient's immune function, induce herpes zoster and prolong the course of disease.In these patients, skin changes can last for months and blisters can recur and cause serious complications such as postherpetic neuralgia.Acupuncture is a common alternative therapy for herpes zoster in East Asia. CASE PRESENTATION: We report a case of an elderly male patient with widespread herpes zoster in the trunk after non-Hodgkin's lymphoma chemotherapy. The patient had received conventional treatment with valaciclovir and mecobalamin within 24 hours of symptom onset. Because neither the clustered blisters nor the nerve pain were improved a week later, acupuncture and related techniques were applied. These included electro-acupuncture, surrounding acupuncture, fire acupuncture, and cupping. The patient recovered 20 days after the herpes zoster attack, and there were no adverse reactions during the treatment process. CONCLUSIONS: This case suggests that acupuncture and related techniques are effective interventions for this condition.This case report is innovative because it shows that acupuncture as an adjuvant treatment can improve the skin lesions in patients with HZ after tumour chemotherapy, relieve pain, and shorten the course of HZ.

NNMT is induced dynamically during beige adipogenesis in adipose tissues depot-specific manner.

Nicotinamide N-methyltransferase (NNMT) is a novel regulator, shown recently to regulate adipose tissue energy expenditure partly through changing NAD + content, which is essential for mitochondrial. We determine whether NNMT plays important role in energy metabolism during the beige adipogenesis in vivo and in vitro. Male C57BL/6 mice at 8 weeks old were exposed to 4 ℃ for 1, 2, 3, 4, and 5 days, respectively. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous WAT (sWAT), and epididymal WAT (eWAT) were harvested for gene and protein expression analysis and the correlation analysis. In addition, cultured primary mice brown adipocyte (BA) and white adipocyte (WA) treated with or without ß3-adrenoceptor agonist (CL316, 243) were also harvested for these analyses. A combination of NNMT and its related genetic (Nmnat1, Nampt, Cyp2e1, Nrk1, Cd38) and proteic analyses and also the NAD + levels demonstrated the dynamical and depot-specific remodeling of NAD metabolism in different adipose tissues in response to cold exposure. While upon CL316, 243 treatment, gene expression of Nnmt, Nampt, Cyp2e1, and Nrk1 was all significantly decreased in WA but not in BA. The increased NAD + amount in BA and WA during the beige adipogenesis was observed. Besides, it is demonstrated that the expression of NNMT both in sWAT and WA showed significant negative correlation with browning markers UCP-1 and PGC-1α at protein levels. Above all, NNMT was induced in WAT during the 'cold remodeling' phase and correlated negatively with the process of browning in sWAT and WA, indicating the specific role of NNMT in the regulation of energy homeostasis during the process of beige adipogenesis.

Four and a Half LIM Domains Protein 2 Mediates Bortezomib-Induced Osteogenic Differentiation of Mesenchymal Stem Cells in Multiple Myeloma Through p53 Signaling and ß-Catenin Nuclear Enrichment.

Myeloma bone disease (MBD), caused by the inhibition of osteoblast activity and the activation of osteoclast in the bone marrow environment, is the most frequent and life-threatening complication in multiple myeloma (MM) patients. Bortezomib (Bzb) was shown to promote MM-derived mesenchymal stem cells (MM-MSCs) differentiation to osteoblast in vitro and in animal models, promoting the bone formation and regeneration, may be mediated via ß-catenin/T-cell factor (TCF) pathway. Further defining molecular mechanism of Bzb-enhanced bone formation in MM will be beneficial for the treatment of myeloma patients. The present study has identified for the first time four and a half LIM domains protein 2 (FHL2), a tissue-specific coregulator that interacts with many osteogenic marker molecules, as a therapeutic target to ameliorate MM bone disease. First, increased messenger RNA (mRNA) and protein levels of FHL2, and the mRNA level of main osteoblast markers (including Runx2, ALP, and Col1A1), were found in MM-patients-derived MSCs after Bzb treatment. FHL2 KD with short hairpin RNA (shRNA) reduced the expression of osteoblast marker genes and blocked the osteogenic differentiation of MM-MSCs regardless of the presence or absence of Bzb, implying that FHL2 is an important activator of the osteogenic differentiation of human MSCs under a proteasome inhibition condition. Molecular analysis showed that the enhanced expression of FHL2 was associated with the Bzb-induced upregulation of p53. No significant change at protein level of total ß-catenin was observed with or without Bzb treatment. However, it was mostly enriched to nuclei in MSCs after Bzb treatment. Moreover, ß-catenin was restricted to the perinuclear region in FHL2 KD cells. These data provide evidence that FHL2 is essential for promoting ß-catenin nuclear enrichment in MM-MSCs. In conclusion, FHL2 is critical for Bzb-induced osteoblast differentiation of MM-MSCs and promotes the osteogenesis, through p53 signaling and ß-catenin activation. Targeting FHL2 in MM may provide a new therapeutic strategy for treating MBD.

STIP1 knockdown suppresses colorectal cancer cell proliferation, migration and invasion by inhibiting STAT3 pathway.

Stress-induced phosphoprotein 1 (STIP1) plays an important role in cancer tumorigenesis and progression. However, the role of STIP1 in colorectal cancer (CRC) remains unclear. This study aimed to explore clinical significance, biological function and potential molecular mechanism of STIP1 in CRC. Immunohistochemistry (IHC) and Western bolt were performed to detect STIP1 protein level in CRC and adjacent normal tissues. DLD1 and HCT116 cell lines were treated with shSTIP1, cell proliferation was detected by CCK8 and colony formation assays, and cell migration and invasion were detected by wound healing and transwell assays. Moreover, western blot and immunofluorescence assays were performed to explore the potential molecular mechanism of STIP1 in the progression of CRC. We found that STIP1 expression in CRC tissues was significantly higher than in adjacent normal tissues. High STIP1 expression was associated with poor overall survival (OS) in CRC patients. Furthermore, secreted STIP1 promoted CRC cell proliferation and invasion through STAT3 signaling pathway, while STIP1 knockdown inhibited the proliferation, migration and invasion of CRC cells. Mechanistically, STIP1 knockdown suppressed the activation of STAT3 signaling pathway in CRC. In conclusion, STIP1 knockdown suppresses CRC cell proliferation, migration and invasion by inhibiting the activation of STAT3 signaling, and STIP1 is a potential target for CRC therapy.

Trim47 overexpression correlates with poor prognosis in gastric cancer.

Trim47 is a member of the tripartite motif (TRIM) family that participates in many pathophysiological processes. However, the expression pattern and biological functions of Trim47 in gastric cancer (GC) remain unclear. The present study aimed to further explore the clinicopathological significance and potential prognostic role of Trim47 expression in GC. Therefore, in this study, Trim47 mRNA level was investigated in the Cancer Genome Atlas (TCGA) and Oncomine database in GC. We detected Trim47 mRNA and protein expression levels in GC and paired adjacent normal tissues. Kaplan-Meier method and Cox proportional hazard regression models were performed to analyze the survival of patients and prognostic factors. A gene set enrichment analysis (GSEA) was performed to determine the mechanism of Trim47 in GC. Our results indicated that Trim47 mRNA expression in GC tissues was significantly higher than adjacent normal tissues, as was Trim47 protein expression. Trim47 overexpression in GC tissues was significantly associated with tumor differentiation, T stage, N stage, M stage, and TNM stage. Kaplan-Meier analyses showed that high Trim47 expression was associated with worse overall survival (OS) and disease-free survival (DFS) in GC patients. Multivariate analysis confirmed that Trim47 expression was an independent prognostic factor for GC patients. Bioinformatics analysis and western blot indicated Trim47 might regulate GC through NF-κB, EMT, hypoxia, and apoptosis signaling pathway in GC. Our results show that Trim47 has the potential to serve as a novel prognostic biomarker in GC patients.

Multiple myeloma hinders erythropoiesis and causes anaemia owing to high levels of CCL3 in the bone marrow microenvironment.

Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.