Geometric Origin of Non-Bloch PT Symmetry Breaking.

The parity-time (PT) symmetry of a non-Hermitian Hamiltonian leads to real (complex) energy spectrum when the non-Hermiticity is below (above) a threshold. Recently, it has been demonstrated that the non-Hermitian skin effect generates a new type of PT symmetry, dubbed the non-Bloch PT symmetry, featuring unique properties such as high sensitivity to the boundary condition. Despite its relevance to a wide range of non-Hermitian lattice systems, a general theory is still lacking for this generic phenomenon even in one spatial dimension. Here, we uncover the geometric mechanism of non-Bloch PT symmetry and its breaking. We find that non-Bloch PT symmetry breaking occurs by the formation of cusps in the generalized Brillouin zone (GBZ). Based on this geometric understanding, we propose an exact formula that efficiently determines the breaking threshold. Moreover, we predict a new type of spectral singularities associated with the symmetry breaking, dubbed non-Bloch van Hove singularity, whose physical mechanism fundamentally differs from their Hermitian counterparts. This singularity is experimentally observable in linear responses.

Cellular immunotherapy combined with platinum-based chemotherapy prolongs survival for non-small cell lung cancer patients.

Platinum-based chemotherapy is the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients without a driver gene mutation, but its efficacy is still modest. Through a potential synergistic effect, autologous cellular immunotherapy (CIT) composed of cytokine-induced killer (CIK), natural killer (NK), and T cells might enhance it. NK cells exhibited in vitro cytotoxicity toward lung cancer cells (A549 cells) following platinum therapy. Using flow cytometry, the expression of MICA, MICB, DR4, DR5, CD112, and CD155 on lung cancer cells was assessed. In this retrospective cohort study, there were included 102 previously untreated stage IIIB/IV NSCLC patients ineligible for tyrosine kinase inhibitor (TKI) target therapy who received either chemotherapy alone (n=75) or combination therapy (n=27). The cytotoxicity of NK cells for A549 cells was increased obviously and a time-dependent enhancement of this effect was also observed. After platinum therapy, the levels of MICA, MICB, DR4, DR5, CD112, and CD155 on the surface of A549 cells were increased. In the combination group, the median PFS was 8.3 months, compared to 5.5 months in the control group (p=0.042); the median overall survival was 18.00 months, compared to 13.67 months in the combined group (p=0.003). The combination group had no obvious immune-related adverse effects. The combination of NK cells with platinum showed synergistic anticancer effects. Combining the two strategies increased survival with minor adverse effects. Incorporating CIT into conventional chemotherapy regimens may improve NSCLC treatment. However, additional evidence will require multicenter randomized controlled trials.

TMED2/9/10 Serve as Biomarkers for Poor Prognosis in Head and Neck Squamous Carcinoma.

Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies' progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated. Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape to investigate the roles of TMED family members in HNSC. Results: Compared with normal tissues, the mRNA expression levels of TMED1/2/4/5/7/8/9/10 were significantly increased in the TCGA HNSC dataset. And we combined GEPIA 2 and Kaplan-Meier Plotter to select TMED2/9/10 with prognostic value. Then we detected the levels of mRNA in the GEO HNSC database and the protein expression in HPA. It was found that the mRNA and protein expression levels of TMED2/9/10 were increased in HNSC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that TMED2/9/10 and their co-expressed genes promoted the malignant behavior of tumors by participating in biological processes such as intracellular transferase complex, protein transport, focal adhesion, intracellular protein processing. Single-cell analysis and immune infiltration analysis suggested that immune responses of cancer-associated fibroblasts and endothelial cells might be associated with prognosis. Finally, the transcription factors-genes network and protein-protein functional interaction network pointed to genes such as X-box binding protein 1 (XBP1) and TMED7, which might cooperate with TMED2/9/10 to change the progression of HNSC. Conclusions: Our study implied that TMED2/9/10 and related genes mightjointly affect the prognosis of HNSC, providing specific clues for further experimental research, personalized diagnosis strategies, and targeted clinical therapy for HNSC.

Local Hyperthermia Versus Cryotherapy for Treatment of Plantar Warts: A Prospective Multi-centre Non-randomized Concurrent Controlled Clinical Trial.

Cryotherapy is one of the most common treatments for warts; however, pain during treatment and relatively high recurrence rates limit its use. Local hyperthermia has also been used successfully in the treatment of plantar warts. The aim of this study was to compare the clinical effectiveness of local hyperthermia vs cryotherapy for the treatment of plantar warts. This multi- centre, open, 2-arm, non-randomized concurrent controlled trial included 1,027 patients, who received either cryotherapy or local hyperthermia treatment. Three months after treatment, local hyperthermia and cryotherapy achieved complete clearance rates of 50.9% and 54.3%, respectively. Recurrence rates were 0.8% and 12%, respectively. Pain scores during local hyperthermia were significantly lower than for cryotherapy. Both local hyperthermia and cryotherapy demonstrated similar efficacy for clearance of plantar warts; while local hyperthermia had a lower recurrence rate and lower pain sensation during treatment.

BMI1 activates P-glycoprotein via transcription repression of miR-3682-3p and enhances chemoresistance of bladder cancer cell.

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.

Comprehensive signature analysis of drug metabolism differences in the White, Black and Asian prostate cancer patients.

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.

Preference for daily versus on-demand pre-exposure prophylaxis for HIV and correlates among men who have sex with men: the China Real-world Oral PrEP Demonstration study.

INTRODUCTION: This study explores the preference for daily versus on-demand pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in developing countries when both regimens are available. METHODS: From 11 December 2018 to 19 October 2019, we recruited MSM for an open-label real-world PrEP demonstration study in four major cities in China. Subjects selected their preferred PrEP (oral tenofovir/emtricitabine) regimen (daily vs. on-demand) at recruitment and underwent on-site screening before initiation of PrEP. We used logistic regression to assess preference for daily PrEP and correlates. RESULTS: Of 1933 recruited MSM, the median age was 29 years, 7.6% was currently married to or living with a female; the median number of male sexual partners was four and 6.1% had used post-exposure prophylaxis (PEP) in the previous six months. HIV infection risk was subjectively determined as very high (>75%) in 7.0% of subjects, high (50% to 75%) in 13.3%, moderate (25% to 49%) in 31.5% and low or none (0% to 24%) in 48.1%. On average, participants preferred on-demand PrEP over daily PrEP (1104 (57.1%) versus 829 (42.9%)) at recruitment. In multivariable analysis, currently being married to or living with a female was associated with 14.6 percentage points lower preference for daily PrEP (marginal effect = -0.146 [95% CI: -0.230, -0.062], p = 0.001); whereas the number of male sexual partners (marginal effect = 0.003 [95% CI: 0.000, 0.005], p = 0.034) and a subjective assessment of being very high risk of HIV infection (vs. low and no risk, marginal effect size = 0.105 [95% CI: 0.012, 0.198], p = 0.027) were associated with increased preference for daily versus on-demand PrEP. Among the 1933 potential participants, 721 (37.3%) did not attend the subsequent on-site screening. Lower-income, lower education level, lower subjective expected risk of HIV infection risk and younger age positively correlated with the absence of on-site screening. CONCLUSIONS: MSM in China prefer both daily and on-demand PrEP when both regimens are provided free. Social structural factors and subjective risk of HIV infection have significant impacts on PrEP preference and use. The upcoming national PrEP guideline should consider incorporating both regimens and the correlates to help implement PrEP in China.

LINC00511 promotes gastric cancer cell growth by acting as a ceRNA.

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.

Integrative molecular characterization of Chinese prostate cancer specimens.

Prostate cancer (PCa) exhibits epidemiological and molecular heterogeneity. Despite extensive studies of its phenotypic and genetic properties in Western populations, its molecular basis is not clear in Chinese patients. To determine critical molecular characteristics and explore correlations between genomic markers and clinical parameters in Chinese populations, we applied an integrative genetic/transcriptomic assay that combines targeted next-generation sequencing and quantitative real-time PCR (qRT-PCR) on samples from 46 Chinese patients with PCa. Lysine (K)-specific methyltransferase 2D (KMT2D), zinc finger homeobox 3 (ZFHX3), A-kinase anchoring protein 9 (AKAP9), and GLI family zinc finger 1 (GLI1) were frequently mutated in our cohort. Moreover, a clinicopathological analysis showed that RB transcriptional corepressor 1 (RB1) deletion was common in patients with a high risk of disease progression. Remarkably, four genomic events, MYC proto-oncogene (MYC) amplification, RB1 deletion, APC regulator of WNT signaling pathway (APC) mutation or deletion, and cyclin-dependent kinase 12 (CDK12) mutation, were correlated with poor disease-free survival. In addition, a close link between KMT2D expression and the androgen receptor (AR) signaling pathway was observed both in our cohort and in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data. In summary, our results demonstrate the feasibility and benefits of integrative molecular characterization of PCa samples in disease pathology research and personalized medicine.

Dramatic increase in gene mutational burden after transformation of follicular lymphoma into TdT+ B-lymphoblastic leukemia/lymphoma.

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.

Correction to: Mowing mitigates the negative impacts of N addition on plant species diversity.

Unfortunately, the panels of (f) in Figures 1, 2, and 4.

Mowing mitigates the negative impacts of N addition on plant species diversity.

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.

Is topical or intravenous tranexamic acid preferred in total hip arthroplasty? A randomized, controlled, noninferiority clinical trial.

PURPOSE: The present study aimed to confirm the efficacy and safety of topical and intravenous tranexamic acid (TXA) compared with that of topical placebo and to assess the noninferiority between the two application methods of TXA in patients undergoing unilateral primary total hip arthroplasty. METHODS: Our randomized controlled trial investigated 170 patients with 1:1:1 allocation to two doses of 10-mg/kg intravenous TXA, 3-g topical TXA, and topical placebo of 60-ml physiological saline groups. The primary outcome, total blood loss, was calculated with Nadler and Gross formula. The secondary outcomes included allogeneic blood transfusion requirement, drain blood loss, decreased hemoglobin level. Noninferiority would be established when the upper limit 95% CI is lower than 250 ml of the noninferiority margin for the mean difference of total blood loss between topical and intravenous TXA. Thromboembolic complication incidence was considered as a safety outcome. RESULTS: The total blood loss of patients administered intravenous (mean±standard deviation, 1125±514 ml) and topical TXA (1211±425 ml) was significantly reduced compared with that of those administered topical placebo (1464±556 ml) (p = 0.0012). Drain blood loss and hemoglobin level reduction in patients administered with TXA were also significantly lower than those in patients administered topical placebo. The mean difference of total blood loss between topical and intravenous TXA is 86 ml (95% CI, -88 to 260 ml). The complications were comparable between patients managed with TXA and patients with topical placebo. CONCLUSION: The noninferiority of topical TXA to intravenous TXA can not be concluded. Considering no significant difference was found in all efficacy outcomes between the two administration methods. Any of the two TXA administration methods can be adopted for blood loss prevention in total hip arthroplasty.

The impacts of nitrogen deposition on community N:P stoichiometry do not depend on phosphorus availability in a temperate meadow steppe.

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.

Intimate Partner Violence Correlates With A Higher HIV Incidence Among MSM: A 12-Month Prospective Cohort Study in Shenyang, China.

Intimate partner violence (IPV) and HIV are highly prevalent worldwide among MSM. However, the association between IPV and HIV seroconversion is virtually unknown. This 12-month prospective cohort study was conducted among MSM in Shenyang, China to explore the causality between IPV and the incidence of HIV. Adjusted Hazard Ratios (aHRs) of HIV acquisition were derived from a multivariate time-dependent Cox model and applied to calculate population attributable fractions (PAFs). Among 476 HIV-negative MSM subjects, 89(18.7%) reported being victims of IPV in the past 3 months (P3M). IPV was significantly correlated with lower education, having more condomless anal intercourse (CAI) and being depressed (each P < 0.05). The incidence of HIV among IPV victims was 11.3/100 PY compared to 3.8/100 PY in non-IPV-victims. Furthermore, IPV victimization was independently associated with HIV seroconversion (aHR = 4.1, PAF = 37.9%). Other predictors for seroconversion included non-local residence in Liaoning province (aHR = 3.9, PAF = 45.2%), engaging in condomless receptive anal intercourse (CRAI)(aHR = 3.1, PAF = 24.2%) or CAI with casual male partners (aHR = 3.8, PAF = 26.3%) in the P3M and syphilis infection (aHR = 4.7, PAF = 33.7%) (each P < 0.05). IPV increased the HIV seroconversion risk of MSM, with a high PAF. HIV prevention programs should integrate IPV screening and intervention, and MSM affected by IPV need to be preferentially enrolled in pre-exposure prophylaxis.

Poppers use and Sexual Partner Concurrency Increase the HIV Incidence of MSM: a 24-month Prospective Cohort Survey in Shenyang, China.

The use of poppers is highly prevalent in MSM, but little is known about the association between their use and HIV incidence in China. A prospective cohort study was conducted from 2011 to 2013 in MSM in Shenyang. 475(79.6%) of eligible HIV-negative MSM participated in this prospective survey and near one fourth MSM (23.4%) ever used poppers. About one-third of the participants had condomless anal intercourse, half had multiple sexual partners and 10.5% were syphilis positive. The HIV incidence densities were15.5 (95% CI:9.4-23.4)/100 PY[person-years]) and 4.6 (95% CI:2.9-7.0)/100 PY in poppers-users and non-poppers-users, respectively. Predictors of HIV seroconversion included poppers-using-behavior, having had more than two male partners, practicing group sex, unprotected anal intercourse(UAI) with male partners, and baseline syphilis positivity (all P < 0.05). In conclusion, the use of poppers, high-risk-sexual behaviors and syphilis infection significantly increase the HIV incidence among Shenyang MSM. It is essential for policy makers to add poppers to the official controlled illicit drug list to reduce HIV transmission among the MSM community. A comprehensive strategy should also be implemented to control both their high-risk-sexual behaviors and risk of syphilis infection, since these may represent novel ways to prevent new HIV infections in these MSM.

Microdissected thin anterolateral thigh perforator flaps with multiple perforators: A series of case reports.

INTRODUCTION: The study aimed to explore the effect of microdissected thin anterolateral thigh (MTALT) perforator flap with multiple perforators on patients with complex defects on the hand, elbow, heel, or knee. METHODS: From March 2012 to February 2013, 5 patients with complex defects on the hand, elbow, heel, or knee were included. During the flap preparation, 2 to 3 perforators penetrating the fascia of the anterolateral femoral area were initially detected, and the deep fascia was incised. The superficial fascia layer of the flap and the deep adipose were then dissected, and removed after verifying the distribution of the blood vessels using an operating microscope. The whole flap was then elevated, and transposed to the recipient areas for microsurgical reparation. RESULTS: Two cases of post-burn scar contracture and 3 cases of traumatic tissue defects were successfully reconstructed with these multiple-perforator MTALT flaps. No complication was reported, and secondary operative procedure was not needed in any patient in the follow-up. CONCLUSION: MTALT perforator flap with multiple perforators is safe and reliable for patients with complex defects on the hand, elbow, heel, or knee.

Highly oriented Langmuir-Blodgett film of silver cuboctahedra as an effective matrix-free sample plate for surface-assisted laser desorption/ionization mass spectrometry.

The design of a homogeneous sample plate to solve the sweet heating spot issues is the key step to expand the applicability of surface-assisted laser desorption/ionization mass spectrometry (SALDI MS). Herein, large-scale and highly oriented Langmuir-Blodgett (LB) films of uniform silver nanocrystals have been fabricated as a highly efficient and matrix-free sample plate for SALDI MS. Three individual silver nanocrystals (cubes, cuboctahedra and octahedra) assembled LB films have been applied as the sample plates for glucose detection by SALDI MS without an additional matrix. The results show that the signal intensity, background noise, signal-to-noise ratio and reproducibility have been significantly improved using LB films as the sample plate in comparison with commercial matrixes of CHCA and DHB. In particular, a relative signal of 5.7% was obtained for LB films of silver cuboctahedra. The significant improvement in the SALDI MS measurement could be attributed to the homogenous dissipation of laser irradiation energy to create a large area of the sweet heating spot on well-oriented silver cuboctahedra-based LB film. This ready-to-use sample plate has the potential for widespread commercial applications in SALDI MS.

Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation.

Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis. Furthermore, MSC-CM induced high level expression of a number of pluripotency factors in the cancer cells. ELISAs revealed MSC-CM contained higher levels of IL-6 and IL-8, which are associated with the progression of cancer. Moreover, MSC-CM downregulated AMPK mRNA and protein phosphorylation, but upregulated mTOR mRNA and protein phosphorylation. The NF-κB pathway was activated after addition of MSC-CM. An in vivo model in Balb/C mice confirmed the ability of MSC-CM to promote the invasion and proliferation of colorectal cancer cells. This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.