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Background In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear. Methods Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses. Results ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway. Conclusions This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.

In order to cut the costs and overcome the leakage current of batteries caused in traditional method, this study introduces an improved voltage transfer method for lithium battery string management chip. This proposed circuit based on the improved voltage transfer method is fabricated in 180‐nm Bipolar‐CMOS‐DMOS is correct technology, and has been successfully applied to a three lithium batteries string management chip. These measurements indicate that this circuit transfers each cell’s voltage reliably and adopt protection against abnormal conditions. Furthermore, analysis of 50 samples shows that the improved method can greatly eliminate the battery leakage. The circuit reduces the leakage current to nanoampere scale and is integrated into the lithium battery string management chip, which is helpful for battery voltage balance and low cost.

Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.

In order to suppress leakage current caused in the traditional multi-cells series Li-ion battery pack protection system, a new battery voltage transfer method is presented in this paper, which uses the current generated in the transfer process of one of the batteries to compensate for the leakage of itself and other cells except the top cell. Based on the 0.18 µm Bipolar and CMOS and DMOS technology, this proposed circuit has been integrated into a 7-cells Li-ion battery charge and discharge protection chip successfully. The experimental results of cell balancing confirm that the balancing algorithm can help with the shortage of the voltage transfer circuit. Furthermore, analysis of 20 samples shows that the new method can greatly suppress the battery leakage. Compared with the traditional solution, the voltage transfer circuit proposed in this paper greatly reduces the leakage current, which helps to extend the service life of the battery.

BACKGROUND Gastric cancer (GC) is one of the most aggressive malignancies, with a high incidence and poor prognosis worldwide. Recently, accumulating evidence has illustrated that long noncoding RNAs (lncRNAs) play pivotal roles in many cancers. It has been reported that LINC00511 contributes to tumorigenesis in various diseases. However, the role of LINC00511 in GC cell growth remains mostly unknown. AIM To determine whether the lncRNA LINC00511 exerted its carcinogenic function in GC via the miR-124-3p/PDK4 axis. METHODS Cell culture and transfection, RNA extraction and quantitative real-time PCR, CCK-8 assay, Colony formation assay, Luciferase reporter assay, RIP assay, RNA pull-down assay, and Western blot analysis were used to show expression and mechanisms of LINC00511 in GC progression and apoptosis. Rescue assays were performed to verify the relationships among LINC00511, miR-124-3p and PDK4 further. RESULTS The expression of LINC00511 was remarkably upregulated in GC cells compared to that in corresponding normal cell lines. Compared to the controls, cell proliferation was inhibited, and cell apoptosis was increased upon LINC00511 knockdown, demonstrating that LINC00511 influenced GC cell growth. An exploration of the molecular mechanism revealed that LINC00511 functioned as a molecular sponge of miR-124-3p and that PDK4 was a downstream target of miR-124-3p in GC. Rescue assays showed that the overexpression of PDK4 could partly restore the inhibitory function of si-LINC00511 in GC. CONCLUSION These data demonstrate that LINC00511 promotes gastric cancer cell growth by acting as a ceRNA to regulate the miR-124-3p/PDK4 axis, which may be a promising therapeutic target for GC.

Following the success of the natural language processing, the transformer for vision applications has attracted significant attention in recent years due to its excellent performance. However, existing deep learning hardware accelerators for vision cannot execute this structure efficiently due to significant model architecture differences. As a result, this paper proposes the hardware accelerator for vision transformers with row-wise scheduling, which decomposes major operations in vision transformers as a single dot product primitive for a unified and efficient execution. Furthermore, by sharing weights in columns, we can reuse the data and reduce the usage of memory. The implementation with TSMC 40nm CMOS technology only requires 262K gate count and 149KB SRAM buffer for 403.2 GOPS throughput at 600MHz clock frequency., Comment: 5 pages, 6 figures, published in IEEE AICAS 2022

The drug response sensitivity and related prognosis of prostate cancer varied from races, while the original mechanism remains rarely understood. In this study, the comprehensive signature including transcriptomics, epigenome and single nucleotide polymorphisms (SNPs) of 485 PCa cases- including 415 Whites, 58 Blacks and 12 Asians from the TCGA database were analyzed to investigate the drug metabolism differences between races. We found that Blacks and Whites had a more prominent drug metabolism, cytotoxic therapy resistance, and endocrine therapy resistance than Asians, while Whites were more prominent in drug metabolism, cytotoxic therapy resistance and endocrine therapy resistance than Blacks. Subsequently, the targeted regulation analysis indicated that the racial differences in cytotoxic therapy resistance, endocrine therapy resistance, might originate from drug metabolisms, and 19 drug metabolism-related core genes were confirmed in the multi-omics network for subsequent analysis. Furthermore, we verified that CYP1A1, CYP3A4, CYP2B6, UGT2B17, UGT2B7, UGT1A8, UGT2B11, GAS5, SNHG6, XIST significantly affected antineoplastic drugs sensitivities in PCa cell lines, and these genes also showed good predictive efficiency of drug response and treatment outcomes for PCa in this cohort of patients. These findings revealed a comprehensive signature of drug metabolism differences for the Whites, Blacks and Asians, and it may provide some evidence for making individualized treatment strategies.

Lithium-ion battery as an efficient, sustainable, and clean energy for electric vehicles (EVs) and smart devices becomes more popular with the worldwide demand for reduction of greenhouse gas emission. In all kinds of applications, an accurate real-time estimation for state of charge (SOC) of battery is necessary. Some conventional methods usually need to sample both battery currents and voltages. This article presents a novel SOC estimation algorithm without current detection. This algorithm just acquires the port voltages of cell to calculate the open-circuit voltage (OCV) which is related to SOC. By extracting a large number of battery voltages based on a step response, some important parameters that can track battery working process are determined. In order to verify the algorithm feasibility and accuracy, it has been tested on a commercial common field-programmable gate array (FPGA) in different application conditions. The algorithm accuracy is mainly limited by model accuracy and sampling sensor accuracy. The maximum error between ideal SOC and calculated SOC by this algorithm is within 4%, and the mean error is about 0.99%. So, this high-feasibility, accredited accuracy, easy integration, and low-cost solution has bright potential in smarter future.

Increasing availability of reactive nitrogen (N) threatens plant diversity in diverse ecosystems. While there is mounting evidence for the negative impacts of N deposition on one component of diversity, species richness, we know little about its effects on another one, species evenness. It is suspected that ecosystem management practice that removes nitrogen from the ecosystem, such as hay-harvesting by mowing in grasslands, would mitigate the negative impacts of N deposition on plant diversity. However, empirical evidence is scarce. Here, we reported the main and interactive effects of N deposition and mowing on plant diversity in a temperate meadow steppe with 4-year data from a field experiment within which multi-level N addition rates and multiple N compounds are considered. Across all the types of N compounds, species richness and evenness significantly decreased with the increases of N addition rate, which was mainly caused by the growth of a tall rhizomatous grass, Leymus chinensis. Such negative impacts of N addition were accumulating with time. Mowing significantly reduced the dominance of L. chinensis, and mitigated the negative impacts of N deposition on species evenness. We present robust evidence that N deposition threatened biodiversity by reducing both species richness and evenness, a process which could be alleviated by mowing. Our results highlight the changes of species evenness in driving the negative impacts of N deposition on plant diversity and the role of mowing in mediating such negative impacts of N deposition.

Nitrogen (N) enrichment has great consequences on several fundamental ecological processes through its impacts on plant nutrition traits (i.e. nutrient concentration and stoichiometric ratios); however, the extent to which the effects of N enrichment depend on phosphorus (P) availability are less well understood. While there is mounting evidence for the species-specific responses of plant nutrition traits to nutrient enrichment, we know little about the changes at the community-level. Here, we measured community-level biomass weighted (CWM) and non-weighted (CM) plant N and P concentrations and N:P ratio in a temperate meadow steppe after four years factorial N and P addition, with biomass and nutrition traits of each species in each plot being recorded. Nitrogen addition significantly increased community-level N concentration, decreased P concentration, and enhanced community N:P ratio. Phosphorus addition had no impacts on community-level N concentration, significantly increased P concentration, and reduced community N:P ratio. The impacts of N addition on community nutrition traits were not dependent on P addition and the community-level nutrition trait responses to N and P additions were primarily driven by intraspecific trait variation (ITV) rather than by species turnover. Community-level nutrition traits in the temperate meadow steppe were sensitive to the projected N and P enrichment. While nutrient enrichment had substantially changed community composition, its impacts on community nutrition traits were driven by ITV. Nitrogen deposition would result in imbalance of N and P in plant community, as indicated by the substantial increase in community-level N:P, which was not affected by increased P availability.

Utilization of g-C3N4 as a single photocatalyst material without combination with other semiconductor remains challenging. Herein, we report a facile green method for synthesizing a metal free modified g-C3N4 photocatalyst. The modification process combines four different strategies in a one-pot thermal reaction: non-metal doping, porosity generation, functionalization with amino groups, and thermal oxidation etching. The as-prepared amino-functionalized ultrathin nanoporous boron-doped g-C3N4 exhibited a high specific surface area of 143.2 m2 g−1 which resulted in abundant adsorption sites for CO2 and water molecules. The surface amino groups act as Lewis basic sites to adsorb acidic CO2 molecules, which can also serve as active sites to facilitate hydrogen generation. Besides, the simultaneous use of ammonium chloride as a dynamic gas bubble template along with thermal oxidation etching efficiently boosts the delamination of the g-C3N4 layers to produce ultrathin sheets; this leads to stronger light–matter interactions and efficient charge generation. Consequently, the newly modified g-C3N4 achieved selective gas-phase CO2 reduction into CO with a production yield of 21.95 µmol g−1, in the absence of any cocatalyst. Moreover, a high hydrogen generation rate of 3800 µmol g-1h−1 and prominent apparent quantum yield of 10.6% were recorded. This work opens up a new avenue to explore different rational modifications of g-C3N4 nanosheets for the efficient production of clean energy.

Background To primarily evaluate the effects and safety of a selective angiotensin II type 1 (AT1) receptor blocker (ARB) allisartan isoproxil combined with amlodipine or indapamide in the treatment of patients with essential hypertension who failed allisartan monotherapy. Methods Patients aged 18–75 years with mild-to-moderate essential hypertension [office systolic blood pressure (SBP) 140 to Results A total of 2,212 patients were enrolled, among them 2,126 patients were included in the efficacy analysis, with an average age of 55.1 ± 10.2 years. A total of 1,463 cases (68.8%) were effective after 4 weeks allisartan treatment, and the mean SBP and DBP were significantly decreased by 14.7 ± 12.2 and 8.0 ± 8.4 mm Hg compared with the baseline levels (all P < 0.001). In nonachievers, allisartan combined with indapamide for 8 weeks significantly lowered the sitting BP (SBP/DBP) by 14.0 ± 12.2/8.3 ± 9.2 mm Hg, respectively, compared with 4 weeks monotherapy with allisartan with a BP targeting rate of 57.7% (169/293). In the allisartan + amlodipine group, the SBP/DBP were significantly decreased by (14.4 ± 12.1/8.2 ± 8.2) mm Hg, respectively, with a BP targeting rate of 62.8% (181/288). There was no statistical significance in BP reduction, targeting rate, or adverse reactions between the 2 combined therapies. Conclusions Allisartan isoproxil combined with indapamide or amlodipine can further improve the BP targeting rate when allisartan monotherapy failed in essential hypertension. The 2 combined therapies have similar efficacy and safety.

Transformation of follicular lymphoma (FL) into B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is rare and results in greatly increased aggressiveness of clinical course. Here we present extensive molecular analysis of this unusual transformation, including immunoglobulin (Ig) gene rearrangement studies, cytogenetic analysis, and whole-exome sequencing (WES) of the patient's FL, B-ALL/LBL, and normal cells. Although FL showed marked somatic hypermutation (SHM) of the Ig genes, SHM appeared to be even more extensive in B-ALL/LBL. Cytogenetically, at least three translocations were identified in the B-ALL/LBL involving the BCL2, BCL6, and MYC genes; two of these, the BCL6 and BCL2 gene rearrangements, were already seen at the FL stage. WES identified 751 single-nucleotide variants with high allelic burden in the patient's cells, with the vast majority (575) present exclusively at the B-ALL/LBL stage. Of note, a TAF3 gene mutation was shared by normal, FL, and B-ALL/LBL tissue. A KMT2D nonsense mutation was identified in both FL and B-ALL/LBL and therefore may have contributed directly to lymphomagenesis. Mutations in KDM6A, SMARCA4, CBX1, and JMY were specific to the B-ALL/LBL stage, possibly contributing to the B-ALL/LBL transformation. Functionally, these identified mutations may lead to dysregulation of DNA repair, transcription, and cell differentiation. Thus, these genetic changes, together with the identified chromosomal translocations, may have contributed to lymphoma development and progression. Our findings may improve the mechanistic understanding of the FL-B-ALL/LBL transformation and may have therapeutic implications for this aggressive disease.

Two new hybrid compounds with chemical formulas [Co(L1)2(H2O)2]2[SiW12O40]·6H2O (1) and [Cu2(C9H22 N)2(L2)2][SiW12O40]·2H2O (2) (L1 = 3,3′-diamino-5,5′-bis(1H-1,2,4-triazole), L2 = 1,2-bis(3-(2-pyridyl)pyrazole-1-ylmethyl)benzene, C9H22 N = tripropylamine) were prepared in a hydrothermal reaction system containing Keggin-type polyoxometalates (POMs), transition metal (TM) salts (cobalt salts and copper salts), and chelate L1/L2 ligands. X-ray structural analysis reveals that 1 and 2 possess 3-D supramolecular host frameworks with large cavities and the polyoxoanions SiW12 reside in these cavities as the guest templates. The photocatalytic activities of 1 and 2 were investigated. Both compounds show efficient catalytic activity for degradation of RhB with 1 > 2. The loading amount of the POM units and the structural features of these POM-based organic-inorganic hybrid compounds may be necessary factors that affect the activity of catalysts in the photocatalytic degradation.

In this paper, a new high-voltage level shifter (HVLS) structure is proposed, which has a significantly improved transient response over existing structures. To overcome signal transfer delay of the conventional HVLS caused by parasitic capacitance due to high-voltage MOSFETs, this structure employs a novel circuit module "inverse Schmitt trigger" to drive the pull-up transistors of conventional HVLS. As a result, the "Miller Plateau" caused by parasitic capacitance can be minimized. Hence, the overall transfer delay of the structure is significantly reduced. The simulation results based on SPECTRE and 0.5 $$\upmu $$μm high-voltage CMOS process show that compared to other currently available structures whose transfer delays are several nanoseconds on average, the proposed structure is able to provide a nanosecond transfer delay without using large boost capacitors which are impractical to be integrated or using complex logic units which decrease reliability of circuit. Also, the typical transfer delay of the proposed structure is a constant 1.3 ns, which is irrelevant to parasitic capacitance and insensitive to transfer voltage level.

After convolutional neural network has been simulated by neuroscience in deep learning, Label-Free Supervision with domain knowledge can also tell us that we shall take advantage of shoulders of giants like Newton in the development of AI. In fact, AI’s development has been on the shoulders of giants, such as Optimization Theory, Calculus. This paper explores whether some of Maslow's Theory can serve as the other (or next) giant of AI's shoulders, and tries to discuss the AI and security issues with Maslow's Theory. The human ego has the basic need that be extended to the security requirements of things in the IoT. Finally, learning from the unity of "natural science", "social science" and "harmony between humanity and nature (Yang-ming WANG’s Cognitive idea)", a mutual development for human intelligence, the intelligence of things and the natural intelligence with respect of each other is discussed.

This paper provides a solution for a self-powered light direction detection with digitized output. Light direction sensors, energy harvesting photodiodes, real-time adaptive tracking digital output unit and other necessary circuits are integrated on a single chip based on a standard 0.18 µm CMOS process. Light direction sensors proposed have an accuracy of 1.8 degree over a 120 degree range. In order to improve the accuracy, a compensation circuit is presented for photodiodes' forward currents. The actual measurement precision of output is approximately 7 ENOB. Besides that, an adaptive under voltage protection circuit is designed for variable supply power which may undulate with temperature and process.

In recent years, the construction of subway in China is in a period of an rapid development. The passengers are in high density within the subway during the operation time, the problem of safety in emergencies has attracted more and more attentions. The structure of atrium metro station is special, fire partition area in the station is difficult to divide. And there is a hidden danger of fire, which is not easy to realize effective exhaust and smoke control. Once there is a fire the magnitude of injuries will be overwhelmingly disastrous. Therefore, more attention should be paid on pedestrian’s evacuation in subway stations. Therefore, an atrium subway station in Beijing is selected, hot smoke test and STEPS software simulation were carried out. We also analyzed the escape environment and escape routes, reasonable evacuation time is obtained, as well as a reasonable escape strategy.

A pseudo-type-III compensation circuit integrated in a 2.25-MHz voltage-mode dc–dc buck regulator is presented. By summing high- and low-frequency signal paths at the outputs of an error amplifier, two zeros are generated to counteract the pair of complex $LC$ poles. Comparing with traditional and various reported type-III compensation, the proposed scheme is compact, and the area of the compensation capacitor is reduced by about 37%. The addition of a high-frequency path also helps to improve the transient response. Experimental results show that the fabricated regulator with the proposed scheme achieves good stability and fast load-step response. The output is settled within 10 $\mu \hbox{s}$ for a load current step of 400 mA. In addition, the measured load regulation and line regulation is 0.2%/A and 0.2%/V, respectively. The current consumption of the compensator is 120 $\mu \hbox{A}$ , and the measured maximum efficiency is up to 96%.

Considering the tradeoff between efficiency and output ripple over a wide load range, a monolithic dc-dc buck converter with switch-on-demand modulation (SODM) and switch size control (SSC) is presented in this paper. SODM achieves a hybrid mode of pulse skip and pulse width modulation (PWM) without mode detection circuit. The converter's on time is adaptively adjusted with the load demand, achieving low output voltage ripple. Detecting the output of the error amplifier by a comparator, the SSC circuit can select appropriate switch size according to load current for reducing switching loss in a light load. The threshold level of the comparator varies with respect to the amount of slope compensation, which maintains a substantially constant switch size changing point. Experimental results show that the fabricated converter with the proposed scheme achieves high efficiency from 83% to 96% over a wide load range from 10 mA to 5 A. The switch size is 1/4 of the maximum value when load current is below 1 A with 0.5-A hysteresis. Also, the measured maximum output ripple is less than 10 mV.

Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration.A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models.The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649(*)(age/86)((-3.3856)), Ka=0.6750 h(-1), V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks.A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.

Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4 + T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4 + T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

Grammar-based test generation (GBTG) has seen extensive study and practical use since the 1970s. GBTG was introduced to generate source code for testing compilers from context-free grammars specifying language syntax. More recently, GBTG has been applied to many other testing problems, including the generation of eXtensible Markup Language (XML) documents and the generation of packets for testing communications protocols. Recent research has shown how to integrate covering-array techniques such as pairwise testing into GBTG tools. While the integration offers considerable power to the tester, there are few practical demonstrations in the literature. We present two case studies showing how to use grammars and covering arrays for automated software testing. The first case study exposes HTML injection vulnerabilities in an RSS feed parser. The second case study determines the effectiveness of network firewalls when faced with TCP flag attacks. The case studies illustrate the use of covering arrays in a GBTG context, the use of visualization to understand large test logs, and the issues and tradeoffs in the design of fully automated GBTG test suites.

In this study, we demonstrate that malignant mature CD4+ T lymphocytes derived from cutaneous T cell lymphomas (CTCL) variably display some aspects of the T regulatory phenotype. Whereas seven cell lines representing a spectrum of primary cutaneous T cell lymphoproliferative disorders expressed CD25 and TGF-β, the expression of FOXP3 and, to a lesser degree, IL-10 was restricted to two CTCL cell lines that are dependent on exogeneous IL-2. IL-2, IL-15, and IL-21, all of which signals through receptors containing the common γ chain, induced expression of IL-10 in the IL-2-dependent cell lines as well as primary leukemic CTCL cells. However, only IL-2 and IL-15, but not IL-21, induced expression of FOXP3. The IL-2-triggered induction of IL-10 and FOXP3 expression occurred by signaling through STAT3 and STAT5, respectively. Immunohistochemical analysis of the CTCL tissues revealed that FOXP3-expressing cells were common among the CD7-negative enlarged atypical and small lymphocytes at the early skin patch and plaque stages. Their frequency was profoundly diminished at the tumor stage and in the CTCL lymph node lesions with or without large cell transformation. These results indicate that the T regulatory cell features are induced in CTCL T cells by common γ chain signaling cytokines such as IL-2 and do not represent a fully predetermined, constitutive phenotype independent of the local environmental stimuli to which these malignant mature CD4+ T cells become exposed.

Objectives. To understand the current risk of HIV infection and transmission and further elucidate the underlying risk factors among men who have sex with men and women (MSMW) in China.Methods. Following PRISMA guidelines, we conducted a systematic review and meta-analysis of searching through Chinese and English available literature databases between January 2000 and June 2014 to identify articles.Results. Thirty-six articles (including 19,730 MSMW and 53,536 MSMO) met the selection criteria and the aggregated results found that MSMW have significantly higher HIV prevalence than MSMO (6.6% versus 5.4%, OR = 1.27, 95% CI = 1.01–1.58). A higher proportion of MSMW had commercial male partners in the past 6 months (18.3% versus 12.2%, OR = 1.56, 95% CI = 1.01–2.42). Additionally, substance use in the past 6 months was significantly more frequent among MSMW than MSMO (alcohol use: 27.1% versus 13.1%, OR = 2.53, 95% CI = 2.14–2.99; illicit drug use: 5.3% versus 2.5%, OR = 2.09, 95% CI = 1.48–2.95).Conclusion. A higher proportion of commercial sex and substance use among MSMW may be a potentially indicative factor for significantly higher HIV prevalence compared to MSMO. Targeted interventions should aim at increasing the frequency of HIV/STIs screening and preventing high risk commercial sex and substance use among MSMW to decrease their HIV transmission to the general population.

Objective: To establish a method to improve the detection of disseminated tumor cells in bone marrow and peripheral blood samples of neuroblastoma patients and analysis of cytogenetic aberration. Methods: Immunofluorescent staining was performed using a cocktail of primary monoclonal neuroblastoma antibodies (14.G2a, 5.1H11). Fluorescence in situ hybridization was applied with fluorescent probes specific for Nmyc genes afterwards. A novel computer assisted scanning system for automatic search, image analysis and repositioning of these positive cells was developed. Fifty-six bone marrow and peripheral blood samples from 7 patients were evaluated by this method. Results: Fluorescence in situ hybridization can be combined with immunofluorescent staining in detecting Nmyc amplification in neuroblastoma patients. Fluorescence in situ hybridization results correlated well with data obtained by conventional cytogenetic procedures. Conclusion: The technique described allows search of tumor cells in the bone marrow as well as detection of Nmyc amplification in interphase nuclei.

Objective: To evaluate the relationship between flow cytometric DNA ploidy, biological features and prognosis in patients with Stage II colorectal cancer. Methods: Nuclear DNA content, proliferation index and S-phase fraction were measured in a prospective series of 45 patients with curatively resected Stage II colorectal adenocarcinomas by means of flow cytometry using frozen tumor samples. Results: Of the 45 samples examined, 17 tumors (38%) were diploid and 28 (62%) aneuploid. The diploid tumors were significantly more common in the proximal colon than in the distal colon (67% vs. 23%; P 0.05). The proliferation index and S-phase fraction in the distal tumors were higher than those in the proximal tumors, but the difference was not significant (P>0.05). When the 5-year survival rate of patients with Stage II colorectal cancer was compared by the log rank test, a significant relationship between DNA ploidy status and disease free survival was observed in the group of all patients. Patients with DNA diploid tumors had a better disease free survival than those with DNA aneuploid tumors (P

In this article, we report that cutaneous T cell lymphoma (CTCL) cells and tissues ubiquitously express the immunosuppressive cell surface protein CD80 (B7-1). CD80 expression in CTCL cells is strictly dependent on the expression of both members of the STAT5 family, STAT5a and STAT5b, as well as their joint ability to transcriptionally activate the CD80 gene. In IL-2–dependent CTCL cells, CD80 expression is induced by the cytokine in a Jak1/3- and STAT5a/b-dependent manner, whereas in the CTCL cells with constitutive STAT5 activation, CD80 expression is also STAT5a/b dependent but is independent of Jak activity. Although depletion of CD80 expression does not affect the proliferation rate and viability of CTCL cells, induced expression of the cell-inhibitory receptor of CD80, CD152 (CTLA-4), impairs growth of the cells. Coculture of CTCL cells with normal T lymphocytes consisting of both CD4+ and CD8+ populations or the CD4+ subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80–CD152 axis may become a therapeutic target in this type of lymphoma.

With this study we have demonstrated that in vitro transduction of normal human CD4(+) T lymphocytes with NPM-ALK results in their malignant transformation. The transformed cells become immortalized and display morphology and immunophenotype characteristic of patient-derived anaplastic large-cell lymphomas. These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of immunosuppressive cytokine IL-10 and cell-surface protein PD-L1/CD274. Implantation of NPM-ALK-transformed CD4(+) T lymphocytes into immunodeficient mice resulted in formation of tumors indistinguishable from patients' anaplastic large-cell lymphomas. Our findings demonstrate that the key aspects of human carcinogenesis closely recapitulating the features of the native tumors can be faithfully reproduced in vitro when an appropriate oncogene is used to transform its natural target cells; this in turn points to the fundamental role in malignant cell transformation of potent oncogenes expressed in the relevant target cells. Such transformed cells should permit study of the early stages of carcinogenesis, and in particular the initial oncogene-host cell interactions. This experimental design could also be useful for studies of the effects of early therapeutic intervention and likely also the mechanisms of malignant progression.

Copyright: © 2013 Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Plasma insulin must traverse the vascular endothelium to reach its major sites of action on myocytes and adipocytes. In study simultaneously measuring plasma and lymphatic insulin concentrations in normal, conscious dogs during euglycemic insulin clamps it was found that the steady-state plasma insulin concentration was consistently higher than lymph with a rough ratio of 3:2 during the basal period. In addition, while plasma insulin concentration rose quickly to reach the steady-state during the insulin clamp, the lymph insulin concentration rose very slowly indicating a barrier function of the vascular endothelium. Most importantly, this study showed that the dynamics of glucose disposal correlated very strikingly with the insulin concentration in lymph but not plasma, suggesting that trans-capillary insulin transport is a rate limiting step for peripheral insulin action [1]. Consistent with this, direct injection of insulin into canine skeletal muscle in vivo was recently noted to significantly hasten the onset of muscle glucose utilization compared with intravenously delivered insulin [2]. Multiple other studies also support such an important role of vascular endothelium during insulin clamp by measurement of the insulin concentration within skeletal muscle interstitium in humans and animals using either lymphatic sampling or microdialysis methods [3-7]. Results obtained using either method indicate that even after several hours of steady state hyperinsulinemia, muscle interstitial insulin concentration is only 40-50% of that in plasma and the time course for insulin-mediated glucose disposal during the euglycemic clamp correlates strongly with interstitial but not plasma insulin concentrations. Based on these findings, it has been estimated that slow trans-endothelial insulin transport may account for 30-40% of insulin resistance seen with human obesity or type-2 diabetes [3,8,9].

To explore the effects of different antihypertensive strategies on blood pressure and urinary albumin excretion in patients with hypertension and microalbuminuria.For this multi-center, randomized, positively controlled clinical trial, a total of 531 patients with mild-to-moderate essential hypertension and microalbuminuria were enrolled. They were divided randomly into calcium channel blocker (CCB), angiotensin II receptor antagonist (ARB) and CCB+ARB groups. The whole treatment period was 6 months.According to ANOVA analysis, the post-therapeutic urinary albumin level decreased 20.6, 27.6 and 30.9 mg/L in CCB, ARB and CCB+ARB groups respectively (P = 0.067). And the extents of urinary albumin reduction were 31.1 and 6.6 mg/L in patients with controlled and uncontrolled blood pressure respectively (P0.001).Effective antihypertensive therapy is a key for decreasing urinary albumin excretion in hypertensive patients. As compared with calcium antagonists, ARB-containing regimens appear to be better in reducing urinary albumin.

The management of patients with refractory immune thrombocytopenia (ITP) is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in combination with cyclosporin A (CsA) for the management of patients with corticosteroid-resistant primary ITP.Thirty-six patients with corticosteroid-resistant ITP were randomly divided into an observation group and control group. In the observation group, 19 patients received subcutaneous injection of rhTPO at a dose of 1 µg/kg (300 U/kg) once daily up to day 14. Simultaneously they also received oral CsA at a dose of 1.5-2.0 mg/kg twice daily for three months. In the control group, rhTPO alone was administered subcutaneously at 1 µg/kg once daily in the other 17 ITP patients for 14 consecutive days and then the treatment was withdrawn.There was no significant difference in the response rate at the end of the first week after treatment initiation between the observation group and the control group (63.2% vs. 58.8%, P0.05), neither was there at the end of the second week (89.5% vs. 94.1%, P0.05). However, the relapse rate in the observation group was significantly lower than that in control group at the end of the first (17.7% vs. 50.0%, P0.05), second (29.4% vs. 68.8%, P0.05) and the third month (29.4% vs. 87.5%, P0.01). In addition, rhTPO plus CsA were well tolerated and adverse events recorded were mild.Combination therapy with rhTPO and CsA was effective in the management of patients with corticosteroidresistant ITP, with a relatively short time to response and low recurrence rate. It might be considered as a potential secondline treatment regimen for ITP.

To explore the characteristics and related risk factors of arterial elasticity in persons with prehypertension, high-normal blood lipid and(or) impaired glucose regulation(impaired fasting glucose and(or) impaired glucose tolerance).After receiving physical and biochemical examinations, a total of 1238 persons were enrolled. Among them, the etiologies were prehypertension (n = 65), high-normal blood lipid (n = 156), impaired glucose regulation (n = 159), prehypertension and high-normal blood lipid (n = 85), prehypertension and impaired glucose regulation (n = 77), high-normal blood lipid and impaired glucose regulation (n = 55) and prehypertension, high-normal blood lipid and impaired glucose regulation (n = 9). Also 332 healthy subjects, 113 hypertensive patients, 150 hyperlipidemics and 37 diabetics were enrolled as controls. Systemic vascular compliance (SVC), systemic vascular resistance (SVR), brachial artery distensibility (BAD) were measured with Dynapulse 200 M (Pulse Metric, Inc., USA).In persons with prehypertension, SVC was lower than healty group ((1.14 ± 0.20) ml vs (1.26 ± 0.23) ml, P0.01)and higher than hypertensive group ((1.11 ± 0.18) ml, P = 0.011), SVR higher than healty group (157 ± 29) kPa×s×L(-1) vs (148 ± 25) kPa×s×L(-1), P = 0.012) and lower than hypertensive group ((166 ± 36) kPa×s×L(-1), P0.01)and BAD lower than healty group(5.93% ± 1.14% vs 6.50% ± 1.30%, P0.01). Among different groups with prehypertension, high-normal blood lipid and(or) impaired glucose regulation, SVC, SVR and BAD had significant differences. As indicated by multiple linear regression analysis, blood pressure was an independent risk factor of arterial elasticity.Vascular function becomes damaged in prehypertensive stage. As an independent risk factor, blood pressure had more potent effect than lipid and blood glucose. Multiple cardiovascular risk factors with high-normal value may affect vascular function more strongly.

Aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. The aim of this study was to assess the effect of aliskiren on arterial stiffness, compared with that of ramipril in mild to moderate essential hypertensive patients.Following a two week placebo run-in period, patients with a mean sitting diastolic blood pressure (ms-DBP) ≥ 95 and110 mmHg (1 mmHg = 0.133 kPa), and a mean sitting systolic blood pressure (ms-SBP)180 mmHg were randomly allocated to treatment with aliskiren (150 mg/d, n = 20) or ramipril (5 mg/d, n = 20) for eight weeks. Blood pressure, plasma renin activity, and the brachial-ankle pulse wave velocity (ba-PWV) were measured before and after eight weeks of treatment.Eight weeks of treatment significantly decreased systolic blood pressure and diastolic blood pressure in both the aliskiren group and ramipril group. The hypotensive effect did not differ between the two groups. Plasma renin activity decreased after aliskiren treatment and increased after ramipril treatment. There was no significant difference in baseline ba-PWV between the aliskiren and ramipril groups (P = 0.892). The ba-PWV was significantly reduced in both the aliskiren group (1535 (1405 - 1666) vs. 1464 (1360 - 1506) cm/s) (P0.01) and the ramipril group (1544 (1433 - 1673) vs. 1447 (1327 - 1549) cm/s) (P0.01). No statistically significant difference was found in the decline of ba-PWV between the two groups (P = 0.766).The current study revealed that aliskiren (150 mg/d) could ameliorate arterial stiffness and its effect was similar to ramipril (5 mg/d) in mild to moderate hypertensive patients, indicating that in addition to lowering blood pressure, aliskiren had beneficial effect on vascular protection.

Objective: To study the association of DNA ploidy abnormality and p53 overexpression with the carcinogenesis of colorectal cancer. Methods: DNA ploidy and p53 expression were measured in a series of 42 colorectal adenocarcinomas by means of flow cytometry and immunohistochemical test. Results: 17 tumors (40%) were diploid and 25 (60%) aneuploid. The aneuploid tumors were significantly more common in the distal colon than in the proximal colon (P