Research progress on dynamic monitoring of ctDNA and drug resistance related concomitant mutations in non-small cell lung cancer

Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer patients is dynamic.By dynamically monitoring the evolution of genes status,differential genes and concomitant genes related to progressive disease could be confirmed early,so as to achieve a more accurate and comprehensive insight of the whole process management of targeted therapy for lung cancer patients.Under the guidance of accurate genetic testing results,it is helpful to provide patients with more effective,long-term,and stable individualized targeted therapy.

Comprehensive and deep profiling of the plasma proteome with protein corona on zeolite NaY

Proteomic characterization of plasma is critical for the development of novel pharmacodynamic biomarkers.However,the vast dynamic range renders the profiling of proteomes extremely challenging.Here,we synthesized zeolite NaY and developed a simple and rapid method to achieve comprehensive and deep profiling of the plasma proteome using the plasma protein corona formed on zeolite NaY.Specifically,zeolite NaY and plasma were co-incubated to form plasma protein corona on zeolite NaY(NaY-PPC),followed by conventional protein identification using liquid chromatography-tandem mass spectrometry.NaY was able to significantly enhance the detection of low-abundance plasma proteins,minimizing the“masking”effect caused by high-abundance proteins.The relative abundance of middleand low-abundance proteins increased substantially from 2.54%to 54.41%,and the top 20 highabundance proteins decreased from 83.63%to 25.77%.Notably,our method can quantify approximately 4000 plasma proteins with sensitivity up to pg/mL,compared to only about 600 proteins identified from untreated plasma samples.A pilot study based on plasma samples from 30 lung adenocarcinoma patients and 15 healthy subjects demonstrated that our method could successfully distinguish between healthy and disease states.In summary,this work provides an advantageous tool for the exploration of plasma proteomics and its translational applications.

Inflammatory/immune-suppressive microenvironment characteristics of pancreatic cancer patients with Shi-Re syndrome identified by extracellular vesicle long RNA profiling

Background:Numerous long RNAs were detected in extracellular vesicles(EVs),some of which were related with the tissue origins and immune cell types.This study examined the molecular basis of different traditional Chinese medicine syndrome diagnoses(also called syndrome differentiation)in pancreatic ductal adenocarcinoma.Methods:128 pancreatic ductal adenocarcinoma patients with different syndrome diagnoses were retrospectively reviewed in this study.Long RNA sequencing was conducted to analyze the EV long RNA profile of plasma samples.Differentially regulated EV long RNAs were annotated and assessed for Gene Ontology pathway enrichment using DAVID.The online program xCell were used to perform the cell-type enrichment analysis.Results:An average of 15,000 annotated genes,mainly including messenger RNAs,were stably detected per sample.Different syndrome diagnoses exhibited unique EV mRNA expression profiles and therefore different enriched pathways.Gene Set Enrichment Analysis discovered transforming growth factor-βand kirsten rat sarcoma viral oncogene homolog signaling activation as the hallmarks of cancer with Shi-Re syndrome.Cell-type enrichment analysis also revealed a varied inflammation/immune cell type distribution among patients with or without Shi-Re diagnosis.Mast cells,platelets and Tregs were significantly enriched but basophils,common lymphoid progenitors,dendritic cells,and conventional dendritic cells were decreased in patients with Shi-Re diagnosis compared with patients without Shi-Re diagnosis.Conclusion:We identified the hallmarks of cancer with different syndrome diagnoses based on plasma EV long RNA sequencing.In particular,transforming growth factor-βand kirsten rat sarcoma viral oncogene homolog signaling activation were the hallmarks of Shi-Re syndrome,which contribute to shape an inflammatory/immune-suppressive tumor microenvironment in pancreatic ductal adenocarcinoma.

Effect of transcutaneous electrical acupoint stimulation combined with palonosetron on chemotherapy-induced nausea and vomiting: a single.blind,randomized, controlled trial

Background: Chemotherapy?induced nausea and vomiting adversely affects the quality of life of patients who receive chemotherapy via intravenous infusion or transcatheter arterial chemoembolization(TACE). This study aimed to investigate the clinical effects of transcutaneous electrical acupoint stimulation(TEAS) on nausea and vomiting after TACE.Methods: A total of 142 patients who received TACE with cisplatin for primary or metastatic liver cancer were assigned to the active?acupuncture(n = 72) or placebo?acupuncture(n Hegu(LI4), Neiguan(P6), an= 70) groups using a covariate?adaptive randomization at a ratio of 1:1. The acupointsd Zusanli(ST36) were stimulated twice daily for 6 days. The effects of TEAS on nausea and vomiting were assessed by using occurrence rate and severity of these symptoms. Anorexia scale and M. D. Anderson Symptom Inventory(MDASI) scores were secondary endpoints and were used to assess the effect of TEAS on patient appetite and quality of life. The safety of the treatments was also monitored.Results: Between the two groups, the differences in occurrence rates and severities of nausea and vomiting after TACE were not significant(all P > 0.05). From the second day after TACE, anorexia scores were significantly lower in the active?acupuncture group than in the placebo?acupuncture group and continued to decrease over time with treat?ment(all P values less than 0.01). On days 0, 1, and 2, the mean MDASI scores for the active?acupuncture group were slightly lower than those for the placebo?acupuncture group, but the differences were not statistically significant(all P > 0.05). No significant differences were found between the two groups in the occurrence rate of any adverse event(P > 0.05).Conclusion: TEAS appears to be a safe and effective therapy to relieve patients' gastrointestinal discomfort after chemotherapy.

Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review

The inflammatory process plays a central role in the development and progression of numerous pathological situations,such as inflammatory bowel disease(IBD),autoimmune and neurodegenerative diseases,metabolic syndrome,and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn's disease(CD) and ulcerative colitis(UC). Both pathological situations usually involve recurring or bloody diarrhea,pain,fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However,surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants,including vegetables and fruits which are the major dietary sources of these compounds for humans,together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids,evidencing a remarkable free-radical scavenging capacity. However,accumulating evidence suggests that flavonoids have many other biological properties,including anti-inflammatory,antiviral,anticancer,and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.

Efficacy of capecitabine and oxaliplatin regimen for extrahepatic metastasis of hepatocellular carcinoma following local treatments

AIM: To investigate the efficacy and safety of capecitabine and oxaliplatin (CapeOx) for extrahepatic metastasis after local treatment of hepatocellular carcinoma (HCC). METHODS: Thirty-two patients with extrahepatic metastasis of HCC after local treatment were prospectively enrolled. The CapeOx regimen consisted of capecitabine 1000 mg/m 2 taken orally twice daily on days 1-14, and oxaliplatin was administered at a total dose of 100 mg/m 2 on day 1. The treatment was repeated every 3 wk until disease progression or unaccetablle toxicity. Efficacy and safety were assessable for all enrolled patients. The primary objective of this study was to assess the overall response rate. The secondary objectives were to evaluate the overall survival (OS), the time to tumor progression (TTP) and the toxicity profile of the combined strategy. TTP and OS were assessed by the Kaplan-Meier method and differences between the curves were analyzed using the log-rank test. The statistical software SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, United States) was used for statistical analysis. All P values were 2-tailed, with statistical significance defined byP ≤ 0.05. RESULTS: Thirty-two patients were assessable for efficacy and toxicity. The median follow-up duration was 15 mo (range, 12-20 mo). At the cut-off date of March 31, 2012, 27 patients died due to tumor progression and one patient died of myocardial infarction. Four patients were still alive (three patients with disease progression). OR was 21.9% (n = 7), the stabilization rate was 40.6% (n = 13), and the disease control rate was 62.5%. The responses lasted from 4 to 19 mo (median, 6 mo). Median TTP was 4.2 mo (95%CI: 2.5-7.4), and the median OS time was 9.2 mo (95%CI: 6.5-17.8). The 1-year survival rate was 43.6% (95%CI: 29.0-66.0). In a multivariate analysis, OS was significantly longer in patients with a Child-Pugh class A compared with class B patients (P = 0.014), with a median OS of 10.1 mo vs 5.4 mo, and there were trends towards longer OS (P = 0.065) in patients without portal vein tumor thrombosis. There were no significant effects of age, gender, performance status, cirrhosis, metastatic sites, and level of alpha fetoprotein (AFP) or hepatitis B virus-DNA on OS. Among the 22 patients with elevated AFP levels at baseline (≥ 400 ng/mL), the level fell by more than 50% during treatment in 6 patients (27.3%). The most frequent treatment-related grade 3 to 4 toxicities included leucopenia/neutropenia, transient elevation of aminotransferases, handfoot syndrome and fatigue. CONCLUSION: CapeOx showed modest anti-tumor activity in metastatic HCC. However, the manageable toxicity profile and the encouraging disease control rate deserve further study for these patients.

shRNA-mediated Slc38a1 silencing inhibits migration, but not invasiveness of human pancreatic cancer cells

Objective：Early metastasis is a major biological feature of pancreatic cancer.The current study examined whether silencing Slc38a1,a gene involved in energy metabolism,using short hairpin RNA （shRNA） could inhibit the growth,migration,and invasiveness of pancreatic cancer cells.Methods：A series of Slc38a1 shRNAs were designed and cloned into the pGPU6/GFP/Neo vectors.An shRNA with the most efficacious inhibitory action on SCL38A1 expression （65％ inhibition） upon screening in DH5α bacteria was used to transfect SW1990 human pancreatic cancer cells.Cell growth,migration,and invasiveness were examined using cell counting kit-8,Boyden chamber without and with Matrigel,respectively.Results：Transfection of SW1990 cells with the SLCs38A1 shRNA significantly decreased the proliferation （P＜0.0001） and migratory potential （by 46.7％,P=0.0399） of the cancer cells.Invasiveness,however,was not affected.Conclusions：Inhibiting Slc38a1 using shRNA technology could decrease the growth and migration of representative pancreatic cancer cells.However,the fact that invasiveness was not affected suggested that SLC38A1 is unlikely to be responsible for early metastasis.

Primary adenosquamous carcinoma of the esophagus

AIM:To investigate the clinical characteristics,diagnosis,treatment,and prognosis of primary adenosquamous carcinoma(ASC)of the esophagus.METHODS:A total of 4015 patients with esophageal carcinoma underwent surgical resection between January 1995 and June 2012 at the Cancer Hospital of Shantou University Medical College.In 37 cases,the histological diagnosis was primary ASC.Clinical data were retrospectively analyzed from these 37 patients,who underwent transthoracic esophagectomy with lymphadenectomy.Theχ2or Fisher’s exact test was used to compare the clinicopathological features between patients with ASC and those with squamous cell carcinoma(SCC).The Kaplan-Meier and Log-Rank methods were used to estimate and compare survival rates.A Cox proportional hazard regression model was used to identify independent prognostic factors.RESULTS:Primary esophageal ASC accounted for0.92%of all primary esophageal carcinoma cases(37/4015).The clinical manifestations were identical to those of other types of esophageal cancer.All of the 24patients who underwent preoperative endoscopic biopsy were misdiagnosed with SCC.The median survival time(MST)was 21.0 mo(95%CI:12.6-29.4),and the1-,3-,and 5-year overall survival rates were 67.5%,29.4%,and 22.9%,respectively.In multivariate analysis,only adjuvant radiotherapy(HR=0.317,95%CI:0.114-0.885,P=0.028)was found to be an independent prognostic factor.The MST for ASC patients was significantly lower than that for SCC patients[21.0 mo(95%CI:12.6-29.4)vs 46.0 mo(95%CI:40.8-51.2),P=0.001].In subgroup analyses,the MST for ASC patients was similar to that for poorly differentiated SCC patients.CONCLUSION:Primary esophageal ASC is a rare disease that is prone to be misdiagnosed by endoscopic biopsy.The prognosis is poorer than esophageal SCC but similar to that for poorly differentiated SCC patients.

Clinicopathological characteristics and prognosis of 232 patients with poorly differentiated gastric neuroendocrine neoplasms

BACKGROUND Poorly differentiated gastric neuroendocrine neoplasms(PDGNENs)include gastric neuroendocrine carcinoma(NEC)and mixed adenoneuroendocrine carcinoma,which are highly malignant and rare tumors,and their incidence has increased over the past few decades.However,the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated.AIM To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs.METHODS The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively.RESULTS Among the 232 patients with PDGNENs,191(82.3%)were male,with an average age of 62.83±9.11 years.One hundred and thirteen(49.34%)of 229 patients had a stage III disease and 86(37.55%)had stage IV disease.Three(1.58%)of 190 patients had no clinical symptoms,while 187(98.42%)patients presented clinical symptoms.The tumors were mainly(89.17%)solitary and located in the upper third of the stomach(cardia and fundus of stomach:115/215,53.49%).Most lesions were ulcers(157/232,67.67%),with an average diameter of 4.66±2.77 cm.In terms of tumor invasion,the majority of tumors invaded the serosa(116/198,58.58%).The median survival time of the 232 patients was 13.50 mo(7,31 mo),and the overall 1-year,3-year,and 5-year survival rates were 49%,19%,and 5%,respectively.According to univariate analysis,tumor number,tumor diameter,gastric invasion status,American Joint Committee on Cancer(AJCC)stage,and distant metastasis status were prognostic factors for patients with PDGNENs.Multivariate analysis showed that tumor number,tumor diameter,AJCC stage,and distant metastasis status were independent prognostic factors for patients with PDGNENs.CONCLUSION The overall prognosis of patients with PDGNENs is poor.The outcomes of patients with a tumor diameter>5 cm,multiple tumors,and stage IV tumors are worse than those of other patients.

Clinicopathological characteristics and prognosis of 77 cases with type 3 gastric neuroendocrine tumours

BACKGROUND For the rarity of type 3 gastric neuroendocrine tumours(g-NETs),their clinicopathological characteristics and prognosis are not well illustrated.AIM To describe the clinicopathological features and outcome of type 3 g-NETs in the Chinese population.METHODS Based on the 2019 WHO pathological classification,the clinicopathological characteristics and prognosis of patients with type 3 g-NETs in China were retrospectively analysed.RESULTS A total of 77 patients(55.8%of females)with type 3 g-NETs were analysed,with a median age of 48 years(range:28-79 years).The tumours were mainly located in the gastric fundus/body(83.1%)and were mostly solitary(83.1%),with a median size of 1.5 cm(0.8-3.5 cm).Of these,there were 37 G1 tumours(48.1%),31 G2(40.3%),and 9 G3(11.7%).Ten(13.0%)and 24(31.2%)patients had lymph node and distant metastasis,respectively.In addition,type 3 g-NETs were heterogeneous.Compared with G1 NETs,G2 NETs had a higher lymph node metastasis rate,and G3 NETs had a higher distant metastasis rate.G1 and G2 NETs with stage I/II disease(33/68)received endoscopic treatment,and no tumour recurrence or tumour-related death was observed within a median follow-up time of 36 mo.Grade and distant metastasis were identified to be independent risk factors for prognosis in multivariable analysis.CONCLUSION Type 3 g-NETs are obviously heterogeneous,and the updated WHO 2019 pathological classification may be used to effectively evaluate their biological behaviors and prognosis.Also,endoscopic treatment should be considered for small(<2 cm),low grade,superficial tumours.

S-1 plus temozolomide as second-line treatment for neuroendocrine carcinoma of the breast:A case report

BACKGROUND Neuroendocrine carcinoma of the breast(NECB)is a rare type of malignant tumor.Due to the rarity of NECB,the relevant literature mostly comprises case reports.Available data on treatment options for NECB are very limited.CASE SUMMARY A 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography(CT)imaging.She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital.The patient initially presented with a painful lesion of the right breast.She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy.She was regularly followed every 3 mo after surgery.Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm×6.3 cm.Chest CT revealed masses in the anterior chest wall and lung.Core needle biopsy of the lesion revealed liver metastases of NECB.A bone scan showed right second anterior rib metastases.Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor.She stopped receiving endocrine therapy and then received etoposide and cisplatin(EP)chemotherapy as a firstline treatment regimen for six cycles at our hospital after liver,bone,and lung metastases.On October 2017,the chemotherapy regimen was changed to S-1(40mg twice daily,days 1-14)combined with temozolomide(200 mg once daily,days 10-14)(STEM)every 21 d as a second-line treatment regimen due to disease progression.Progression-free survival(PFS)and adverse effects after treatment were analyzed,and the efficacy of the STEM regimen was assessed using RECIST version 1.1.This patient achieved a partial response after using the STEM regimen,with a PFS of 23 mo.Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy.CONCLUSION This case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB.STEM is still highly effective in patients who show disease progression with the EP regimen.More evidence is needed to prove the validity of STEM.

Impact of cell death manipulation on the efficacy of photodynamic therapy-generated cancer vaccines

The main task of cancer vaccines is to deliver tumorspecifc antigens to antigen-presenting cells for immune recognition that can lead to potent and durable immune response against treated tumor. Using photodynamic therapy （PDT）-generated vaccines as an example of autologous whole-cell cancer vaccines, the importance is discussed of the expression of death-associated molecules on cancer vaccine cells. This aspect appears critical for the optimal capture of vaccine cells by host’s sentinel phagocytes in order that the tumor antigenic material is processed and presented for immune recognition and elimination of targeted malignancy. It is shown that changing death pattern of vaccine cells by agents modulating apoptosis, autophagy or necrosis can significantly alter the therapeutic impact of PDT-generated vaccines. Improved therapeutic effect was observed with inhibitors of necrosis/necroptosis using IM-54, necrostatin-1 or necrostatin-7, as well as with lethal autophagy inducer STF62247. In contrast, reduced vaccine potency was found in case of treating vaccine cells with apoptosis inhibitors or lethal autophagy inhibitor spautin-1. Therefore, PDT-generated cancer vaccine cells undergoing apoptosis or lethal autophagy are much more likely to produce therapeutic benefit than vaccine cells that are necrotic. These fndings warrant further detailed examination of the strategy using cell death modulating agents for the enhancement of the efficacy of cancer vaccines.

Increased macrophage inflammation response in pancreatic cancer patients with a diagnosis of Shi-Re

Objective:Traditional Chinese medicine(TCM)is a comprehensive system of medical practice.ZHENG(also known as syndrome differentiation)is the essence of TCM;however,its molecular basis remains unknown.This study evaluated the molecular basis of Shi-Re ZHENG in patients with pancreatic cancer.Methods:A total of 144 patients with pathologically-confirmed locally advanced or metastatic pancreatic ductal adenocarcinoma(PDAC)were retrospectively recruited between June 2015 and February 2016.Two cohorts,including the discovery cohort(n=60)and validation cohort(n=84),were included in this study.QPlex multiplex array and an enzyme-linked immunosorbent assay were used to evaluate serum inflammatory cytokine levels of pancreatic cancer patients with different TCM ZHENG.Receiver operating characteristic(ROC)curve analysis was used to evaluate the importance of the systemic inflammation response index(SIRI)in the detection of Shi-Re ZHENG.Results:Shi-Re ZHENG patients exhibited a different expression pattern of cytokines,including interleukin(IL)-6,IL-8,chemokine(C-C motif)ligand 18(CCL18),and C-reactive protein,than patients with other ZHENG diagnoses.M2-like macrophage-related inflammatory cytokines,such as IL-10,CCL17,and CCL22,were increased in Shi-Re ZHENG compared with non-Shi-Re ZHENG patients.The SIRI score was significantly increased in Shi-Re ZHENG compared with non-Shi-Re ZHENG patients(P<0.001).ROC analysis revealed that SIRI had a diagnostic value for Shi-Re ZHENG both in the discovery cohort(area under the curve[AUC]=0.833,95%confidence interval[CI]=0.709–0.957)and validation cohort(AUC=0.810,95%CI=0.716–0.905).Additionally,pancreatic cancer patients with Shi-Re ZHENG had a significantly shorter survival time than non-Shi-Re ZHENG(P=0.002).Conclusion:Shi-Re pancreatic cancer patients are characterized by an increased macrophage inflammation response,which may contribute to a poorer prognosis when compared to those with other ZHENG diagnoses.

A highly degradable Mg-Al-Ca alloy with superior anti-tumor efficacy

Molecule hydrogen(H_(2)) has been used to suppress tumor growth. To employ the H_(2) therapy, it is necessary to use a proper agent for continuous generation of H_(2). As a biodegradable metal, magnesium(Mg) generates H_(2) in an aqueous environment, but the H_(2) release rate is still too low. Here, we design a Mg-Al-Ca(AX) alloy that degrades very rapidly due to the presence of a secondary phase Al_(2)Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al_(2)Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al_(2)Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors.This work suggests that the H_(2) therapy using highly degradable Mg alloys may provide an effective cancer treatment.

The acceptance of traditional Chinese medicine among patients with Parkinson's disease:A hospital survey

Objective:The efficacy of medications for Parkinson’s disease(PD)tend to decline over time,which has a serious impact on patients’health and quality of life.To some extent,traditional Chinese medicine(TCM)can resolve the distressing problem of ineffective dopaminergic medication in PD patients.The purpose of this study was to investigate the attitude,acceptance,and independent predictors of TCM in PD patients admitted to the outpatient department of a tertiary hospital.Methods:A cross-sectional study of PD patients was conducted in the outpatient department of a large tertiary hospital in Beijing from March 2022 to June 2023.A self-report questionnaire was developed to investigate PD patients’attitudes and acceptance of TCM based on the questionnaire.Multivariate logistic regression analyses were also performed to further clarify the independent predictors influencing patients’adoption of TCM therapy.Results:A total of 397 patients completed the questionnaire,of which 78.09%were willing to be treated with TCM and 21.91%indicated that they were not willing to use TCM.Multifactorial logistic regression analysis showed that several parameters were correlated with a patient’s willingness to include TCM in their therapeutic regime.These included education level of a bachelor’s degree(odds ratio[OR)=8.554;95%confidence interval[CI]:4.112–17.794;P<0.001,vs junior high school education),living in an urban setting(OR=8.022;95%CI:4.577–14.060;P<0.001,vs rural),having other underlying diseases(OR=5.126;95%CI:3.078–8.537;P<0.001,vs none),having previously used TCM(OR=3.083;95%CI:1.852–5.134;P<0.001,vs not used),believing that TCM therapy is safe(OR=3.530;95%CI:1.446–8.616;P=0.006,vs not thought),believing that TCM therapy is effective(OR=3.859;95%CI:1.482–10.047;P=0.006,vs not understood),and being willing to discuss ongoing TCM therapy with an attending physician(OR=62.468;95%CI:30.350–128.574;P<0.001,vs not informed).Conclusion:This study initially investigated the acceptance,attitude,and independent predictors of TCM use among PD patients.To expand the prevalence of TCM use among patients with PD,we recommend to broadening the public outreach for TCM via contemporary means of Internet and broadcast communication,enhancing access to TCM services in rural communities,and strengthening the communication between doctors and patients.

Hsa-miR-202-3p,up-regulated in type 1 gastric neuroendocrine neoplasms,may target DUSP1

AIM To detect abnormal micro RNA(miRNA) expression in type 1 gastric neuroendocrine neoplasms(g-NENs) and find potential target genes.METHODS Tumour tissues from patients with type 1 g-NENs were used as experimental samples, and gastric mucosal tissues from the same patients obtained during gastroscopy review after several months were used as control samples. miRNA expression was examined with Agilent human miRNA chips and validated via RTPCR. Three types of target gene prediction software(TargetScan, PITA, and microRNAorg) were used to predict potential target genes of the differentially expressed miRNAs, and a dual-luciferase reporter assay system was used for verification. RESULTS Six miRNAs were significantly upregulated or downregulated in the tumours compared to the control samples. Among them, miR-202-3 p was extraordinarily upregulated. RT-PCR of seven sample sets confirmed that miR-202-3 p was upregulated in tumour tissues. In total, 215 target genes were predicted to be associated with miR-202-3 p. Among them, dual-specificity phosphatase 1(DUSP1) was reported to be closely related to tumour occurrence and development. The dual-luciferase reporter assay showed that miR-202-3 p directly regulated DUSP1 in 293 T cells. CONCLUSION miR-202-3 p is upregulated in type 1 g-NEN lesions and might play important roles in the pathogenesis of type 1 g-NENs by targeting DUSP1.

Clinical practice guidelines for the treatment of primary liver cancer with integrative traditional Chinese and Western medicine

Traditional Chinese medicine （TCM） is an important part of the treatment of primary liver cancer （PLC） in China; however, the current instructions for the integrative use of traditional Chinese and Western medicine for PLC are mostly based on expert opinion. There is no evidence-based guideline for clinical prac-tice in this field. Therefore, the Shanghai Association of Chinese Integrative Medicine has established a multidisciplinary working group to develop this guideline, which focuses on the most important questions about the use of TCM during PLC treatment. This guideline was developed following the method- ological process recommended by the World Health Organization Handbook for Guideline Development. Two rounds of questionnaire survey were performed to identify clinical questions; published evidence was searched; the Grading of Recommendations Assessment, Development and Evaluation approach was used to evaluate the body of evidence; and recommendations were formulated by combining the quality of evidence, patient preferences and values, and other risk factors. The guideline was written based on the Reporting Items for Practice Guidelines in Healthcare tool. This guideline contains 10 recommendations related to 8 questions, including recommendations for early treatment by TCM after surgery, TCM combined with transcatheter arterial chemoembolization for advanced PLC, TCM drugs for external use, and acupuncture and moxibustion therapy.

Advances in medical treatment for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PanNENs)are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years.For patients with locally advanced or distant metastatic PanNENs,systemic treatment options vary due to the different differentiations,grades and stages.The available options for systemic therapy include somatostatin analogs,molecularly targeted agents,cytotoxic chemotherapeutic agents,immune checkpoint inhibitors,and peptide receptor radionuclide therapy.In addition,the development of novel molecularly targeted agents is currently in progress.The sequence of selection between different chemotherapy regimens has been of great interest,and resistance to chemotherapeutic agents is the major limitation in their clinical application.Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents.Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors,and greater therapeutic efficacy may be achieved by emerging radiolabeled peptides.Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity,dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy.Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments.In the future,the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.

Lymph node ratio-based staging system for esophageal squamous cell carcinoma

AIM: To analyze a modified staging system utilizing lymph node ratio(LNR) in patients with esophageal squamous cell carcinoma(ESCC).METHODS: Clinical data of 2011 patients with ESCC who underwent surgical resection alone between January 1995 and June 2010 at the Cancer Hospital of Shantou University Medical College were reviewed. The LNR, or node ratio(Nr) was defined as the ratio of metastatic LNs ompared to the total number of resected LNs. Overall survival between groups was compared with the log-rank test. The cutoff point of LNR was established by grouping patients with 10% increment in Nr, and then combining the neighborhood survival curves using the log-rank test. A new TNr M staging system, was constructed by replacing the American Joint Committee on Cancer(AJCC) N categories with the Nr categories in the new TNM staging system. The time-dependent receiver operating characteristic curves were used to evaluate the predictive performance of the seventh edition AJCC staging system and the TNr M staging system.RESULTS: The median number of resected LNs was 12(range: 4-44), and 25% and 75% interquartilerangeswere8 and 16. Patients were classified into four Nr categories with distinctive survival differences(Nr0: LNR = 0; Nr1: 0% < LNR ≤ 10%; Nr2: 10% < LNR ≤ 20%; and Nr3: LNR > 20%). From N categories to Nr categories, 557 patients changed their LN stage. The median survival time(MST) for the four Nr categories(Nr0-Nr3) was 155.0 mo, 39.0 mo, 28.0 mo, and 19.0 mo, respectively, and the 5-year overall survival was 61.1%, 41.1%, 33.0%, and 22.9%, respectively(P < 0.001). Overall survival was significantly different for the AJCC N categories when patients were subgrouped into 15 or more vs fewer than 15 examined nodes, except for the N3 category(P = 0.292). However, overall survival was similar when the patients in all four Nr categories were subgrouped into 15 or more vs fewer than 15 nodes. Using the time-dependent receiver operating characteristic, we found that the Nr category and TNr M stage had higher accuracy in predicting survival than the AJCC N category and TNM stage. CONCLUSION: A staging system based on LNR may have better prognostic stratification of patients with ESCC than the current TNM system, especially for those undergoing limited lymphadenectomy.

Xijiao Dihuang Decoction combined with Yinqiao Powder reverses influenza virus-induced F-actin reorganization in PMVECs by inhibiting ERM phosphorylation

Objective:It has been documented that ezrin/radixin/moesin(ERM)phosphorylation by the p38 mitogen-activated protein kinase(MAPK),Rho/ROCK,and protein kinase C(PKC)pathways leads to filamentous actin(F-actin)reorganization and microvascular endothelial cell hyperpermeability.In this study,we investigated the effects of Xijiao Dihuang Decoction combined with Yinqiao Powder(XDY)on influenza virus(IV)-induced F-actin restructuring and ERM phosphorylation regulated by the Rho/Rho kinase 1(ROCK),p38 MAPK,and PKC signaling pathways in pulmonary microvascular endothelial cells(PMVECs).Methods:Serum containing XDY(XDY-CS;13.8 g/kg)was acquired using standard protocols for serum pharmacology.Primary PMVECs were obtained from male Wistar rats and cultured.After adsorption of IV A(multiplicity of infection,0.01)for 1 h,medium with 20%XDY-CS was added to the PMVECs.The distributions of F-actin and phosphorylated ERM were determined by confocal microscopy,and F-actin expression was measured by flow cytometry.The expression levels of ROCK1,phosphorylated myosin phosphatase target-subunit(p-MYPT),phosphorylated MAPK kinase,phosphorylated p38(p-p38),phosphorylated PKC(p-PKC),and phosphorylated ERM(p-ERM)were determined by western blotting.Results:F-actin reorganization in IV-infected PMVECs was reversed by XDY-CS treatment,which was accompanied by reduced p-ERM production.The p-ERM protein accumulated at plasma membrane of PMVECs infected with IV,which was also inhibited by XDY-CS treatment.