A chemically inducible IL-2 receptor signaling complex allows for effective in vitro and in vivo selection of engineered CD4+ T cells.

Engineered T cells represent an emerging therapeutic modality. However, complex engineering strategies can present a challenge for enriching and expanding therapeutic cells at clinical scale. In addition, lack of in vivo cytokine support can lead to poor engraftment of transferred T cells, including regulatory T cells (Treg). Here, we establish a cell-intrinsic selection system that leverages the dependency of primary T cells on IL-2 signaling. FRB-IL2RB and FKBP-IL2RG fusion proteins were identified permitting selective expansion of primary CD4+ T cells in rapamycin supplemented medium. This chemically inducible signaling complex (CISC) was subsequently incorporated into HDR donor templates designed to drive expression of the Treg master regulator FOXP3. Following editing of CD4+ T cells, CISC+ engineered Treg (CISC EngTreg) were selectively expanded using rapamycin and maintained Treg activity. Following transfer into immunodeficient mice treated with rapamycin, CISC EngTreg exhibited sustained engraftment in the absence of IL-2. Furthermore, in vivo CISC engagement increased the therapeutic activity of CISC EngTreg. Finally, an editing strategy targeting the TRAC locus permitted generation and selective enrichment of CISC+ functional CD19-CAR-T cells. Together, CISC provides a robust platform to achieve both in vitro enrichment and in vivo engraftment and activation, features likely beneficial across multiple gene-edited T cell applications.

[Safety Climate in Hospitals: From Science to Policy-The Progress of Needlestick Prevention in Taiwan].

In hospitals, safety climate refers to the safety policies and regulations established by medical institutions and the measures taken to ensure medical personnel feel safe while working at these institutions. Safety climate can directly affect the overall work performance of medical personnel and indirectly affect patient care quality, which in turn impacts the rate of occupational hazards. Common occupational hazards in the medical workplace include contracting infectious diseases, overwork, irregular circadian rhythm due to working shifts, changes in sleep patterns and dietary habits, musculoskeletal discomfort, workplace violence, workplace stress, and needlestick injuries. This paper was developed to explore the history of promoting needlestick prevention in Taiwan, and discusses how to use the results of empirical research as scientific evidence and critical proofs to advocate for needlestick prevention and to establish related policies. In addition, the process of how improvements to the hospital safety climate and the prevention of occupational hazard incidents mutually influence and complement each other was examined. Future studies are encouraged to explore this topic to further elucidate the sources of workplace stress and to devise methods to ameliorate their influence on workplace stress in medical institutions. The results of these studies may be referenced by relevant government agencies and medical institutions when developing policies promoting safe environments in hospitals that improve the safe-work perceptions of nursing personnel and create comfortable and friendly medical environments.

[Monitoring of gastrointestinal dysfunction by near-infrared spectroscopy in children with sepsis: a prospective study]. / åº”ç”¨è¿‘çº¢å¤–å ‰è°±æŠ€æœ¯ç›‘æµ‹è„“æ¯’ç—‡æ‚£å„¿èƒƒè‚ åŠŸèƒ½éšœç¢çš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To investigate the incidence and mortality of gastrointestinal dysfunction in children with sepsis, the application of near-infrared spectroscopy (NIRS) in monitoring mesenteric regional tissue oxygen saturation (rSO2), and the association between rSO2 and gastrointestinal dysfunction. METHODS: In this prospective study, 79 children with sepsis in the pediatric intensive care unit (sepsis group) and 40 children who underwent physical examination in the Department of Child Healthcare (healthy control group) from January to December, 2021 were enrolled as subjects. The related medical data were collected, including general information on admission and at discharge, treatment during hospitalization, and laboratory examination results. NIRS was used to measure mesenteric rSO2. Clinical characteristics were compared between the patients with and without gastrointestinal dysfunction. RESULTS: For the 79 children with sepsis, the incidence rate of gastrointestinal dysfunction was 49% (39/79), and the mortality rate of the children with gastrointestinal dysfunction was 26% (10/39). The children with gastrointestinal dysfunction had a longer duration of mechanical ventilation and a higher 28-day mortality rate (P<0.05). The children with gastrointestinal dysfunction had a significantly lower median rSO2 (64%) than the children without gastrointestinal dysfunction (72%) and the healthy control group (78%) (P<0.05). CONCLUSIONS: There are high incidence and mortality rates of gastrointestinal dysfunction in children with sepsis, and the reduction in rSO2 may be associated with the development of gastrointestinal dysfunction.

Miro1 functions as an inhibitory regulator of MFN at elevated mitochondrial Ca2+ levels.

Mitochondria function as an integrated network that moves along the microtubules within cells and changes the morphology through membrane fusion and fission events. Mitofusin (MFN) mediates membrane tethering and subsequent fusion of the mitochondrial outer membrane. Understanding the regulatory mechanisms of MFN function is critical to tackling the pathology related to mitochondrial network imbalance. Here, we reveal a novel inhibitory mechanism of MFN-mediated fusion by mitochondrial Rho GTPase (Miro1) in response to elevated mitochondrial Ca2+ concentration ([Ca2+ ]m ). We showed that elevated [Ca2+ ]m prevents the fusion between mitochondria forming the outer membrane tether by ectopically expressing MFN. Lowering [Ca2+ ]m by treating cells with an inhibitor of mitochondrial calcium uniporter or knocking down Miro1/2 induces more fused networks. Miro1 interacts with MFN as supported by co-immunoprecipitation and protein association identified by proximity labeling proteomics. It suggests that Miro1 functions as a Ca2+ -sensor and inhibits MFN function at elevated [Ca2+ ]m. Miro1 EF-hand mutant has a compromised inhibitory effect, which reiterates Ca2+ -modulated regulation. Dysregulated Ca2+ -handling and mitochondrial network imbalance are highly relevant in the pathology of cancers, cardiovascular, and neurodegenerative diseases. Miro1 functions as a coordinated Ca2+ -responder by pausing mitochondrial transport while reducing network fusion and cooperating with Drp1-mediated fission. It likely prevents the detrimental effect of Ca2+m overload and facilitates mitophagy. Our finding reveals a novel regulation of mitochondrial network dynamics responding to [Ca2+ ]m through the interplay of Miro1 and MFN. Modulation of Miro1 and MFN interaction is a potential intervention to promote network homeostasis.

Boosting Photocatalytic Water Oxidation Over Bifunctional Rh0 -Rh3+ Sites.

Photocatalytic water splitting provides an economically feasible way for converting solar energy into hydrogen. Great efforts have been devoted to developing efficient photocatalysts; however, the surface catalytic reactions, especially for the sluggish oxygen evolution reaction (OER), still remain a challenge, which limits the overall photocatalytic energy efficiency. Herein, we design a Rhn cluster cocatalyst, with Rh0 -Rh3+ sites anchoring the Mo-doped BiVO4 model photocatalytic system. The resultant photocatalyst enables a high visible-light photocatalytic oxygen production activity of 7.11 mmol g-1 h-1 and an apparent quantum efficiency of 29.37 % at 420 nm. The turnover frequency (TOF) achieves 416.73 h-1 , which is 378 times higher than that of the photocatalyst only with Rh3+ species. Operando X-ray absorption characterization shows the OER process on the Rh0 -Rh3+ sites. The DFT calculations further illustrate a bifunctional OER mechanism over the Rh0 -Rh3+ sites, in which the oxygen intermediate attacks the Rh3+ sites with assistance of a hydrogen atom transfer to the Rh0 sites, thus breaking the scaling relationship of various oxygen intermediates.

Fractional flow reserve-guided complete revascularization versus culprit-only revascularization in acute ST-segment elevation myocardial infarction and multi-vessel disease patients: a meta-analysis and systematic review.

BACKGROUND: Approximately 30-50% patients with acute ST-segment elevation myocardial infarction (STMEI) were found to have non-infarct-related coronary artery (IRA) disease, which was significantly associated with worse prognosis. However, challenges still remain for these patients: which non-infarct-related lesion should be treated and when should the procedure be performed? The present study aims to investigate Fractional flow reserve (FFR)-guided complete revascularization (CR) in comparison to culprit-only revascularization (COR) in patients with ST-segment elevation myocardial infarction (STEMI) and multi-vessel disease (MVD). METHODS: Three appropriate randomized controlled trials (RCTs) were selected from the PubMed/Medline, EMBASE, and the Cochrane library /CENTRAL databases. 1631 patients (688 patients underwent FFR-guided CR and 943 patients underwent COR) following-up 12-44 months was evaluated. RESULTS: FFR-guided CR significantly reduced major adverse cardiac event (MACE) (OR 0.47, 95% CI: 0.35-0.62, P < 0.00001) and ischemia-driven repeat revascularization (OR 0.36, 0.26-0.51, P < 0.00001), as compared to COR. However, there is no difference in all-cause mortality (OR 1.24, 0.65-2.35, P = 0.51). CONCLUSIONS: In patients with STEMI and MVD, FFR-guided CR is better than COR in terms of MACE and ischemia-driven repeat revascularization, while there are almost similar in all-cause mortality. TRIAL REGISTRATION: All analyses were based on previous published studies, thus no ethical approval and patient consent are required COMPARE-ACUTE trial number NCT01399736 ; DANAMI-3-PRIMULTI trial number NCT01960933 .

Workplace justice and intention to leave the nursing profession.

BACKGROUND:: Poor psychosocial work environments are considered critical factors of nurses' intention to leave their profession. Workplace injustice has been proven to increase the incidence of psychiatric morbidity among workers. However, few studies have directly investigated the effect of workplace justice on nurses' intention to leave their profession and the population attributable risk among nurses. OBJECTIVE:: This study identified factors associated with workplace justice and nurses' intention to leave the profession. METHOD:: A cross-sectional survey was conducted using a self-administered structured questionnaire. Approximately 10% of all secondary referral centers in Taiwan were stratified and randomly sampled. Multiple logistic regression and population attributable risks were preformed to assess the effect of workplace justice on nurses' intention to leave the nursing profession. ETHICAL CONSIDERATIONS:: This study was approved by the Research and Ethical Committee of National Taiwan University Hospital. Only nurses who consented to the study participated in the survey. RESULT:: A total of 2268 nurses were recruited, of whom 1417 (62.5%) satisfactorily completed the questionnaire. The participants were classified and 342 (24.1%) of them were placed into the low workplace justice group. Nurses with low workplace justice had a higher intention of leaving the profession (adjusted odds ratio = 1.34, 95% confidence interval = 1.02-1.77). "Employees' opinions are influential in hospital's decision making" and "employees' performance is evaluated fairly" were the most influential factors of the participants' intention to quit. The adjusted population attributable risk was 3.7% for low workplace justice. CONCLUSION:: This study has identified that workplace justice is a protective factor of nurses' leaving their current profession. A fair performance appraisal system and increased autonomy at work are warranted to dissuade nurses from leaving the nursing profession.

[Features of new-onset organ dysfunction in children with sepsis].

OBJECTIVE: To study the features of new-onset organ dysfunction in children with sepsis in the pediatric intensive care unit (PICU). METHODS: A retrospective analysis was performed for the clinical data of children with sepsis who were admitted to the PICU from 2015 to 2016. There were 34 children with severe sepsis and 69 with non-severe sepsis, and the two groups were compared in terms of the incidence rate of new-onset organ dysfunction and the functional status on admission and at discharge. RESULTS: The severe sepsis group had a significantly higher incidence rate of new-onset organ dysfunction than the non-severe sepsis group (38% vs 6%; P<0.05). The children in the non-severe sepsis group had a relatively good functional status on admission, with marked improvement in the overall functional status at discharge. The children in the severe sepsis group had a poor functional status on admission, with mild/moderate abnormalities in consciousness, sensation, communication and respiratory function at discharge. CONCLUSIONS: Children with non-severe sepsis have a low incidence rate of new-onset organ dysfunction and a good prognosis, and those with severe sepsis often have a high incidence rate of new-onset organ dysfunction and a poor prognosis.

Asymmetric light diffraction of two-dimensional electromagnetically induced grating with PT symmetry in asymmetric double quantum wells.

An asymmetric double semiconductor quantum well is proposed to realize two-dimensional parity-time (PT) symmetry and an electromagnetically induced grating. In such a nontrivial grating with PT symmetry, the incident probe photons can be diffracted to selected angles depending on the spatial relationship of the real and imaginary parts of the refractive index. Such results are due to the interference mechanism between the amplitude and phase of the grating and can be manipulated by the probe detuning, modulation amplitudes of the standing wave fields, and interaction length of the medium. Such a system may lead to new approaches of observing PT-symmetry-related phenomena and has potential applications in photoelectric devices requiring asymmetric light transport using semiconductor quantum wells.

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer.

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg-1·d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg-1·d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

Enhanced gap junctional channel activity between vascular smooth muscle cells in cerebral artery of spontaneously hypertensive rats.

The aim of the present study is to investigate the effects of hypertension on the gap junctions between vascular smooth muscle cells (VSMCs) in the cerebral arteries (CAs) of spontaneously hypertensive rats (SHRs). The functions of gap junctions in the CAs of VSMCs in SHRs and control normotensive Wistar-Kyoto (WKY) rats were studied using whole-cell patch clamp recordings and pressure myography, and the expression levels of connexins were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blot analyses. Whole-cell patch clamp measurements revealed that the membrane capacitance and conductance of in situ VSMCs in the CAs were significantly greater in SHRs than in WKY rats, suggesting that gap junction coupling is enhanced between VSMCs in the CAs of SHRs. Application of the endothelium-independent vasoconstrictors KCl or phenylephrine (PE) stimulated a greater vasoconstriction in the CAs of SHRs than in those of WKY rats. The EC50 value of KCl was 24.9 mM (n = 14) and 36.9 mM (n=12) for SHRs and WKY rats, respectively. The EC50 value of PE was 0.9 µM (n = 7) and 2.2 µM (n = 7) for SHRs and WKY rats, respectively. Gap junction inhibitors 18ß-glycyrrhetinic acid (18ß-GA), niflumic acid (NFA), and 2-aminoethoxydiphenyl borate (2-APB) attenuated KCl-induced vasoconstriction in SHRs and WKY rats. The mRNA and protein expression levels of the gap junction protein connexin 45 (Cx45) were significantly higher in the CAs of SHRs than in those of WKY rats. Phosphorylated Cx43 protein expression was significantly higher in the CAs of SHRs than in those of WKY rats, despite the total Cx43 mRNA and protein expression levels in the cerebral artery (CA) exhibiting no significant difference between SHRs and WKY rats. Increases in the expression of Cx45 and phosphorylation of Cx43 may promote gap junction communication among VSMCs in the CAs of SHRs, which may enhance the contractile response of the CA to vasoconstrictors.

Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen.

AIM: Dexamethasone (DEX) is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer (NSCLC). METHODS: The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX (2 or 4 mg·kg(-1)·d(-1), ig) or the positive control tamoxifen (50 mg·kg(-1)·d(-1), ig) for 32 d. The expression of estrogen sulfotransferase (EST) in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. RESULTS: DEX displayed mild cytotoxicity to the NSCLC cells (IC50 >500 µmol/L) compared to tamoxifen (IC50 <50 µmol/L), but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX (0.1-10 µmol/L) dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth. Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. CONCLUSION: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC.

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

AIM: Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. METHODS: ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. RESULTS: The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. CONCLUSION: The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

Effects of Intraoperative Hemodynamics on Incidence of Postoperative Delirium in Elderly Patients: A Retrospective Study.

BACKGROUND: Postoperative delirium (POD) is a common complication in the elderly. This retrospective study investigated the effect of intraoperative hemodynamics on the incidence of POD in elderly patients after major surgery to explore ways to reduce the incidence of POD. MATERIAL/METHODS: Based on the incidence of POD, elderly patients (81±6 y) were assigned to a POD (n=137) or non-POD group (n=343) after elective surgery with total intravenous anesthesia. POD was diagnosed based on the guidelines of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), using the confusion assessment method. The hemodynamic parameters, such as mean arterial pressure, were monitored 10 min before anesthesia (baseline) and intraoperatively. The incidence of intraoperative hypertension, hypotension, tachycardia, and bradycardia were calculated. RESULTS: At 30 min and 60 min after the initiation of anesthesia and at the conclusion of surgery, the monitored hemodynamic parameter values of the POD group, but not those of the non-POD group, were significantly higher than at baseline. Multivariate logistic regression analysis showed that intraoperative hypertension and tachycardia were significantly associated with POD. CONCLUSIONS: Intraoperative hypertension and tachycardia were significantly associated with POD. Maintaining intraoperative stable hemodynamics may reduce the incidence of POD in elderly patients undergoing surgery.

The microtubule-associated protein EB1 links AIM2 inflammasomes with autophagy-dependent secretion.

Inflammasomes are multi-protein complexes that regulate chronic inflammation-associated diseases by inducing interleukin-1 ß (IL-1ß) secretion. Numerous components involved in inflammasome activation have been identified, but the mechanisms of inflammasome-mediated IL-1ß secretion have not yet been fully explored. Here, we demonstrate that end-binding protein 1 (EB1), which is required for activation of AIM2 inflammasome complex, links the AIM2 inflammasome to autophagy-dependent secretion. Imaging studies revealed that AIM2 inflammasomes colocalize with microtubule organizing centers and autophagosomes. Biochemical analyses showed that poly(dA-dT)-activated AIM2 inflammasomes induce autophagy and IL-1ß secretion in an LC3-dependent fashion. Furthermore, depletion of EB1 decreases autophagic shedding and intracellular trafficking. Finally, we found that the 5'-AMP activated protein kinase may regulate this EB1-mediated autophagy-based inflammasome-induced secretion of IL-1ß. These findings reveal a novel EB1-mediated pathway for the secretion of IL-1ß.

Retrospective evaluation of the efficacy of first-line treatment of advanced gastric cancer with docetaxel and oxaliplatin.

The incidence rate of gastric cancer is highest in China, where 5 in 10 new cases of stomach cancer across the world are diagnosed. Even though surgical management is the treatment of choice, it is not significantly effective due to advanced stage of the disease at diagnosis and the increased chances of primary tumor recurrence and metastasis to secondary organs. First-line chemotherapy of advanced gastric cancer patients recommend oxaliplatin and docetaxel; however, not much is known about their usage in Chinese patients. Therefore we retrospectively analyzed 199 cases of advanced gastric cancer (intestinal, diffuse, and mixed types) receiving either docetaxel or oxaliplatin-based first-line chemotherapy. The end-points determined were objective response rate (ORR, sum of complete and partial responses), disease control rate (DCR, sum of complete response, partial response, and stable disease), median progression-free survival (mPFS), and median overall survival (OS) time. Both docetaxel and oxaliplatin-based chemotherapy exhibited improved ORR and DCR; however, the comparison of short-term objective efficacy (ORR and DCR) was not statistically significant (p > .05) between the two groups. Our results indicated that PFS and OS of intestinal-type gastric cancer were extended compared with diffuse-type and mixed-type gastric cancer. Adverse reactions were within the control range and after symptomatic treatment were significantly ameliorated. Both docetaxel and oxaliplatin-based chemotherapy thus had a robust treatment outcome and can prospectively be used as one of the effective chemotherapy regimens for advanced gastric cancer patients in China.

Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208.

AIM: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo. METHODS: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg(-1)·d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses. RESULTS: Treatment with TM208 (10, 15 and 20 µmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo. CONCLUSION: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.

Prognostic Factors of Cholangiocarcinoma After Surgical Resection: A Retrospective Study of 293 Patients.

BACKGROUND: Cholangiocarcinoma is one of the most common malignancies in China. Surgical resection is the only treatment option; however, diagnosis at advanced stage precludes surgery. Comprehensive knowledge of prognostic markers is missing. Hence, the aim of this study was to determine clinicopathological indexes that would be indicative of prognosis in post-operative cases of cholangiocarcinoma. MATERIAL AND METHODS: A retrospective analysis of 293 cases of cholangiocarcinoma patients attending the 301 Military Hospital in Beijing, China between January 2004 and December 2010 were included in the study. The patients had follow-up history until August 2012. Cox proportional hazards model analysis was performed to identify indexes of prognosis. All indicators were analyzed by univariate and multivariate analysis. RESULTS: The median follow-up time was 55.90 months, with recurrence and metastasis in 162 cases (55.3%) and death in 223 cases (76.1%). The 1-year, 3-year, and 5-year survival rates were 71.7%, 38.2%, and 10.6%, respectively. The independent risk factors of overall survival were degree of tumor differentiation, TNM stage, surgical margin, intraoperative blood transfusion, tumor location, alkaline phosphatase levels in blood, and relapse. CONCLUSIONS: Good prognosis in cholangiocarcinoma patients is indicated by highly differentiated tumor, early stages of TNM staging, no resection margin invaded, no intraoperative blood transfusion, intrahepatic tumor, normal alkaline phosphatase levels, and no relapse.

Correlations between drug resistance of Beijing/W lineage clinical isolates of Mycobacterium tuberculosis and sublineages: a 2009-2013 prospective study in Xinjiang province, China.

BACKGROUND: The prevalence of drug-resistant tuberculosis (TB) in Xinjiang is higher than in other regions of China, and Beijing/W lineage Mycobacterium tuberculosis (MTB) is the dominant strain of MTB in Xinjiang. However, information on multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, particularly the correlation between MDR and the Beijing/W lineage and the correlation between drug resistance and the Beijing/W sublineage strains, is limited. MATERIAL/METHODS: We conducted a prospective study to describe the prevalence of MDR/XDR TB, Beijing/W lineage and sublineage strains in Xinjiang in China from 2009 to 2013. All MTB underwent drug susceptibility testing to the first- and second-line anti-tuberculosis drugs. The Beijing/W lineages and sublineages were detected by large-sequence polymorphisms with polymerase chain reaction. RESULTS: A total of 410 clinical isolates were identified. The overall percentage of MDR and XDR cases in Xinjiang was 13.2% (54/410) and 13.0% (7/54), respectively. Overall, 9.8% (14/143) of the Beijing lineage MTB were MDR patients, and 15.6% (40/257) of the Non-Beijing lineage MTB were MDR patients. In the 143 Beijing MTB lineages, 11.2% isolates were in sublineage 105, 15.4% isolates were in sublineage 207, 69.2% isolates were in sublineage 181, and 4.2% isolates were in sublineage 150. None of the isolates were detected in sublineage 142. Significant differences between the Beijing/W and non-Beijing/W strains were observed regarding INH and EMB resistance, respectively. CONCLUSIONS: The prevalence of the MDR TB in Xinjiang remains high and imposes challenges for TB control. Four Beijing/W sublineage isolates were observed in Xinjiang. There was no correlation between MDR and the Beijing/W lineage and no correlation between drug resistance and the Beijing/W sublineage strains. Surveillance of the clinical isolates of MTB is recommended to strengthen the identification of MDR/XDR TB and sublineages of the Beijing/W strains.

Intranasal administration of butorphanol benefits old patients undergoing H-uvulopalatopharyngoplasty: a randomized trial.

BACKGROUND: To evaluate intranasal administration of butorphanol on postoperative pain and early postoperative cognitive dysfunction in old patients undergoing H-uvulopalatopharyngoplasty (H-UPPP). METHODS: A total of 260 male patients (65 to 77 years old) with obstructive sleep apnea hypopnea syndrome and scheduled for H-UPPP were divided randomly to receive intranasal butorphanol, intravenous butorphanol, intranasal fentanyl, or intravenous saline (controls). The definition of preemptive analgesia is that the tested drugs are given before anesthesia induction. Visual analog scale (VAS) and Bruggrmann comfort scale (BCS) scores were recorded at postoperative 1, 6, 12, 18, 24, 36, and 48 h. Postoperative cognitive dysfunction (POCD) was evaluated by Mini-Mental State Examination (MMSE) scores assessed one day before, and 1, 3, and 7 days postsurgery. RESULTS: Compared with control group, those given preemptive analgesia required significantly less sufentanil during surgery, had less pain at postoperative 6-12 h; those given butorphanol experienced less nausea and vomiting, less pain at postoperative 6-24 h, and less POCD. Compared with patients given fentanyl, those given butorphanol required significantly less postoperative fentanyl, had less pain at postoperative 18-24 h, less nausea and vomiting, and less POCD. Compared with patients given intravenous butorphanol, those who received butorphanol by nasal route required significantly less postoperative fentanyl, had less pain at 36 and 48 h, and less POCD. CONCLUSION: Intranasal administration of butorphanol is safe and effective, reducing postoperative usage of analgesics and the incidence of POCD in old patients undergoing H-UPPP. TRIAL REGISTRATION: ChiCTR-TRC-14004121.