Long-Term Remission in T315I+ Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Blinatumomab and Allogeneic Stem Cell Transplantation: Two Case Studies.

BACKGROUND Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults has a poor prognosis with conventional chemotherapy. Treatment with tyrosine kinase inhibitors (TKIs) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved clinical outcomes; however, the relapse rate is still high. Therapeutic options for patients with relapsed/refractory (R/R) Ph+ ALL are scarce, with very few studies focusing on these patients. Blinatumomab is a novel bispecific T-cell engager antibody construct showing promising efficacy in R/R Ph+ ALL. CASE REPORT Here, we present 2 cases of relapsed Ph+ ALL with T315I mutation refractory to multiple TKIs and chemotherapy. Patient 1 was a 48-year-old woman who had increased leukocytes in her peripheral blood cells, with 90% abnormal cells and decreased platelets. Bone marrow (BM) smear showed 95% blasts. Patient 2 was a 20-year-old man who had leukocytosis with thrombocytopenia, while all other parameters were normal. BM aspirate showed 98% immature granulocytes/blasts. The immunophenotypic observations of both the patients on BM were consistent with the presence of ALL. Both patients were effectively treated with a combination of blinatumomab and allo-HSCT and achieved complete remission in 1 month with minimal residual disease negativity and remained in remission for a long period. CONCLUSIONS The findings suggest, that for patients with R/R Ph+ ALL with T315I mutation who respond poorly to TKIs, salvage therapy with blinatumomab is a potentially effective treatment for improving clinical outcomes. The treatment with blinatumomab can further act as a bridge to HSCT in these patients, helping them to attain deeper remission.

Comparative Analysis of Radial Corrective Osteotomy and Sauvé-Kapandji Procedure for Malunited Distal Radius Fractures in Older Adults.

PURPOSE: Malunited distal radius fractures frequently occur in the older population, posing a dilemma in selecting ideal management for symptomatic patients. Radial corrective osteotomy (RCO) and the Sauvé-Kapandji procedure (SK) have been used to treat this challenging condition. However, it remains unknown which approach is better for the older population. The objective of this study was to compare the outcomes of RCO with those of SK for the treatment of symptomatic distal radius malunion in older adults. METHODS: Thirty-three patients aged ≥60 years, with malunited distal radius fractures, were randomized to be treated with either RCO or SK and followed for a minimum of 2 years. The primary evaluation parameter was grip strength, and secondary outcome parameters were surgical time, range of motion of the wrist, exercise-related wrist pain assessment using visual analog scale scores, radiographic results, patient-reported outcomes evaluated using the Disability of the Arm, Shoulder, and Hand (DASH), and Patient-Related Wrist Evaluation (PRWE) scores. RESULTS: The average follow-up duration was 36.7 ± 10.2 months. The grip strength was significantly higher in the RCO group. The surgical time was shorter in the SK group than in the RCO group. The postoperative wrist range of motion and visual analog scale scores for exercise-related pain alleviation were similar in both groups. The ulnar variance decreased in both groups and was similar when compared with the postoperative images. The DASH and PRWE scores were similar between the RCO and SK groups. CONCLUSIONS: Radial corrective osteotomy and SK surgeries have similar clinical and functional outcomes in patients aged ≥60 years. Grip strength is higher in the RCO group than in the SK group. However, the operating time to accomplish SK is shorter than RCO. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Isolation and quantification of L1CAM-positive extracellular vesicles on a chip as a potential biomarker for Parkinson's Disease.

Extracellular vesicles (EVs) carry disease-specific molecular profiles, demonstrating massive potential in biomarker discovery. In this study, we developed an integrated biochip platform, termed EVID-biochip (EVs identification and detection biochip), which integrates in situ electrochemical protein detection with on-chip antifouling-immunomagnetic beads modified with CD81 antibodies and zwitterion molecules, enabling efficient isolation and detection of neuronal EVs. The capability of the EVID-biochip to isolate common EVs and detect neuronal EVs associated with Parkinson's disease in human serum is successfully demonstrated, using the transmembrane protein L1-cell adhesion molecule (L1CAM) as a target biomarker. The EVID-biochip exhibited high efficiency and specificity for the detection of L1CAM with a sensitivity of 1 pg/mL. Based on the validation of 76 human serum samples, for the first time, this study discovered that the level of L1CAM/neuronal EV particles in serum could serve as a reliable indicator to distinguish Parkinson's disease from control groups with AUC = 0.973. EVID-biochip represents a reliable and rapid liquid biopsy platform for the analysis of complex biofluids offering EVs isolation and detection in a single chip, requiring a small sample volume (300 µL) and an assay time of 1.5 h. This approach has the potential to advance the diagnosis and biomarker discovery of various neurological disorders and other diseases.

Clinical characteristics of the well-defined upper eyelid vascular network pattern in patients with rosacea.

BACKGROUND: Rosacea is a chronic inflammatory skin disease. The diagnosis is based on the symptoms and physical signs, which still lacks objective laboratory tests or imaging tests. OBJECTIVES: To propose and evaluate the upper eyelid network pattern in rosacea. METHODS: Participants included patients diagnosed with rosacea, other facial erythematous skin diseases, and normal controls, all of whom underwent full-face imaging utilizing the VISIA® system software. According to these images, researchers evaluated the condition of the upper eyelid vascular network, developed the grading scale and then compared the difference of distribution in the three groups. RESULTS: The occurrence rate of upper eyelid vascular network in rosacea was significantly higher than that in other facial erythematous skin diseases (84.3 vs. 32.0%, P < 0.001) and normal controls (84.3 vs. 28.0%, P < 0.001). The upper eyelid vascular network pattern was proposed (none [no clearly reticular vessels], mild [10-50% area of reticular vessels], moderate-to-severe [>50% area of reticular vessels]). Moderate-to-severe grade was defined as well-defined upper eyelid vascular network pattern, which was specific to patients with rosacea (rosacea vs. other facial erythematous skin diseases, adjusted odds ratio [aOR] = 5.814, 95% confidence interval [CI]: 3.899-8.670) (rosacea vs. heathy controls, aOR = 12.628, 95% CI: 8.334-19.112). The severity of the well-defined pattern had no significant association with age, duration, and phenotypes of rosacea (P > 0.05). CONCLUSION: The well-defined upper eyelid vascular network pattern specifically appeared in patients with rosacea, which could be a possible clue to the diagnosis of rosacea.

Ligand Mediation for Tunable and Oxide Suppressed Surface Gold-Decorated Liquid Metal Nanoparticles.

Gallium-based liquid metal systems hold vast potential in materials science. However, maximizing their possibilities is hindered by gallium's native oxide and interfacial functionalization. In this study, small-molecule ligands are adopted as surfactants to modify the surface of eutectic gallium indium (EGaIn) nanoparticles and suppress oxidation. Different p-aniline derivatives are explored. Next, the reduction of chloroanric acid (HAuCl4 ) onto these p-aniline ligand modified EGaIn nanoparticles is investigated to produce gold-decorated EGaIn nanosystems. It is found that by altering the concentrations of HAuCl4 or the p-aniline ligand, the formation of gold nanoparticles (AuNPs) on EGaIn can be manipulated. The reduction of interfacial oxidation and presence of AuNPs enhances electrical conductivity, plasmonic performance, wettability, stability, and photothermal performance of all the p-aniline derivative modified EGaIn. Of these, EGaIn nanoparticles covered with the ligand of p-aminobenzoic acid offer the most evenly distributed AuNPs decoration and perfect elimination of gallium oxides, resulting in the augmented electrical conductivity, and highest wettability suitable for patterning, enhanced aqueous stability, and favorable photothermal properties. The proof-of-concept application in photothermal therapy of cancer cells demonstrates significantly enhanced photothermal conversion performance along with good biocompatibility. Due to such unique characteristics, the developed gold-decorated EGaIn nanodroplets are expected to offer significant potential in precise medicine.

An ethynyl-modified interpenetrated metal-organic framework for highly efficient selective gas adsorption.

An ethynyl-modified interpenetrated MOF material with lvt topology, [Cu2(BTEB)(NMF)2]·NMF·8H2O (compound 1, H4BTEB = 4,4',4'',4'''-(benzene-1,2,4,5-tetrayltetrakis(ethyne-2,1-diyl))tetrabenzoic acid, NMF = N-Methylformamide), was successfully synthesized by using an alkynyl-functionalized H4BTEB organic ligand under solvothermal conditions. Structural analysis shows that compound 1, consisting of a tetradentate carboxylic acid ligand and classical [Cu2(CO2)4] paddle-wheel structure building units, has a rare 4-connected lvt topology with dual interpenetrating structure, which can improve the framework stability, as well as the gas adsorption capacity and selectivity due to the restricted pore channel. According to the study of gas adsorption performance, compound 1 with a larger surface area, boasts a superior adsorption capacity for small gas molecules. Also, ideal adsorption solution theory (IAST) computational simulation shows that compound 1 has good gas adsorption selectivity for C3H8/CH4, indicating its potential application in gas separation.

Combined inhibition of XIAP and autophagy induces apoptosis and differentiation in acute myeloid leukaemia.

Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells. Intriguingly, birinapant-induced cell death was aggravated in combination with ATG5 siRNA or an autophagy inhibitor spautin-1, suggesting that autophagy may be a pro-survival signalling. Spautin-1 further enhanced the ROS level and myeloid differentiation in THP-1 cells treated with birinapant. The mechanism analysis showed that XIAP interacted with MDM2 and p53, and XIAP inhibition notably downregulated p53, substantially increased the AMPKα1 phosphorylation and downregulated the mTOR phosphorylation. Combined treatment using birinapant and chloroquine significantly retarded AML progression in both a subcutaneous xenograft model injected with HEL cells and an orthotopic xenograft model injected intravenously with C1498 cells. Collectively, our data suggested that XIAP inhibition can induce autophagy, apoptosis and differentiation, and combined inhibition of XIAP and autophagy may be a promising therapeutic strategy for AML.

Aging-related genes related to the prognosis and the immune microenvironment of acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML), one of the common malignancies of the hematologic system, has progressively increased in incidence. Aging is present in both normal tissues and the tumor microenvironment. However, the relationship between senescence and AML prognosis is still not elucidated. METHODS: In this study, RNA sequencing data of AML were obtained from TCGA, and prognostic prediction models were established by LASSO-Cox analysis. Differences in immune infiltration between the different risk groups were calculated using the CIBERSORT and ESTIMATE scoring methods. The KEGG and GO gene enrichment and GSEA enrichment were also used to enrich for differential pathways between the two groups. Subsequently, this study collected bone marrow samples from patients and healthy individuals to verify the differential expression of uncoupling protein 2 (UCP2) in different populations. Genipin, a UCP2 protein inhibitor, was also used to examine its effects on proliferation, cell cycle, and apoptosis in AML cell lines in vitro. RESULTS: It showed that aging-related genes (ARGs) expression was correlated with prognosis. And there was a significant difference in the abundance of immune microenvironment cells between the two groups of patients at high risk and low risk. Subsequently, UCP2 expression was found to be elevated in AML patients. Genipin inhibits UCP2 protein and suppresses the proliferation of AML cell lines in vitro. CONCLUSION: ARGs can be used as a predictor of prognosis in AML patients. Moreover, suppressing UCP2 can reduce the proliferation of AML cell lines, alter their cell cycle, and promote apoptosis in vitro.

Toxoplasma gondii infection triggers ongoing inflammation mediated by increased intracellular Cl- concentration in airway epithelium.

Toxoplasma gondii is a widespread parasitic protozoan causing toxoplasmosis including pulmonary toxoplasmosis. As the first line of host defense, airway epithelial cells play critical roles in orchestrating pulmonary innate immunity. However, the mechanism underlying the airway inflammation induced by the T. gondii infection remains largely unclear. This study demonstrated that after infection with T. gondii, the major anion channel located in the apical membranes of airway epithelial cells, cystic fibrosis transmembrane conductance regulator (CFTR), was degraded by the parasite-secreted cysteine proteases. The intracellular Cl- concentration ([Cl-]i) was consequently elevated, leading to activation of nuclear factor-κB (NF-κB) signaling via serum/glucocorticoid regulated kinase 1. Furthermore, the heightened [Cl-]i and activated NF-κB signaling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP level through NF-κB-mediated up-regulation of phosphodiesterase 4. Conversely, the sulfur-containing compound allicin conferred anti-inflammatory effects on pulmonary toxoplasmosis by decreasing [Cl-]i via activation of CFTR. These results suggest that the intracellular Cl- dynamically modulated by T. gondii mediates sustained airway inflammation, which provides a potential therapeutic target against pulmonary toxoplasmosis.

Retroperitoneal bronchogenic cyst with fluid­fluid level: A case report and literature review.

Bronchogenic cyst is a benign lesion with congenital dysplasia. Although the occurrence of this type of cyst is rare in the retroperitoneum, the presence of fluid-fluid levels is an even rarer phenomenon in bronchogenic cysts. Therefore, it can be easily misdiagnosed due to the lack of a universal guideline of specific imaging manifestations. The present report describes the case of a patient with a bronchogenic cyst with fluid-fluid levels whilst also performing a brief literature review to summarize the findings of previous reports on this condition. A 48-year-old male individual presented with severe lower back pain without any obvious causes. A CT scan revealed a low-density cystic mass of ~3x4x6 cm in the left front of the T12-L2 area, which originated from the left crus of the diaphragm. MRI revealed a fluid-fluid level in the cyst. Anterior thoracolumbar surgery was performed to completely resect the mass. During the surgery, it was confirmed that the cyst originated from the left crus of the diaphragm and the lesion was diagnosed to be a bronchogenic cyst by pathological analysis. The patient's symptoms improved after the surgery and no recurrence of the cyst was observed during the 3-year follow-up period. The presence of a fluid-fluid level in a retroperitoneal bronchogenic cyst is rare, particularly in the abdominal aorta and paravertebral regions, rendering it easily misdiagnosed. It may be associated with protein, hemorrhage and calcium-containing mucus deposition in the cysts. In the present study, a rare case of fluid-fluid level in bronchogenic cyst was reported and a literature review was provided.

Allicin Facilitates Airway Surface Liquid Hydration by Activation of CFTR.

Airway epithelium plays critical roles in regulating airway surface liquid (ASL), the alteration of which causes mucus stasis symptoms. Allicin is a compound released from garlic and harbors the capacity of lung-protection. However, the potential regulatory effects of allicin on airway epithelium remain elusive. This study aimed to investigate the effects of allicin on ion transport across airway epithelium and evaluate its potential as an expectorant. Application of allicin induced Cl- secretion across airway epithelium in a concentration-dependent manner. Blockade of cystic fibrosis transmembrane conductance regulator (CFTR) or inhibition of adenylate cyclase-cAMP signaling pathway attenuated allicin-induced Cl- secretion in airway epithelial cells. The in vivo study showed that inhaled allicin significantly increased the ASL secretion in mice. These results suggest that allicin induces Cl- and fluid secretion across airway epithelium via activation of CFTR, which might provide therapeutic strategies for the treatment of chronic pulmonary diseases associated with ASL dehydration.

Increase of CD3+CD7- T cells in bone marrow predicts invasion in patients with T-cell non-Hodgkin's lymphoma.

Background: The T-cell non-Hodgkin's lymphoma (T-NHL) patients with bone marrow (BM) invasion have a poor prognosis. Although BM biopsy is still a confirmed diagnosis method, the low sensitivity restricts its use to detect the minimal BM invasion. It is of great clinical significance to establish a rapid and highly sensitive method to evaluate BM invasion. Methods: We conducted a retrospective study of 85 patients with new diagnosed T-NHL patients enrolled in our institute. The bone marrow mononuclear cells (BMMNCs) cells were isolated, stained with different combinations of antibody and subjected to flow cytometry analysis. Results: We found that CD3+CD7- T cells increased significantly in the BM in T-NHL patients with BM invasion. The patients were divided into the low and high groups according to the cutoff value of 1.035% obtained by analyzing the receiver operating characteristic (ROC) curve of the percentage of CD3+CD7- T cells of nucleated cells at diagnosis. The ratio of invasion in high group was markedly higher than that in low group. Furthermore, CD3+CD7- T cells presented significantly higher level of programmed cell death-1 (PD-1), lymphocyte-activation-gene-3 (LAG3) and CD4/CD8 ratio. Conclusions: Our study revealed the percentage of CD3+CD7- T cells of nucleated cells in BM was a potential diagnostic predictor of BM invasion with T-NHL.

G protein-coupled estrogen receptor promotes acrosome reaction via regulation of Ca2+ signaling in mouse sperm†.

G protein-coupled estrogen receptor (GPER), a seven-transmembrane G protein-coupled receptor, mediates the rapid pre-genomic signaling actions of estrogen and derivatives thereof. The expression of GPER is extensive in mammal male reproductive system. However, the functional role of GPER in mouse sperm has not yet been well recognized. This study revealed that GPER was expressed at the acrosome and the mid-flagellum of the mouse sperm. The endogenous GPER ligand 17ß-estradiol and the selective GPER agonist G1 increased intracellular Ca2+ concentration ([Ca2+]i) in mouse sperm, which could be abolished by G15, an antagonist of GPER. In addition, the G1-stimulated Ca2+ response was attenuated by interference with the phospholipase C (PLC) signaling pathways or by blocking the cation channel of sperm (CatSper). Chlortetracycline staining assay showed that the activation of GPER increased the incidence of acrosome-reacted sperm. Conclusively, GPER was located at the acrosome and mid-flagellum of the mouse sperm. Activation of GPER triggered the elevation of [Ca2+]i through PLC-dependent Ca2+ mobilization and CatSper-mediated Ca2+ influx, which promoted the acrosome reaction of mouse sperm.

SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl- accumulation in respiratory epithelium.

SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl- is a crucial regulator of host defense, whereas the role of Cl- signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl- concentration ([Cl-]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl-]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl-]i. Our findings suggested that Cl- acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl- signaling pathway might be a novel therapeutic strategy for COVID-19.

Clinical application of oral Chinese Patent Medicines in ophthalmology: a scoping review protocol.

INTRODUCTION: The prevalence of eye diseases has been increasing worldwide. In China, in addition to conventional medicine, Traditional Chinese Medicine (TCM) plays an important role in maintaining people's vision health. Although less flexible and targeted than TCM decoction, Chinese Patent Medicines (CPMs) are stable and well used. In recent years, CPMs have been increasingly used in ophthalmology clinics by TCM practitioners and by Western doctors in general hospitals. However, comprehensive evidence for using CPMs in ophthalmology is lacking. AIM: We will apply the methodology of scoping review to systematically search and sort out the available evidence on oral CPMs for the treatment of eye diseases, identify the distribution of evidence in this field and provide a basis for clinical practice and medical decisions. METHODS: The scoping review will be implemented in the following seven steps: (1) defining the research question; (2) searching National Essential Medicines List (2018 edition), National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug Catalog (2020 edition) and Chinese Pharmacopoeia (2020 edition) for oral CPMs for the treatment of eye diseases; (3) searching Embase, Web of Science, PubMed, Cochrane Library, Chongqing VIP Chinese Scientific Journals Database, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database and Wanfang Database for relevant literature published from inception to December 2021; (4) developing eligibility criteria; (5) screening the studies based on inclusion criteria; (6) extracting relevant data and lastly, (7) collating, summarising and reporting the results. ETHICS AND DISSEMINATION: Since the scoping review aims at collecting data from publicly available publications, this study does not require ethical approval. The results will be published in a peer-reviewed journal and presented at scientific conferences.

Genetic, environmental and other risk factors for progression of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a commonly inherited disease of the retina, which is characterized by progressive loss of visual function due to specific genetic mutations. There are many risk factors that may have effect on the progression of RP, such as inheritance patterns, genotype, gender, age, smoking, physical activity, and other demographic and environmental factors. Baseline visual field conditions, changes of ellipsoid zone, photoreceptor layer thickness, and choroidal structure are reported to be the phenotype risk factors for RP progression. Moreover, aqueous flare and high-sensitivity C-reactive protein are probable inflammation biomarkers for assessing the progression of RP. Increased oxidative stress is considered to be one of the potential factors for the existence of RP. The risk factors can be combined to form a corresponding prediction model to predict disease progression. This review is to summarize the current literature that studies the genetic, environmental, phenotypic, demographic, inflammatory and other risk factors of RP progression and discuss the most reliable risk factors that could provide predictive models.

LINC01087 Promotes the Proliferation, Migration, and Invasion of Thyroid Cancer Cells by Upregulating PPM1E.

This study is aimed at investigating the effect and mechanism of LINC01087 on the malignant evolution of thyroid cancer cells. The expression levels of LINC01087, miR-135a-5p, and PPM1E in thyroid carcinoma tissues were detected by QRT-PCR. Cell viability was detected using the CCK-8 method. Transwell assay was used to assess the ability of cells to invade. The targeting relationship between LINC01087 and miR-135a-5p was detected by dual luciferase reporting assay. In comparison with normal thyroid tissues and cells, the expression level of LINC01087 in thyroid cancer tissues and TPC-1 and K1 cells increased, and the expression level of miR-135a-5p in thyroid cancer tissues and TPC-1 and K1 cells decreased. LINC01087 knockdown and the high expression of miR-143-3p inhibited the proliferation, invasion, and EMT processes of TPC-1 and K1 in thyroid cancer cells. LINC01087 negatively targeted miR-135a-5p. Has-miR-135a-5p inhibited the malignant evolution and EMT of thyroid cancer by targeting PPM1E. The PPM1E overexpression can reverse the inhibitory effect of LINC01087 gene knockdown on the proliferation, migration, and invasion of thyroid cancer cells. LINC01087 can promote the proliferation and apoptosis of thyroid cancer cells, and its mechanism may be related to the miR-135a-5p/PPM1E axis.

Activation of TRPV4 stimulates transepithelial K+ secretion in rat epididymal epithelium.

The maturation of sperms is dependent on the coordinated interactions between sperm and the unique epididymal luminal milieu, which is characterized by high K+ content. This study investigated the involvement of transient receptor potential vanilloid 4 (TRPV4) in the K+ secretion of epididymal epithelium. The expression level and cellular localization of TRPV4 and Ca2+-activated K+ channels (KCa) were analyzed via RT-PCR, real-time quantitative PCR, western blot and immunofluorescence. The functional role of TRPV4 was investigated using short-circuit current (ISC) and intracellular Ca2+ imaging techniques. We found a predominant expression of TRPV4 in the corpus and cauda epididymal epithelium. Activation of TRPV4 with a selective agonist, GSK1016790A, stimulated a transient decrease in the ISC of the epididymal epithelium. The ISC response was abolished by either the TRPV4 antagonists, HC067047 and RN-1734, or the removal of basolateral K+. Simultaneously, the application of GSK1016790A triggered Ca2+ influx in epididymal epithelial cells. Our data also indicated that the big conductance KCa (BK), small conductance KCa (SK) and intermediate conductance KCa (IK) were all expressed in rat epididymis. Pharmacological studies revealed that BK, but not SK and IK, mediated TRPV4-elicited transepithelial K+ secretion. Finally, we demonstrated that TRPV4 and BK were localized in the epididymal epithelium, which showed an increased expression level from caput to cauda regions of rat epididymis. This study implicates that TRPV4 plays an important role in the formation of high K+ concentration in epididymal intraluminal fluid via promoting transepithelial K+ secretion mediated by BK.

Predictive Factor of Large-Volume Central Lymph Node Metastasis in Clinical N0 Papillary Thyroid Carcinoma Patients Underwent Total Thyroidectomy.

Large-volume central lymph node metastasis (large-volume CLNM) is associated with high recurrence rate in papillary thyroid carcinoma (PTC) patients. However, sensitivity in investigating large-volume CLNM on preoperative ultrasonography (US) is not high. The aim of this study is to investigate the clinical factors associated with large-volume CLNM in clinical N0 PTC patients. We reviewed 976 PTC patients undergoing total thyroidectomy with central lymph node dissection during 2017 to 2019. The rate of large-volume LNM was 4.1% (40 of 967 patients). Multivariate analysis showed that male gender and young age (age<45 years old) were independent risk factors for large-volume CLNM with odds ratios [(OR), 95% confidence interval (CI)] of 2.034 (1.015-4.073) and 2.997 (1.306-6.876), respectively. In papillary thyroid microcarcinoma (PTMC), capsule invasion was associated with large-volume CLNM with OR (95% CI) of 2.845 (1.110-7.288). In conventional papillary thyroid cancer (CPTC), tumor diameter (>2cm) was associated with large-volume CLNM, with OR (95% CI) 3.757 (1.061-13.310), by multivariate analysis. In ROC curve analysis on the diameter of the CPTC tumor, the Area Under Curve (AUC) =0.682(p=0.013), the best cut-off point was selected as 2.0cm. In conclusion, male gender and young age were predictors for large-volume CLNM of cN0 PTC. cN0 PTMC patient with capsule invasion and cN0 CPTC patient with tumor diameter >2cm were correlated with large-volume CLNM. Total thyroidectomy with central lymph node dissection may be a favorable primary treatment option for those patients.

Interaction between CD9 and PI3K­p85 activates the PI3K/AKT signaling pathway in B­lineage acute lymphoblastic leukemia.

Our previous study has shown that CD9 knockdown could suppress cell proliferation, adhesion, migration and invasion, and promote apoptosis and the cytotoxicity of chemotherapeutic drugs in the B­lineage acute lymphoblastic leukemia (B­ALL) cell line SUP­B15. In this study, we further investigated the molecular mechanism underlying the effects of CD9 on leukemic cell progression and the efficacy of chemotherapeutic agents in B­ALL cells. Using the CD9­knockdown SUP­B15 cells, we demonstrated that the silencing of the CD9 gene significantly reduced the expression of phosphorylated­phosphatidylinositol­3 kinase (p­PI3K), phosphorylated­protein kinase B (p­AKT), P­glycoprotein (P­gp), multidrug resistance­associated protein 1 (MRP1), breast cancer resistance protein (BCRP), matrix metalloproteinase 2 (MMP2) and phosphorylated­focal adhesion kinase (p­FAK). In addition, glutathione S­transferase (GST) pull­down assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vitro, while co­immunoprecipitation assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vivo. Furthermore, the PI3K/AKT inhibitor LY294002 mirrored the effects of CD9 knockdown in SUP­B15 cells. Taken together, these findings demonstrated that CD9 activates the PI3K/AKT signaling pathway through direct interaction with PI3K­p85 in B­ALL cells. Our data provide evidence for the inhibition of the PI3K/AKT pathway as a novel therapeutic option in CD9 antigen­positive B­ALL.