Efficacy and safety of preoperative immunotherapy in patients with mismatch repair-deficient or microsatellite instability-high gastrointestinal malignancies

BACKGROUND Programmed death protein(PD)-1 blockade immunotherapy significantly prolongs survival in patients with metastatic mismatch repair-deficient(dMMR)/microsatellite instability-high(MSI-H)gastrointestinal malignancies such gastric and colorectal cancer.However,the data on preoperative immunotherapy are limited.AIM To evaluate the short-term efficacy and toxicity of preoperative PD-1 blockade immunotherapy.METHODS In this retrospective study,we enrolled 36 patients with dMMR/MSI-H gastrointestinal malignancies.All the patients received PD-1 blockade with or without chemotherapy of CapOx regime preoperatively.PD1 blockade 200 mg was given intravenously over 30 min on day 1 of each 21-d cycle.RESULTS Three patients with locally advanced gastric cancer achieved pathological complete response(pCR).Three patients with locally advanced duodenal carcinoma achieved clinical complete response(cCR),followed by watch and wait.Eight of 16 patients with locally advanced colon cancer achieved pCR.All four patients with liver metastasis from colon cancer reached CR,including three with pCR and one with cCR.pCR was achieved in two of five patients with nonliver metastatic colorectal cancer.CR was achieved in four of five patients with low rectal cancer,including three with cCR and one with pCR.cCR was achieved in seven of 36 cases,among which,six were selected for watch and wait strategy.No cCR was observed in gastric or colon cancer.CONCLUSION Preoperative PD-1 blockade immunotherapy in dMMR/MSI-H gastrointestinal malignancies can achieve a high CR,especially in patients with duodenal or low rectal cancer,and can achieve high organ function protection.

Linking anisotropy with Fe_3C distribution in AISI 1045 steel

The anisotropy of the microstructure, thermal expansion behavior, corrosion resistance and magnetic properties of AISI 1045 steel was investigated. The distribution of Fe3C lameUae in the investigation plane parallel to the radial directions of molds was observed to differ from that in the investigation plane perpendicular to the radial directions by transmission electron microscopy. The lattice constants a0 of α-Fe deduced from the XRD patterns of samples prepared using a sand （S）-mold and cut parallel to the radial direction of the mold （S//） and using a metal （M）-mold and cut parallel to the radial direction （M//）, the corrosion resistance measured using an electrochemical work- station, and the magnetic permeability obtained by vibrating sample magnetometry also indicated the existence of anisotropy in the tested samples. The anisotropic change of corrosion potential （Eeorr）, pitting potential （Epit） and magnetic permeability （μ） of the samples was observed to depend on the orientation factorF200 of α-Fe in the measured samples, which is controlled by the distribution of Fe3C lamellae in the eutectoid structure.

A Baseline Correction Algorithm for FAST

The Five-hundred-meter Aperture Spherical radio Telescope(FAST)is the most sensitive ground-based,singledish radio telescope on Earth.However,the original HⅠspectra produced by FAST are affected by standing waves.To maximize the power of FAST for high-sensitivity observations,we proposed an algorithm that combines fast Fourier transforms and extreme envelope curves to automatically correct the baselines of FAST HⅠspectra and remove standing waves from the baselines.This algorithm can reduce the amplified noise level caused by standing waves to a near-ideal level without losing signals or introducing false signals.The root mean square of the average baseline reaches~8 mK,approaching the theoretical sensitivity of an HⅠspectrum produced by FAST for an integration time of 335 minutes,i.e.,~6 m K.

Advances in Medical Treatment of Primary Aldosteronism

Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

Network pharmacology and molecular docking-based analyses to predict the potential mechanism of Huangqin decoction in treating colorectal cancer

BACKGROUND To analyze the potential action mechanism of Huangqin decoction(HQD)in colorectal cancer(CRC)treatment on the basis of network pharmacology and molecular docking.AIM To investigate the molecular mechanisms of HQD for CRC treatment by using network pharmacology and molecular docking.METHODS All HQD active ingredients were searched using the Systematic Pharmacology and Traditional Chinese Medicine Systems Pharmacology databases and the Bioinformatics Analysis Tool for Molecular Mechanisms in traditional Chinese medicine.Then,the targets of the active ingredients were screened.The abbreviations of protein targets were obtained from the UniProt database.A“drug–compound–target”network was constructed to screen for some main active ingredients.Some targets related to the therapeutic effect of CRC were obtained from the GeneCards,DisGeNET,Therapeutic Target Database,and Online Mendelian Inheritance in Man databases.The intersection of targets of Chinese herbs and CRC was taken.A Venn diagram was drawn to construct the intersection target interactions network by referring to the STRING database.Topological analysis of the protein interaction network was performed using Cytoscape 3.7.2 software to screen the core HQD targets for CRC.The core targets were imported into the DAVID 6.8 analysis website for gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses and visualization.Finally,molecular docking was performed using AutoDockTool and PyMOL for validation.RESULTS In total,280 potential drug-active ingredients were present in HQD,including 1474 targets of the drug-active ingredients.The main active ingredients identified were betulin,tetrahydropalmatine,and quercetin.In total,10249 CRC-related targets and 1014 drug-disease intersecting targets were identified,including 28 core targets of action such as Jun proto-oncogene,AP-1 transcription factor subunit,signal transducer and activator of transcription 3,tumor protein p53,vascular endothelial growth factor,and AKT serine/threonine kinase 1.The gene ontology enrichment functional analysis yielded 503 enrichment results,including 406 biological processes that were mainly related to the positive regulation of both gene expression and transcription and cellular response to hypoxia,etc.In total,38 cellular components were primarily related to polymer complexes,transcription factor complexes,and platelet alpha granule lumen.Then,59 molecular functions were closely related to the binding of enzymes,homologous proteins,and transcription factors.The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis yielded 139 enrichment results,involving epidermal growth factor receptor tyrosine kinase inhibitor resistance and HIF-1 and mitogen-activated protein kinase signaling pathways.CONCLUSION HQD can play a role in CRC treatment through the“multi-component-target–pathway”.The active ingredients betulin,tetrahydropalmatine,and quercetin may act on targets such as Jun proto-oncogene,AP-1 transcription factor subunit,signal transducer and activator of transcription 3,tumor protein p53,vascular endothelial growth factor,and AKT serine/threonine kinase 1,which in turn regulate HIF-1 and mitogen-activated protein kinase signaling pathways in CRC treatment.The molecular docking junction clarified that all four key target proteins could bind strongly to the main HQD active ingredients.This indicates that HQD could slow down CRC progression by modulating multiple targets and signaling pathways.

Autophagy and multidrug resistance in cancer

Multidrug resistance(MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence.Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.

Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer

BACKGROUND Carcinoembryonic antigen(CEA)is a commonly used biomarker in colorectal cancer.However,controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer.Here,we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level,which may better reflect the malignancy of rectal cancer.AIM To assess the prognostic impact of preoperative CEA/tumor size in rectal cancer.METHODS We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012.These patients were randomly divided into two cohorts for cross-validation:training cohort and validation cohort.The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model.Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size.The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data.Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size.The primary and secondary outcomes were overall survival(OS)and disease-free survival(DFS),respectively.RESULTS In all,556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort(2/3 of 556,n=371)and the validation cohort(1/3 of 556,n=185).The cutoff was 2.429 ng/mL per cm.Comparison of the baseline data showed that high CEA/tumor size was correlated with older age,high TNM stage,the presence of perineural invasion,high CEA,and high carbohydrate antigen 19-9(CA 19-9).Kaplan-Meier curves showed a manifest reduction in 5-year OS(training cohort:56.7%vs 81.1%,P<0.001;validation cohort:58.8%vs 85.6%,P<0.001)and DFS(training cohort:52.5%vs 71.9%,P=0.02;validation cohort:50.3%vs 79.3%,P=0.002)in the high CEA/tumor size group compared with the low CEA/tumor size group.Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS(training cohort:hazard ratio(HR)=2.18,95%confidence interval(CI):1.28-3.73,P=0.004;validation cohort:HR=4.83,95%CI:2.21-10.52,P<0.001)as well as DFS(training cohort:HR=1.47,95%CI:0.93-2.33,P=0.096;validation cohort:HR=2.61,95%CI:1.38-4.95,P=0.003).CONCLUSION Preoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer.Higher CEA/tumor size is associated with worse OS and DFS.

Laparoscopy-assisted transanal total mesorectal excision for lower rectal cancer:A feasible and innovative technique

BACKGROUND Transanal total mesorectal excision(taTME)is a new technique with many potential technical advantages.Laparoscopy-assisted taTME is a combination of transabdominal taTME and transluminal endoscopic surgery taTME.Laparoscopy-assisted taTME is a combination of techniques such as minimally invasive surgery,intersphincter-assisted resection,natural orifice extraction,ta minimally invasive surgery,and ultralow-level preservation of the anus.AIM To verify the feasibility and safety of an innovative technique of taTME for treatment of cancer located in the lower rectum.METHODS From January 2016 to March 2018,we attempted to perform laparoscopy-assisted taTME surgery in 24 patients with lower rectal cancer.RESULTS The new technique of laparoscopy-assisted taTME was successfully performed in all 24 patients.Mean operating time was 310.0 min and mean intraoperative blood loss was 69.1 mL.The mean time to passing of first flatus was 3.1 d,and mean postoperative hospital stay was 9.2 d.Two patients were given postoperative analgesics due to anal pain.Twenty-three patients were able to walk in first 2 d,and five patients had postoperative complications.CONCLUSION Laparoscopy-assisted taTME is suitable for selected patients with lower rectal cancer,and this technique is worthy of further recommendation.

Effect of proppant pumping schedule on the proppant placement for supercritical CO_(2) fracturing

Supercritical CO_(2)fracturing is a potential waterless fracturing technique which shows great merits in eliminating reservoir damage,improving shale gas recovery and storing CO_(2)underground.Deep insight into the proppant-transport behavior of CO_(2)is required to better apply this technique in the engineering field.In the present paper,we adopted a coupled Computational Fluid Dynamics and Discrete Element Method(CFD-DEM)approach to simulate the proppant transport in a fracking fracture with multiple perforation tunnels.Previous experiments were first simulated to benchmark the CFD-EDM approach,and then various pumping schedules and injection parameters(injection location,multi-concentration injection order,multi-density injection order and injection temperature)were investigated to determine the placement characteristics of proppant.Results indicate that the swirling vortex below the injection tunnels dominates the proppant diffusion in the fracture.The velocity of fluid flow across the proppant bank surface in multi-concentration injection shows a positive correlation with the proppant concentration.Injecting high-density proppant first can promote the transportation of low-density proppant injected later in the fracture to a certain extent.Decreasing the initial injection temperature of supercritical CO_(2)slurry helps enhance the particle-driving effect of fluid and improve the performance of supercritical CO_(2)in carrying proppant.

Immunopotentiating activities and TLR4/MAPK related molecular mechanisms research of Lycium barbarum polysaccharide

OBJECTIVE To observe the effect and molecular mechanisms of Lycium barbarum polysaccharide(LBP) and glycopeptides on T,B lymphocytes and macrophages.METHODS ~3H-TdR incorporation method was used to compare the effects of LBP and glycopeptides on the proliferation lymphocytes.Peritoneal macrophages induced by sodium thioglycolate were used to compare the effects of LBP and glycopeptides.T and B lymphocytes were purified by immunomagnetic beads method.Using antibody blocking methods screening polysaccharide activity related receptors.C3H/HeJ mice were further used to observe the activity of LBP.Biolayer interference method was used to observe the binding kinetics of LBP with TLR4 in vitro.TLR4 level was tested by flow cytometry.Western blotting was used to observe the phosphorylation of p-38,SAPK/JNK and ERK.RESULTS The monosaccharide compo.sition of LBP is rhamnose,arabinose and galactose,and does not contain amino acids.The mixed lymphocyte proliferation experiment showed that LBP had more obvious effect on the proliferation of B cells,and glycosides induced T cells proliferation was more obvious.On the purify lymphocytes,it was found that LBP-induced B cells proliferation requires the involvement of macrophages.Further research found that anti-TLR4 antibody had significant inhibitory effect on LBP-induced macrophage release of TNF-α and IL-1β but not the anti-CR3 treatment.C3 H/HeJ mice related results further demonstrated that TLR4 is necessary for LBP activity.Although biolayer interference showed no obvious binding of TLR4/MD2 with LBP,flow cytometry confirmed that LBP could increase TLR4 expression.Western Blot experiments showed that the effect of LBP on macrophage was related to its activation of p-38/MAPK pathway and inhibition of ERK/MAPK and JNK/MAPK pathways.CONCLUSION TLR4 is the activity related receptors of LBP.LBP cannot directly bind to TLR4/MD2 complex in vitro,but can increase TLR4 expression and activate macrophage p-38/MAPK signaling pathway,inhibiting ERK-MAPK and JNK-MAPK signaling pathways.

Non-monotonic influence of a magnetic field on the electrochemical behavior of Fe_(78)Si_9B_(13) glassy alloy in NaOH and NaCl solutions

The corrosion behavior and microstructure of Fe78Si9B13 glassy alloy in NaOH and NaCl solutions under a 0.02-T magnetic field were investigated through electrochemical testing and scanning electron microscopy （SEM）. The current-density prepeak （PP） in the anodic polarization curves in low-concentration NaOH solutions （classified as type I） tends to disappear when the NaOH concentration is increased to 0.4 mol/L and the magnetic field is applied. Under the magnetic field, the height of the second current-density peak is increased in low-concentration NaOH solutions （type I） but decreased in high-concentration NaOH solutions （type Ⅱ）. The non-monotonic effect of the magnetic field was similarly observed in the case of polarization curves of samples measured in NaCl solutions, Ring-like corroded patterns and round pits are easily formed under the magnetic field in NaOH and NaC1 solutions. These experimental results were discussed in terms of the magnetohydrodynamic （MHD） effect.

A 95 GHz methanol emission survey toward eight small supernova remnants

We report on a 95 GHz（80-71A＋） methanol（CH3OH） emission survey with the Purple Mountain Observatory Delingha 13.7 m telescope. Eight supernova remnants（SNRs） with angular size〈10′ were observed, but emission was only detected in three SNRs near the Galactic center（Sgr A East,G 0.1–0.1 and G 359.92–0.09）. CH3OH emission mainly surrounds the SNRs and can be decomposed into nine spatial peaks with the velocity range of eight peaks being（-30, 70） km s-1, and the other is（70, 120） km s-1. They are probably excited by interaction with these SNRs and adjacent molecular gas in the central molecular zone（CMZ）, although star formation may play an important role in exciting CH3OH emission in some regions of CMZ. We infer that tidal action is unlikely to be an excitation source for CH3OH emission.

HLA Class I Expressions on Peripheral Blood Mononuclear Cells in Colorectal Cancer Patients

Objective： To investigate the expression change of human leukocyte antigen （HLA） class I on human peripheral blood mononuclear ceils （PBMCs） at both mRNA and protein levels, and to evaluate its roles in the development of colorectal cancer （CRC）. Methods： In the present study, 50 patients with CRC, 35 patients with benign colorectal lesion and 42 healthy volunteers were enrolled. Expression levels of HLA class I mRNA and protein were determined using real-time quantitative reverse transcription PCR （RT-PCR） and flow cytometry analysis, respectively. Results： The expression levels of HLA class I mRNA and proteins were not influenced by age and gender. The relative ratios of HLA class I mRNA were 0.99±0.27 in healthy controls, 0.76±0.19 in benign patients, and 0.48±0.21 in CRC patients. Mean fluorescence intensities of HLA class I were 145.58±38.14 in healthy controls, 102.05±35.98 in benign patients and 87.44±34.01 in CRC patients. HLA class I on PBMCs was significantly down-regulated at both mRNA and protein levels in patients with stage III and IV CRC. CRC patients with lymph node metastasis also showed a decreased HLA class I expression at protein level. Conclusion： HLA class I expressions on PBMCs are associated with staging of CRC and lymph node metastasis. Monitoring the expression of HLA class I on PBMCs may provide useful information for diagnosis and metastasis judgement of CRC.

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

Drug resistance and pathogenic spectrum of patients coinfected with nontuberculous mycobacteria and human-immunodeficiency virus in Chengdu, China

Background:Human-immunodeficiency virus (HIV) infection is increasing worldwide and nontuberculous mycobacteria (NTM) is an established microbiologic cause of pulmonary disease,lymphadenitis,and disseminated disease in cases of advanced immune suppression.Data on patients coinfected with HIV and NTM are limited.Thus,this study aimed to analyze the clinical characteristics,drug resistance,and pathogen spectrum of patients coinfected with both HIV and NTM in the Chengdu area of China.Methods:Data of 59 patients coinfected with both HIV and NTM collected from the Public Health Clinical Center of Chengdu,between January 2014 and December 2018,were analyzed.NTM drug sensitivity testing was performed using the microporous plate ratio method.Data were analyzed using SPSS 19.0,and the change in drug resistance rate was analyzed using the chi-square (x2) test.Results:Seven species/complex of NTM were identified from patients coinfected with HIV and NTM in this study,with Mycobacterium avium-intracellulare complex (52.5%) and M.kansasii (27.1%) as the predominant species.Male patients were more affected 50/59 (84.7%);the mean age of the 59 cases was 45 years.The clinical characteristics mainly included anemia (86.4%),cough and expectoration (79.7%).The baseline CD4 count was <50 cells/μL (84.7%).Patients were mainly in advanced acquired immunodeficiency syndrome (AIDS) stage.Chest imaging mainly showed patchy shadows (42.4%) and nodules (32.2%),with various degrees of AIDS-defining diseases.The drug resistance of NTM was severe,and the rate of isoniazid resistance (100.0%) was the highest,followed by rifampicin (94.9%),streptomycin (94.9%),ofloxacin (93.2%),and others.Ethambutol (52.5%) and clarithromycin (33.9%) were relatively low.No significant difference was found in the drug resistance rate of NTM strain against nine antituberculosis drugs in 5 years (P > 0.05).Condusions:The immune level of patients coinfected with HIV and NTM is low in advanced AIDS stage;more male are affected in patients who are mainly infected with MAC and M.kansasii and with serious drug resistance,The drug resistance rate of ethambutol and clarithromycin is relatively low.

Evaluation of a new frequency-volume chart for children with primary monosymptomatic nocturnal enuresis:a prospective,comparative study

Introduction To improve compliance with voiding diaries in children with primary monosymptomatic nocturnal enuresis(PMNE),a new modified 3-day weekend frequency-volume chart(FVC)was designed,and the compliance and validity of this modified FVC was evaluated by comparing with the International Children's Continence Society(ICCS)recommended voiding diary.Methods A total of 1200 patients with PMNE were enrolled in the study from 13 centers in China and were randomly assigned to record this modified FVC or the ICCS-recommended voiding diary.The primary outcome measure was the compliance,assessed by comparing the completing index and the quality score of diaries between two groups.The secondary outcome measure was the validity,evaluated by comparing the constituent of subtypes,micturition parameters and response rate to desmopressin.Results Among the 1200 participants enrolled in the study,447 patients completed the ICCS-recommended voiding diary and 469 completed the modified diary.The diurnal completing index and the quality score of the modified FVC group were better than those of the ICCS group.In addition,there was no significant difference between these two groups in the subtype classification,or in the response rate to desmopressin.Conclusions The modified FVC could be applied to obtain the voiding characteristics of children with PMNE as the ICCS-recommended voiding diary does and offers a reasonable and better choice for children with PMNE from the unselected population in the future.