Increased resected lymph node stations improved survival of esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery have been recommended as the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC). In addition, nodal metastases decreased in frequency and changed in distribution after neoadjuvant therapy. This study aimed to examine the optimal strategy for lymph node dissection (LND) in patients with ESCC who underwent nCRT. METHODS: The hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were calculated using the Cox proportional hazard model. To determine the minimal number of LNDs (n-LNS) or least station of LNDs (e-LNS), the Chow test was used. RESULTS: In total, 333 patients were included. The estimated cut-off values for e-LNS and n-LNS were 9 and 15, respectively. A higher number of e-LNS was significantly associated with improved OS (HR: 0.90; 95% CI 0.84-0.97, P = 0.0075) and DFS (HR: 0.012; 95% CI: 0.84-0.98, P = 0.0074). The e-LNS was a significant prognostic factor in multivariate analyses. The local recurrence rate of 23.1% in high e-LNS is much lower than the results of low e-LNS (13.3%). Comparable morbidity was found in both the e-LNS and n-LND subgroups. CONCLUSION: This cohort study revealed an association between the extent of LND and overall survival, suggesting the therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, more lymph node stations being sampled leads to higher survival rates among patients who receive nCRT, and standard lymphadenectomy of at least 9 stations is strongly recommended.

Biodegradation and optimization of bilge water in a sequencing batch reactor using response surface methodology.

Bilge water is a significant source of pollution in the marine environment and has captured widespread international attention. In this study, a sequencing batch reactor (SBR) combined with strain S2 identified as Bacillus licheniformis was employed to assess the biodegradation of Chemical Oxygen Demand (COD) from bilge water. The influencing variables such as temperature, pH level and inoculum concentration on the performance SBR system were optimized by utilizing response surface methodology (RSM). The experimental results showed that the maximum COD removal of 77.81% was reached at the optimal SBR operation conditions of temperature 35.44 °C pH 8.13, and inoculum concentration 31.47 mL. In the practical application of SBR, it was found that the decrease in hydraulic retention time (HRT) was accompanied by a decrease in COD degradation rate. The biodegradation kinetics of COD in bilge water were well fitted with the first-order equation with a higher R2 value of 0.98106. In conclusion, COD in bilge water can be efficiently biodegraded by SBR under the optimization of RSM.

Maintenance Treatment With Low-Dose Decitabine After Allogeneic Hematopoietic Cell Transplantation in Patients With Adult Acute Lymphoblastic Leukemia.

BACKGROUND: Post-transplant relapse remains a principal leading cause of failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with adult acute lymphoblastic leukemia (ALL). The aim of this study was to investigate the efficacy and safety of low-dose decitabine on the prevention of adult ALL relapse after allo-HSCT. METHODS: In this prospective study, we enrolled 34 patients with ALL who underwent allo-HSCT from August 2016 to April 2020 and received low-dose decitabine maintenance treatment after transplantation. The primary objectives were cumulative incidence of relapse rate (CIR), overall survival (OS), and disease-free survival (DFS). The secondary objectives were graft-versus-host disease (GVHD) and safety. RESULTS: Among the enrolled 34 patients, 6 patients relapsed and 6 patients died. The 2-year CIR, OS, and DFS were 20.2, 77.5, and 73.6%, respectively. Subgroup analysis revealed the 2-year CIR, OS, and DFS rates of 12 patients with T-ALL/lymphoblastic lymphoma (LBL) were 8.3, 90, and 81.5%, respectively. None of the seven patients with T-ALL relapsed. During maintenance treatment, only one patient (2.9%) developed grade IV acute GVHD and four (11.8%) patients had severe chronic GVHD. Thirty-two patients (94.1%) developed only grade I to II myelosuppression, and two patients (5.8%) developed grade III to IV granulocytopenia. CONCLUSIONS: Maintenance treatment with low-dose decitabine after allo-HSCT may be used as a therapeutic option to reduce relapse in patients with adult ALL, especially in patients with T-ALL. Our findings require confirmation in larger-scale controlled trials. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trials Registry, identifier ChiCTR1800014888.

Prognostic value of RASD1 transcript levels in adult Philadelphia-negative B-cell acute lymphoblastic leukemia.

OBJECTIVES: Ras-related dexamethasone-induced 1 (RASD1) is abnormally expressed in many solid cancers. However, its potential role in adults with B-cell acute lymphoblastic leukemia (B-ALL) is unclear. Therefore, we aim to clarify the abnormal expression of the tumor-associated biomarker, RASD1, as a potential target for diagnosis and prognosis in adult Philadelphia-negative B-ALL. METHODS: The expression of RASD1 was detected with RT-qPCR in 92 adults with de novo Ph-negative B-ALL and 40 healthy controls. The correlation between RASD1 transcript levels and relapse was assessed. RESULTS: RASD1 transcript levels in patients with Ph-negative B-ALL (median 81.76%, range 0.22%-1824.52%) were significantly higher than those in healthy controls (7.59%, 0.46%-38.66%; P<0.0001). Patients with low RASD1 transcript levels had a lower 5-year relapse-free survival (RFS, 47.5% [32.9%, 62.1%] vs. 63.1% [49.0%, 77.2%]; P = 0.012) and a higher 5-year cumulative incidence of relapse (CIR, 52.0% [37.4%, 66.6%] vs. 36.2% [22.2%, 50.2%]; P = 0.013) especially in patients receiving chemotherapy only. Multivariate analysis showed that a low RASD1 transcript level was an independent risk factor for RFS (HR = 2.938 [1.427, 6.047], P = 0.003) and CIR (HR = 3.367 [1.668, 6.796], P = 0.001) in patients with Ph-negative B-ALL. CONCLUSIONS: RASD1 transcript levels were significantly higher in patients with Ph-negative B-ALL and a low RASD1 transcript level was independently correlated with increased relapse risk.

S100A16 suppresses the growth and survival of leukaemia cells and correlates with relapse and relapse free survival in adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia.

Refinement of risk stratification in Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukaemia (ALL) might aid the identification of patients who are likely to relapse. Abnormal S100 calcium binding protein A16 (S100A16) has been implicated in various cancers, but its function remains unclear. We found S100A16 transcript levels were higher in 130 adults with newly-diagnosed Ph-negative B-cell ALL compared with 33 healthy controls. In 115 of 130 patients who achieved first complete remission, those with high S100A16 transcript levels displayed a lower 3-year cumulative incidence of relapse (CIR; 34% [21, 47%] vs. 40% [48, 72%]; P = 0·012) and higher 3-year relapse-free survival (RFS; 65% [53, 78%] vs. 35% [23, 46%]; P = 0·012), especially when receiving chemotherapy only. In multivariate analysis a low S100A16 transcript level was independently-associated with a higher CIR (Hazard ratio [HR] = 3·74 [1·01-13·82]; P = 0·048) and inferior RFS (HR = 5·78 [1·91, 17·84]; P < 0·001). Function analysis indicated that knockdown of S100A16 promoted proliferation and anti-apoptosis and reduced chemosensitivity. S100A16 over-expression revealed an opposite trend, especially in a xeno-transplant mouse model. Western blotting analysis showed upregulation of PI3K/AKT and ERK1/2 in S100A16-knockdown and S100A16-overexpression B-cell ALL cell lines respectively. Inhibition assays suggested these two signalling pathways participated in the S100A16-mediated proliferation and survival effects in B-cell ALL cell lines. Trial Registration: Registered in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940]; http://www.chictr.org.cn.

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.

Prognostic impact of minimal extrathyroidal extension in papillary thyroid carcinoma.

BACKGROUND: It is widely accepted that maximal extrathyroidal extension (ETE) plays a vital role in the prognosis of papillary thyroid carcinoma (PTC). However, there is no consensus among researchers about the meaning of minimal ETE (mETE) in PTC. Herein, we conducted a systematic review and meta-analysis to examine the role of mETE in the prognosis of PTC. METHODS: We searched PubMed, EMBASE, and Cochrane search trials databases in English to identify studies comparing data on disease recurrence in PTC patients with mETE and those with no ETE. To summarize the data related to mETE status, risk ratios and hazard ratios adjusted for potential confounders were used to assess the number of recurrence and time-dependent risks related to mETE status, respectively. RESULTS: According to the inclusion criteria, a total of 7951 patients from 9 studies were included. The recurrence rate in patients with mETE is significantly higher when compared with those with no ETE (risk ratio = 1.70, 95% confidence interval: 1.26-2.28, I = 56%). According to the data summarized with hazard ratios, PTC patients with mETE showed a significantly increased risk of disease recurrence. CONCLUSION: mETE is a risk factor for poor prognosis in patients with PTC. Our innovative classification of ETE has its value in assessing the prognosis of PTC.

[Significance of ST2 in the Early Diagnosis and Treatment of Graft-Versus-Host Disease--Review].

Graft-versus-host disease (GVHD) is a major complication of allo-hematopoietic stem cell transplantation. It is reported that IL-2R, TNFR1, elafin (for skin GVHD) and REG-3α (for gastrointestinal GVHD) can be used in the early diagnosis of acute GVHD, but they cannot predict the response to therapy independently. Therefore, it is urgent to find a biomarker to predict GVHD and glucocorticoid resistance. ST2 is a member of IL-1 receptor family and specially binds to IL-33. Researchers have found that higher ST2 level is associated with increased GVHD risk, glucocorticoid resistance and transplantation-related mortality. This review focuses on the structure, function, signal transduction pathway of ST2/IL-33, and its roles in diagnosis and treatment of autoimmune diseases and GVHD.

Clinicopathological significance of TERT promoter mutation in papillary thyroid carcinomas: a systematic review and meta-analysis.

BACKGROUND: The prognostic value of the telomerase reverse transcriptase (TERT) promoter mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma (PTC), has been generally confirmed. To data, there is no high-level evidence approving the association of TERT promoter mutation and aggressive clinical behaviours in PTC. To systematically evaluate it, a systematic review and meta-analysis of the published literatures were carried out. METHODS: We conducted a systematic search in PubMed, EMBASE, OVID and Web of Science databases for relevant studies. We selected all the studies that reported clinicopathological features of PTC patients with information available on TERT promoter mutation status. Individual study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, as were Mantel-Haenszel pooled odds ratios for the combined studies. RESULTS: Eight eligible trials involved 2035 patients were included in the analysis. The average prevalence of the TERT promoter mutation was 10·32%. Compared with the wild-type TERT promoter gene, the TERT promoter mutation was associated with male gender, lymph node metastasis, extrathyroidal extension, distant metastasis, advanced TNM stage III/IV, poor clinical outcome (persistence or recurrence) and mortality. The associations were generally consistent across the different study populations. CONCLUSIONS: Thus, our findings from this large meta-analysis definitively demonstrate that TERT promoter mutation-positive PTC is more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the TERT promoter mutation is likely to be useful in assisting the risk stratification and management of PTC.

The Prostaglandin Transporter: Eicosanoid Reuptake, Control of Signaling, and Development of High-Affinity Inhibitors as Drug Candidates.

We discovered the prostaglandin transporter (PGT) and cloned the human cDNA and gene. PGT transports extracellular prostaglandins (PGs) into the cytoplasm for enzymatic inactivation. PGT knockout mice have elevated prostaglandin E2 (PGE2) and neonatal patent ductus arteriosus, which reflects PGT's control over PGE2 signaling at EP1/EP4 cell-surface receptors. Interestingly, rescued PGT knockout pups have a nearly normal phenotype, as do human PGT nulls. Given the benign phenotype of PGT genetic nulls, and because PGs are useful medicines, we have approached PGT as a drug target. Triazine library screening yielded a lead compound of inhibitory constant 50% (IC50) = 3.7 µM, which we developed into a better inhibitor of IC50 378 nM. Further structural improvements have yielded 26 rationally designed derivatives with IC50 < 100 nM. The therapeutic approach of increasing endogenous PGs by inhibiting PGT offers promise in diseases such as pulmonary hypertension and obesity.

MicroRNA-375 functions as a tumor suppressor in osteosarcoma by targeting PIK3CA.

Osteosarcoma has become one of the most common primary malignant bone tumors in childhood and adult. Numerous studies have demonstrated that aberrant microRNA (miRNA) expression is involved in human disease including cancer. To date, the potential miRNAs regulating osteosarcoma growth and progression are not fully identified yet. Herein, we showed that miR-375 was frequently downregulated in osteosarcoma tissue and cell lines compared to normal human colon tissues. Overexpression of miR-375 resulted in decreased expression of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) at both mRNA and protein levels. We found that miR-375 overexpression markedly suppressed cell proliferation in vitro. And inhibition of miR-375 promotes osteosarcoma growth. Mechanistic studies showed that PIK3CA was a potential target of miR-375 and it mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. Taken together, our results demonstrate that miR-375 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA in osteosarcoma.

Failure of postnatal ductus arteriosus closure in prostaglandin transporter-deficient mice.

BACKGROUND: Prostaglandin E(2) (PGE(2)) plays a major role both in maintaining patency of the fetal ductus arteriosus and in closure of the ductus arteriosus after birth. The rate-limiting step in PGE(2) signal termination is PGE(2) uptake by the transporter PGT. METHODS AND RESULTS: To determine the role of PGT in ductus arteriosus closure, we used a gene-targeting strategy to produce mice in which PGT exon 1 was flanked by loxP sites. Successful targeting was obtained because neither mice hypomorphic at the PGT allele (PGT Neo/Neo) nor global PGT knockout mice (PGT(-/-)) exhibited PGT protein expression; moreover, embryonic fibroblasts isolated from targeted mice failed to exhibit carrier-mediated PGE(2) uptake. Although born in a normal mendelian ratio, no PGT(-/-) mice survived past postnatal day 1, and no PGT Neo/Neo mice survived past postnatal day 2. Necropsy revealed patent ductus arteriosus with normal intimal thickening but dilated cardiac chambers. Both PGT Neo/Neo and PGT(-/-) mice could be rescued through the postnatal period by giving the mother indomethacin before birth. Rescued mice grew normally and had no abnormalities by gross and microscopic postmortem analyses. In accordance with the known role of PGT in metabolizing PGE(2), rescued adult PGT(-/-) mice had lower plasma PGE(2) metabolite levels and higher urinary PGE(2) excretion rates than wild-type mice. CONCLUSIONS: PGT plays a critical role in closure of the ductus arteriosus after birth by ensuring a reduction in local and/or circulating PGE(2) concentrations.

[A case report of giant cemento-ossifying fibroma].

Cemento-ossifying fibroma is a rare benign tumor from periodontium, which usually occurs in mandible body and mandible ramus. It consists of collagen fibrils, fibroblast, and cementoblast. This article reported a case of giant cemento-ossifying fibroma and discussed the clinical features and treatment.

[Arsenic trioxide inhibits cell growth in imatinib-resistant bcr-abl mutant cell lines in vitro].

OBJECTIVE: To explore the effect of arsenic trioxide (As2O3) on the growth inhibition of imatinib (IM)-resistant bcr-abl mutant cell lines in vitro. METHODS: Cell growth of one IM-sensitive cell line, 32Dp210 and 15 IM-resistant cell lines including T315I and other 14 bcr-abl mutants were detected by MTT assay after treatment with IM and As2O3. The cell lines with 5 frequently observed mutants in CML patients were analyzed for apoptosis by flow cytometry with Annexin V and PI staining as well as the expression of bcr-abl fusion protein, phosphorylated CRKL protein and apoptosis-related proteins by Western blot. RESULTS: The fifty percent inhibition concentration (IC50) values of As2O3 for 15 IM-resistant cell lines were 2.6-5.3 fold lower than that for IM-sensitive cell line. For the 5 bcr-abl mutants frequently happened in CML patients, As2O3 significantly inhibited the expression of bcr-abl fusion protein and phosphorylated CRKL and induced apoptosis in a dose-dependent manner as compared with that for 32Dp210. Coincidently, the cell apoptosis was induced through caspase-3, 8 and 9 pathways. CONCLUSION: As2O3 remarkably inhibits cell growth and induces apoptosis of IM-resistant bcr-abl mutant cell lines in vitro, suggesting that it might be a potential therapeutic agent for IM-resistant CML patients.

[Growth inhibition and differentiation of imatinib-resistant chronic myeloid leukemia cell induced by cell differentiation agent in vitro].

OBJECTIVE: To investigate the effects of uroacitide (CDA-2), a cell differentiation agent, on the growth inhibition and differentiation of imatinib-(IM) resistant chronic myeloid leukemia (CML) cells. METHODS: IM resistant CML cell line K562R was established from the line K562. K562 and K562R CML cells were cultured with CDA-2 of different concentrations. MTI method was used to detect the survival rates. Bone marrow cells of IM-resistant and non-IM-resistant CML patients were collected and co-incubated with K562 and K562R cells. MTT and colony-forming assays were used to evaluate the efficacy of CDA-2 treatment for cell growth in K562 and K562R cell lines, and IM-resistant or non-IM-resistant bone marrow cells of the CML patients; Annexin-V staining was employed to detect the apoptosis. Cell differentiation was assessed by flow cytometry analysis with CD11b/CD14 markers, reverse transcriptase PCR (RT-PCR) for mRNA levels of NCF-1 and ORM-1 genes and Giemsa staining for the observation in morphology. Cell cycle distribution was detected by stained with propidium iodide and then analyzed by flow cytometer. RT-PCR also was employed for the expression of DNA methyltransferase. RESULTS: Significant cell growth inhibition was found at a dose-dependent manner in the IM-resistant K562R cell line and IM-resistant bone marrow cells of the CML patients compared with the non-resistant K562 cell line and bone marrow cells of the CML patients following 7 days exposure to CDA-2. Although CDA-2 could significantly induce the apoptosis of K562R (15.38%) compared with K562 (5.28%) (P < 0.05), the major reason for the cell growth inhibition of K562R is CDA-2-induced cell differentiation, including the increase of expression of differentiation-related antigens CD11b/CD14, mRNA expression of NCF-1 and ORM-1, and cell cycle arrest in G1-phase at a dose-dependent manner. Because CDA-2 could significantly activate the p21 and p27 gene expression, downregulate the expression of cyclin D1, and down-regulate the expressions of DNMT1 and DNMT(3B) at mRNA level, CDA-2 might be a DNMT inhibitor for restoring some gene function that involved in cell cycle control by demethylation. CONCLUSION: Inhibiting the growth and inducing the differentiation of K562R cells, CDA-2 is very likely to be a potential agent for the treatment of IM resistance CML patients.

The two-step model of prostaglandin signal termination: in vitro reconstitution with the prostaglandin transporter and prostaglandin 15 dehydrogenase.

Termination of prostaglandin (PG) signaling has been proposed to involve carrier-mediated uptake across the plasma membrane followed by cytoplasmic oxidation. Here, we tested this hypothesis directly by coexpressing the PG uptake carrier prostaglandin transporter (PGT) in various cell types with and without human PG 15 dehydrogenase (PG15DH). In HeLa cells, which express neither PGT nor PG15DH, exogenously added PGE2 or PGF2alpha were rapidly oxidized to the 13, 14-dihydro, 15-keto metabolites only when PGT and PG15DH were coexpressed, directly confirming the two-step hypothesis. Cells expressing PG15DH that were broken open formed more PG metabolites than cells in which the PGs could gain access to PG15DH only via PGT. Similar results were obtained using the human prostate cancer cell line LNCaP, in which endogenous PG15DH is induced after exposure to dihydrotestosterone. Because PGT in vivo is expressed in renal collecting duct epithelia, we also expressed PGT in Madin-Darby canine kidney cells grown on filters, where it mediated both the active uptake of PGE2 across the apical membrane and the transepithelial transport of PGE2 to the basolateral compartment. When PG15DH was coexpressed with PGT in these epithelial monolayers, about half of the PGE2 taken up apically was oxidized to 13, 14-dihydro, 15-keto-PGE2, which in turn exited the cells nondirectionally into both the apical and basolateral compartments. Our data represent reconstitution of the longstanding model of PG metabolism consisting of sequential carrier-mediated PG uptake, cytoplasmic oxidation, and diffusional efflux of the PG metabolite.

[Study on the constituents of volatile oil from Ocimum basilicum].

OBJECTIVE: To study the constituents of volatile oil from Ocimum basilicum. METHOD: GC-MS technique was used. RESULT: Forty-five compounds was elucidated through consulting literature and searching database by computer. CONCLUSION: The main constituent in volatile oil from O. basilicum are 1, 7-dimethyl-1, 6-octadien-3-ol, which accounts for 29.87%.

Prostaglandin transporter PGT is expressed in cell types that synthesize and release prostanoids.

PGT is a broadly expressed transporter of prostaglandins (PGs) and thromboxane that is energetically poised to take up prostanoids across the plasma membrane. To gain insight into the function of PGT, we generated mouse monoclonal antibody 20 against a portion of putative extracellular loop 5 of rat PGT. Immunoblots of endogenous PGT in rat kidney revealed a 65-kDa protein in a zonal pattern corresponding to PG synthesis rates (papilla congruent with medulla > cortex). Immunocytochemically, PGT in rat kidneys was expressed in glomerular endothelial and mesangial cells, arteriolar endothelial and muscularis cells, principal cells of the collecting duct, medullary interstitial cells, medullary vasa rectae endothelia, and papillary surface epithelium. Proximal tubules, which are known to take up and metabolize PGs, were negative. Immunoblotting and immunocytochemistry revealed that rat platelets also express abundant PGT. Coexpression of the PG synthesis apparatus (cyclooxygenase) and PGT by the same cell suggests that prostanoids may undergo release and reuptake.

Expression of PGT in MDCK cell monolayers: polarized apical localization and induction of active PG transport.

The PG transporter (PGT) is expressed in subapical vesicles in the kidney collecting duct. To gain insight into the possible function of the PGT in this tubule segment, we tagged rat PGT with green fluorescent protein at the COOH terminus and generated stable PGT-expressing Madin-Darby canine kidney cell lines. When grown on permeable filters, green fluorescent protein-PGT was expressed predominantly at the apical membrane. Although the basal-to-apical transepithelial flux of [(3)H]PGE(2) was little changed by PGT expression, the apical-to-basolateral flux was increased 100-fold compared with wild-type cells. Analysis of driving forces revealed that this flux represents PGT-mediated active transepithelial PGE(2) transport. We propose that endogenous PGT is exocytically inserted into the collecting duct apical membrane, where it could control the concentration of luminal PGs.