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Cancer treatment is a promising clinical application of cold atmospheric plasma due to its selectivity in killing cancer cells. Whether there are differences in selectively killing of canners among direct plasma treatment, plasma-activated media (PAM), and exogenous reactive oxygen and nitrogen species (RONS) solutions made by chemical methods is an important issue that needs to be addressed. In this study, human keratinocytes (HaCaT cells) and melanoma cells (A875) were chosen as in vitro models to compare the biological effects of direct plasma treatment, PAM, and exogenous long-lived RONS solutions on human nonmalignant and cancer cells. Cell viability assay and intracellular ROS measurement were performed on HaCaT cells and A875 cells after treatment. The concentrations of long-lived species in PAM were measured. It was found that PAM and exogenous RONS solutions exhibited more toxicity on normal HaCaT cells than A875 cells while direct plasma treatment can selectively kill A875 cells when the treatment time was well controlled. These results indicated that PAM treatment seems to have no obvious differences in terms of its selectivity in killing A875 cells compared to the exogenous RONS solutions. The biological effects of direct plasma treatment and PAM treatment are not similar in all cases.

This paper proposes an integrated multifunctional power converter topology, where a traction battery charger (TBC), an auxiliary battery charger (ABC), and a motor drive converter (MDC) merge into an effective system. Traction battery charging, auxiliary battery charging, and motor driving operation modes can be realized by sharing power components. For the battery charging mode, a single-phase power supply charges the traction battery, and the circuit is capable of power factor correction (PFC) and active power decoupling (APD) (G2V mode). For the purpose of enhancing its charging power, the traction battery can also be connected to a three-phase power supply. For the battery discharging mode, the traction battery can feed energy back to a single-phase grid or a three-phase grid (V2G mode). When necessary, the traction battery can charge an auxiliary battery through a DC–DC converter (T2A mode). In the motor driving mode, the energy of the traction battery is used to drive a motor (T2M mode). Each of the charging modes can be implemented under the galvanic isolated condition. Power relays are used to switch the operating modes of the proposed topology.

Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA has also been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According to recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, its impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.

Background Intraductal papillary mucinous neoplasms (IPMNs) are characterized by their abundant mucin production and malignant potential. IPMNs of the pancreas are mainly managed according to their radiographic indications, but this approach lacks accuracy with regard to IPMN grading. Therefore, serological biomarkers such as CA19-9 and CA125 (MUC16) should be employed to assist in predicting the invasiveness of IPMNs. Methods We investigated the preoperative serum levels of CA19-9, CA125 and CEA in 381 surgical patients with a definite pathological diagnosis of IPMN from July 2010 to December 2019 at the Shanghai Cancer Center. We calculated the Youden indices of each point on the receiver operating characteristic (ROC) curves to identify the most appropriate cut-off values of CA19-9, CA125 and CEA for recognizing malignant IPMNs. Serological biomarker differences were correlated with clinicopathological features of IPMNs, and diagnostic indices of different scenarios were calculated to find the optimum strategy. Results The malignant group had higher serum levels of CA19-9, CA125 and CEA. According to the ROC curves, the cut-off values of CA19-9, CA125 and CEA were readjusted to 38.3 U/ml, 13.4 U/ml and 5.3 μg/L. CA19-9 elevation was significantly associated with vascular invasion and perineural infiltration. CA125 showed good efficacy in predicting invasive IPMN in the CA19-9-negative subgroup. Conclusions Serological biomarkers are useful and sensitive indicators for recognizing invasive IPMNs. CA19-9 is the most important diagnostic index among all routinely measured serum biomarkers for differentiating malignant from benign IPMNs. CA19-9 should be combined with CA125 to enable more accurate predictions of IPMN malignancy.

To evaluate the clinical value of preoperative markers in predicting occult metastases in resectable pancreatic body and tail cancer judged by a recent multidetector computed tomography (MDCT) scan of the abdomen. The data from a retrospective collected database from 2010 to 2019 with 699 patients who had MDCT scan predicted resectable mass in pancreatic body and tail and were pathological confirmed as adenocarcinoma after surgery. Receiver operating characteristic (ROC) curve was plotted for serum CA19-9, CA125, CEA and tumor size measured by MDCT. The optimal cut-off point-related sensitivity and specificity were calculated, respectively. Occult metastases were found in 73 (73/699, 10.4%) pancreatic body and tail cancer patients underwent exploration. The area under curve (AUC) for CA19-9, CA125, CEA and tumor size were 0.624, 0.733, 0.561 and 0.697, respectively. The optimal cut-off for CA19-9, CA125 and tumor size is 226 U/ml, 22.1 U/ml and 3.3 cm, respectively. The sensitivity and specificity of CA19-9 for predicting occult metastases were 67.1% and 60.4%, 72.6% and 64.7% for CA125, 80.8% and 51.4% for tumor size. CA125 is superior to CA19-9 and tumor size for predicting occulting metastases in MDCT scan suggested resectable pancreatic body and tail cancer. The high level of CA125 (≥ 22.1 U/ml) is regarded as high risk for occulting metastases, and laparoscopy should be applied for these patients.

BackgroundGerminomas (IG) account for up to 50% of all intracranial germ cell tumours. These tumours are reputed to be more prevalent in Oriental populations in comparison to Western cohorts. Biological characteristics of IG in other ethnic groups are unknown. Singapore is a multi-ethnic country with diverse cultures. Owing to inter-racial heterogeneity, the authors hypothesize there are molecular differences between paediatric IG patients in our local population. The aims of this study are exploratory: firstly, to identify molecular characteristics in this tumour type and circulating CSF unique to different racial cohorts; and next, to corroborate our findings with published literature.MethodsThis is a single-institution, retrospective study of prospectively collected data. Inclusion criteria encompass all paediatric patients with histologically confirmed IG. Excess CSF and brain tumour tissues are collected for molecular analysis. Tumour tissues are subjected to a next generation sequencing (NGS) targeted panel forKIT and PDGRA. All CSF samples are profiled via a high-throughput miRNA multiplexed workflow. Results are then corroborated with existing literature and public databases.ResultsIn our cohort of 14 patients, there areKITexon variants in the tumour tissues and CSF miRNAs corroborative with published studies. Separately, there are alsoKITexon variants and miRNAs not previously highlighted in IG. A subgroup analysis demonstrates differential CSF miRNAs between Chinese and Malay IG patients.ConclusionThis is the first in-depth molecular study of a mixed ethnic population of paediatric IGs from a Southeast Asian cohort. Validation studies are required to assess the relevance of novel findings in our study.

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

With the advantages of less carbon dioxide emissions and high fuel efficiency, plug-in hybrid electrical vehicle (PHEV) is an attractive means of transportation. This article presents an electrified powertrain for PHEV containing switched reluctance generator (SRG), switched reluctance motor (SRM), and integrated power converters, which could achieve various driving and flexible on-board charging functions. The operation states of SRG and SRM with the integrated topology is analyzed. Five driving modes for PHEV are implemented and can be smoothly switched by controlling the front-end converter according to the load conditions. For the PHEV charging mode, a single-phase ac–dc rectifier is constituted by the windings and power converter of SRG with the capability of input power factor correction. The traction and auxiliary batteries chargers are formed by the windings and power converter of SRM. Three charging modes also are achieved and no complex control strategies are required to avoid the rotation of rotors. The three-phase 12/8 poles SRG and SRM experimental platform are built. The experiments are carried out to verify the effectiveness of proposed integrated powertrain and the corresponding control schemes.

There lacks an ideal model for accurately predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). This study aimed at developing a nomogram with high accuracy in predicting CR-POPF after PD. A total of 1182 patients undergoing PD in the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU, n = 762) and Fudan University Shanghai Cancer Center (FUSCC, n = 420) between January 2010 and May 2018 were enrolled. The patients from FAHSYSU were assigned as testing cohort, and those from FUSCC were used as external validation cohort. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors for CR-POPF. Nomogram was developed on the basis of significant predictors. The performance of nomogram was evaluated by area under receiver operating characteristic (ROC) curve (AUC), calibration curve, and decision curve analysis. In testing cohort, 87 out of 762 patients developed CR-POPF. Three predictors were significantly associated with CR-POPF, including body mass index ≥24.0 kg/m2, pancreatic duct diameter

Yitao Gong,1– 4,* Zhiyao Fan,1– 4,* Guopei Luo,1– 4,* Qiuyi Huang,1– 4 Yunzhen Qian,1– 4 He Cheng,1– 4 Kaizhou Jin,1– 4 Quanxing Ni,1– 4 Xianjun Yu,1– 4 Chen Liu1– 4 1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Shanghai Pancreatic Cancer Institute, Shanghai 200032, People’s Republic of China; 4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xianjun Yu; Chen LiuDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai 200032, People’s Republic of ChinaTel + 86 21-64175590 ext 1307Fax + 86 21-64031446Email yuxianjun@fudanpci.org; liuchen@fudanpci.orgPurpose: Pancreatic neuroendocrine tumours (panNETs) are rare tumours of pancreas. Lymphocyte subsets in the peripheral blood are reported to reflect tumour prognosis and progression. The objective of the study is to investigate the hypotheses that the levels of peripheral lymphocytes may reflect tumour progression and may predict the prognosis of pancreatic neuroendocrine tumours (panNETs).Patients and Methods: A retrospective cohort study consisting of 73 patients diagnosed with panNETs was conducted. Kaplan–Meier methods and Log rank tests were used to compare the survival rates, and a Cox regression model was used to perform multivariate analyses.Results: panNET patients with distant metastasis were associated with lower peripheral total T cell (p = 0.039) and CD4+ T cell (p = 0.006) counts. Lower peripheral B cells (p = 0.007) and higher peripheral NK cell (p = 0.001) counts indicated worse progression-free survival (PFS) in Log rank tests. In multivariate analyses, low B cell count (hazard ratio (HR): 6.769, 95% confidence interval (CI): 2.158 to 21.228, p = 0.001) and high NK cell count (HR: 3.715, 95% CI: 1.164 to 11.855, p = 0.027) were independent risk factors for progression. NK cells and B cells were also significantly associated with PFS following radical surgical resection.Conclusion: Peripheral total T cell and CD4+ T cell counts may reflect the distant metastasis status in panNET patients. The absolute count of peripheral B cells and NK cells may independently predict the progression of panNET patients, making them promising prognostic indicators and potential targets for treatment of panNETs.Keywords: pancreatic neuroendocrine tumours, panNETs, lymphocyte subsets, progression-free survival, B cells

Mounting evidence has suggested that acute pancreatitis (AP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but its role in survival in PDAC patients was rarely investigated. The objective was to investigate the association of a history of AP with survival among PDAC patients who underwent surgical resection.A retrospective cohort study comprising 632 patients who were diagnosed with resectable PDAC was conducted. Survival was evaluated by history of AP prior to a diagnosis of PDAC using Kaplan-Meier methods and log-rank tests. Multivariate analyses for mortality were estimated using the Cox proportional hazards model. Propensity score matching methods were used to balance the difference of clinical characteristics between patients with and without AP history.The log-rank tests showed that patients with a history of AP had a worse overall survival than those without a history of AP (p = 0.006). The multivariable-adjusted hazard ratio (HR) for mortality comparing participants with AP to those without AP was 1.808 (95% CI: 1.241-2.632, p = 0.002). Patients with a recent history of AP (2 years), rather than patients with a remote history of AP (≥2 years), were found to have significantly worse survival (p = 0.014) than those without a history of AP. After adjusted for PSM, history of AP remained an independent survival predictor of PDAC following surgical resection.Our findings indicate that a history of AP, especially a recent history of AP, is associated with poor survival among patients with resectable pancreatic ductal adenocarcinoma.

Diabetic neuropathic pain is one of the most common complications of diabetes. Mechanisms underlying the central modulation are still unclear. Here, we investigated the role of the neuron-restricted silencing factor (NRSF/REST) in diabetic-related neuropathic pain. Mechanical allodynia and thermal hyperalgesia were assessed to evaluate painful behaviors. Our results found that in the anterior cingulate cortex (ACC) of db/db mice, NRSF/REST levels increased significantly. Reduction of NRSF/REST improved the painful sensation. Meanwhile, in vitro study found that high glucose and high palmitic acid treatment induced elevation of NRSF/REST and its cofactors (mSin3A, CoREST and HDAC1), whereas downregulation of GluR2 and NMDAR2B. Knockdown of NRSF/REST could attenuate the LDH release and partially reversed the expression changes of HDAC1 and NMDAR2B. Our results suggested that the elevation of NRSF/REST in the ACC area of db/db mice is one of the key mediators of diabetic neuropathic pain.

Patients with distal (body/tail) pancreatic cancer have been found to present worse outcome than patients with head cancer, which is generally attributed to the great proportion of advanced stages for body/tail cancers upon detection. However, differences in prognosis between head and body/tail pancreatic cancers controlled by stage have not been analyzed in-depth. In this study, differences in prognosis between head and body/tail pancreatic cancers were examined using the Surveillance, Epidemiology, and End Results Program (SEER) (1973-2014 registry, 85,715 cases). We found that patients with body/tail pancreatic cancer had worse prognosis than patients with head cancer for all combined stages [adjusted hazard ratio (HR), 1.03, 95% confidence interval (CI), 1.00-1.05, P=0.025]. Compared with patients with head cancer, patients with body/tail cancer had lower mortality for stage I cancers (HR, 0.85, 95% CI, 0.76-0.94, P=0.001), no difference in mortality for stages II or III (stage II, HR, 1.00, 95% CI, 0.95-1.06, P=0.965; stage III, 0.97, 95% CI, 0.91-1.04, P=0.398), and higher mortality for stage IV (HR, 1.07, 95% CI, 1.04-1.10, P

Purpose Kras mutation and abnormal immune status are associated with pancreatic cancer development and progression. In this study, we evaluated the Kras mutation status in circulating tumor DNA and circulating T cell subsets in a cohort of advanced pancreatic cancer patients. Methods Samples were retrospectively obtained from a series of 210 pathological advanced pancreatic cancer patients between 2012 and 2014. The Kras mutation status was detected in cell‐free circulating tumor DNA (ctDNA) by ddPCR and circulating T cell subsets were analyzed by flow cytometry. Results Univariate analysis found that tumor node metastasis (TNM) stage, chemotherapy, circulating regulatory T cells, CA19‐9 levels, CA125 levels, and KrasG12D and KrasG12V mutations were significantly related to overall survival in advanced pancreatic cancer patients. Multivariate analysis identified that TNM stage (P = .03, HR:1.422), Tregs (P = .004, HR:1.522), CA19‐9 levels (P = .009, HR:1.488), KrasG12D mutation (P = .044, HR:1.353), and KrasG12V mutation (P = .001, HR:1.667) were independent prognostic markers. Furthermore, we found that KrasG12V mutation in ctDNA was correlated with high circulating proportion of Tregs, and patients with both KrasG12V mutation and high levels of Tregs were associated with extremely poor survival in advanced pancreatic cancer. Conclusion KrasG12V mutation was associated with high circulating regulatory T cell levels, and both of them predicted worse prognosis in advanced pancreatic cancer patients., KrasG12V mutation in ctDNA was correlated with high circulating proportion of Tregs. Patients with both KrasG12V mutation and high levels of Tregs were associated with extremely poor survival in advanced pancreatic cancer.

Background and Purpose Cerebral organoids (COs) have been used for studying brain development, neural disorders, and species‐specific drug pharmacology and toxicology, but the potential of COs transplantation therapy for brain injury remains to be answered. Methods With preparation of traumatic brain injury (TBI) model of motor dysfunction, COs at 55 and 85 days (55 and 85 d‐CO) were transplanted into damaged motor cortex separately to identify better transplantation donor for brain injury. Further, the feasibility, effectiveness, and underlying mechanism of COs transplantation therapy for brain injury were explored. Results 55 d‐CO was demonstrated as better transplantation donor than 85 d‐CO, evidenced by more neurogenesis and higher cell survival rate without aggravating apoptosis and inflammation after transplantation into damaged motor cortex. Cells from transplanted COs had the potential of multilinage differentiation to mimic in‐vivo brain cortical development, support region‐specific reconstruction of damaged motor cortex, form neurotransmitter‐related neurons, and migrate into different brain regions along corpus callosum. Moreover, COs transplantation upregulated hippocampal neural connection proteins and neurotrophic factors. Notably, COs transplantation improved neurological motor function and reduced brain damage. Conclusions This study revealed 55 d‐CO as better transplantation donor and demonstrated the feasibility and efficacy of COs transplantation in TBI, hoping to provide first‐hand preclinical evidence of COs transplantation for brain injury.

Pancreatic ductal adenocarcinoma is one of the deadliest malignant tumors, and many genes play important roles in its development. The hepatocyte nuclear factor-1a (HNF-1a) gene encodes HNF-1a, which is a transcriptional activator. HNF-1a regulates the tissue-specific expression of multiple genes, especially in pancreatic islet cells and in the liver. However, the role of the HNF-1a gene in the development of pancreatic cancer is still unclear. Here, we used immunohistochemical staining and real-time PCR to analyze HNF-1a expression in pancreatic cancer tissue. Stable cell lines with HNF-1a knockdown or overexpression were established to analyze the role of HNF-1a in pancreatic cancer cell proliferation and apoptosis by colony formation assay and flow cytometry. We also analyzed the L-type pyruvate kinase (PKLR) promoter sequence to identify the regulatory effect of HNF-1a on PKLR transcription and confirmed the HNF-1a binding site in the PKLR promoter via a chromatin immunoprecipitation assay. HNF-1a was found to be overexpressed in pancreatic cancer and promoted proliferation while inhibiting apoptosis in pancreatic cancer cells. PKLR was identified as the downstream target gene of HNF-1a and binding of HNF-1a at two sites in PKLR (-1931/-1926 and -966/-961) regulated PKLR transcription. In conclusion, HNF-1a is overexpressed in pancreatic cancer, and the transcription factor HNF-1a can promote pancreatic cancer growth and apoptosis resistance via its target gene PKLR.

Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl−/− (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl−/− mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl−/− mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl−/− mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.

Chest wall tumors are a relatively uncommon disease in clinical practice. Most of the published studies about chest wall tumors are usually single-center retrospective studies, involving few patients. Therefore, evidences regarding clinical conclusions about chest wall tumors are lacking, and some controversial issues have still to be agreed upon. In January 2019, 73 experts in thoracic surgery, plastic surgery, science, and engineering jointly released the Chinese Expert Consensus on Chest Wall Tumor Resection and Chest Wall Reconstruction (2018 edition). After that, numerous experts put forward new perspectives on some academic issues in this version of the consensus, pointing out the necessity to further discuss the points of contention. Thus, we conducted a survey through the administration of a questionnaire among 85 experts in the world. Consensus has been reached on some major points as follows. (I) Wide excision should be performed for desmoid tumor (DT) of chest wall. After excluding the distant metastasis by multi-disciplinary team, solitary sternal plasmacytoma can be treated with extensive resection and adjuvant radiotherapy. (II) Wide excision with above 2 cm margin distance should be attempted to obtain R0 resection margin for chest wall tumor unless the tumor involves vital organs or structures, including the great vessels, heart, trachea, joints, and spine. (III) For patients with chest wall tumors undergoing unplanned excision (UE) for the first time, it is necessary to carry out wide excision as soon as possible within 1-3 months following the previous surgery. (IV) Current Tumor Node Metastasis staging criteria (American Joint Committee on Cancer) of bone tumor and soft tissue sarcoma are not suitable for chest wall sarcomas. (V) It is necessary to use rigid implants for chest wall reconstruction once the maximum diameter of the chest wall defect exceeds 5 cm in adults and adolescents. (VI) For non-small cell lung cancer (NSCLC) invading the chest wall, wide excision with neoadjuvant and/or adjuvant therapy are recommended for patients with stage T3-4N0-1M0. As clear guidelines are lacking, these consensus statements on controversial issues on chest wall tumors and resection could possibly serve as further guidance in clinical practice during the upcoming years. ispartof: TRANSLATIONAL LUNG CANCER RESEARCH vol:10 issue:11 pages:4057-4083 ispartof: location:China status: published

Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment. Electronic supplementary material The online version of this article (10.1007/s12975-019-00773-0) contains supplementary material, which is available to authorized users.

Purpose The aim of this work was to evaluate the prognostic value of tumor length and diameter for patients with esophageal squamous cell cancer (ESCC) treated with definitive (chemo)radiotherapy to identify potential indicators for separate nonsurgical T staging, which are needed in clinical practice. Materials and Methods A total of 682 patients with ESCC who underwent definitive (chemo)radiotherapy between 2009 and 2015 were reviewed. Esophageal tumor length and diameter were determined by barium esophagography and computed tomography before treatment. Univariate and multivariate analyses were used to assess the impact of tumor length and diameter on long‐term overall survival (OS) and progression‐free survival (PFS). Propensity score matching (PSM) analysis was also used to control intergroup heterogeneity. Results The median OS and PFS were 22.2 months and 15.4 months, respectively, in the tumor length ≤ 6 cm group, which were significantly longer than those in the tumor length > 6 cm group (13.4 and 8.5 months, respectively). The median OS and PFS were 23.3 months and 15.9 months, respectively, in the tumor diameter ≤ 3.5 cm group, which were also significantly longer than those in the tumor diameter > 3.5 cm group (13.3 and 8.8 months, respectively). Similar results were found after PSM. Univariate and multivariate analyses showed that tumor length and diameter were both independent predictors of long‐term survival. Conclusion Tumor length and diameter are both independent prognostic factors for ESCC patients treated with definitive (chemo)radiotherapy. These two imaging parameters have the potential for development and use in nonsurgical T staging., Tumor length and diameter are both independent prognostic factors for esophageal squamous cell cancer patients treated with definitive (chemo)radiotherapy. These two imaging parameters have the potential to develop nonsurgical T staging.

Gemcitabine (GEM) is the standard chemotherapy drug for pancreatic cancer. Because of widespread drug resistance, the effect is limited. Therefore, it is urgent to reveal the underlying mechanism. Glycolysis is the most remarkable character of tumor aberrant metabolism, which plays vital roles on tumor drug resistance. Hexokinase 2 (HK2), as the key enzyme regulating the first‐step reaction of glycolysis, is overexpressed in many kinds of tumors. The putative role of HK2 resisting GEM therapy was investigated in this study. We found that HK2 was overexpressed in pancreatic cancer and associated with poor prognosis. HK2 knockdown decreased pancreatic cancer cell proliferation, migration viability, and promoted cell apoptosis in vitro. HK2 high expression in pancreatic cancer showed GEM resistance. HK2 knockdown increased the sensitivity of pancreatic cancer cell to GEM, the growth of xenograft tumor with HK2 knockdown was also further decreased with the GEM treatment compared with control in vivo. GEM‐resistant pancreatic cancer showed the increase of HK2 dimer rather than HK2 mRNA or protein. Our study revealed that the ROS derived from GEM promoted HK2 dimerization combining with voltage‐dependent anion channel, which resulted in the resistance to GEM. Meanwhile, our study established a new sight for GEM resistance in pancreatic cancer., Hexokinase 2 (HK2) overexpression promoted pancreatic cancer growth and gemcitabine (GEM) resistance. ROS mediated the HK2 dimerization induced by GEM.

Rare germline variations contribute to missing heritability of human complex diseases including cancers. Given their very low frequency, discovering and testing disease-causing rare germline variations remains challenging. The tag-SNP rs17728461 in 22q12.2 is highly associated with lung cancer risk. Here we identified a functional rare germline variation rs548071605 (A>G) in a p65-responsive enhancer located within 22q12.2. The enhancer significantly promoted lung cancer cell proliferation in vitro and in a xenograft mouse model by upregulating the leukemia inhibitory factor (LIF) gene via formation of a chromatin loop. Differential expression of LIF and its significant correlation with first progression survival time of patients further supported the lung cancer driving effects of the 22q-Enh enhancer. Importantly, the rare variation was harbored in the p65 binding sequence and dramatically increased the enhancer activity by increasing responsiveness of the enhancer to p65 and B-cell lymphoma 3 protein (BCL3), an oncoprotein that assisted the p65 binding. Our study revealed a regulatory rare germline variation with a potential lung cancer-driving role in the 22q12.2 risk region, providing intriguing clues for investigating the "missing heritability" of cancers, and also offered a useful experimental model for identify causal rare variations. This article is protected by copyright. All rights reserved.

Advances in liposomal formulation carrying multiple neuroprotective drugs, such as ceftriaxone (CEF), FK506, and nilotinib, can point toward an approach to obviating the difficulties in Parkinson's disease (PD) treatment. We prepared functionalized liposomes decorated with glutathione (GSH) to penetrate the blood-brain barrier (BBB) and cardiolipin (CL) to link up apoptotic neurons. Further, the effect of CEF-FK506-nilotinib-GSH-CL-liposomes on a PD model established by SH-SY5Y cells with 1-methyl-4-phenylpyridinium-induced neurotoxicity was investigated. An increment of the mole percentage of dihexadecyl phosphate and CL increased the particle size and the absolute value of ζ potential, improved the entrapment efficiency of CEF, FK506, and nilotinib, and reduced the drug-releasing rate. The toxicity studies revealed that CEF, FK506, and nilotinib-encapsulated liposomes could enhance the survival of SH-SY5Y cells. Western blot and immunofluorescence revealed that incorporation of CL in a lipid bilayer ameliorated the docking of CEF-FK506-nilotinib-GSH-CL-liposomes at α-synuclein (α-syn), indicating a better targeting capability of the liposomes to degenerated neurons. Treatment with CEF-FK506-nilotinib-GSH-CL-liposomes reduced the expression of Bax and α-syn and promoted the expression of Bcl-2, tyrosine hydroxylase, and the dopamine transporter. GSH- and CL-conjugated liposomes showed combined activity of targeting the BBB and α-syn and augmented the efficiency of the three drugs in rescuing dopaminergic neurons for neurodegenerative therapy.

Purpose The CRP/albumin (Alb) ratio, a recently reported predictor, has shown value for prognosis in various human cancers. This study aimed to determine the prognostic value of baseline CRP/Alb and to explore the relevance between postchemotherapy CRP/Alb and the efficacy of chemotherapy in advanced pancreatic cancer patients. Patients and methods Five hundred and ninety-five patients diagnosed with locally advanced or metastatic adenocarcinoma of the pancreas were enrolled. Cut-off Finder was used to calculate the best cut‑off value for baseline CRP/Alb. The primary endpoint was overall survival, which was analyzed by Kaplan-Meier survival curves with 95% confidence intervals. The log rank test and Cox proportional hazard model were used to evaluate the univariate and multivariate analyses. Results The optimal cut-off value for baseline CRP/Alb was determined to be 0.18. Both the baseline CRP/Alb (CRP/Alb≥0.18 vs. CRP/Alb

Adjuvant chemotherapy (AC) has been proven to yield an approximately 5% improvement in 5-year survival for patients with early-stage non-small-cell lung cancer. With such small gains in survival, the optimal treatment regimen remains to be established. Traditional Chinese medicine (TCM) treatment in combination with AC is frequently used in China. The efficacy and safety of this integrated approach should be scientifically evaluated. We present the rationale and study design of the Combined Adjuvant Chemotherapy and Traditional Chinese Medicine (ACTCM) trial (ChiCTR-IPR-16009062). The ACTCM trial, a prospective multicenter double-blind randomized placebo-controlled study, will recruit 312 patients overall from 5 clinical research centers in China. Within 6 weeks of the thoracic surgery, eligible participants with stages IB-IIIA non-small-cell lung cancer will be randomly assigned in a 1:1 ratio to either the treatment or control group. Patients in the treatment group will receive AC combined with TCM herbal treatment for 4 cycles, then TCM herbal plus injection treatment for 4 cycles. Patients in the control group will receive AC combined with TCM placebo for 4 cycles and then TCM placebo for 4 cycles. Treatment will be discontinued if disease progression or unacceptable toxicity occurs. The primary end point is 2-year disease-free survival. Secondary end points include disease-free survival and quality of life. Other end points are TCM symptoms, performance status, and safety of the regimens. Recruitment started in October 2016 and is ongoing.

Background Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. Methods Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973–2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. Results In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). Conclusions The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

Background The impact of sex on prognosis of patients with esophageal squamous cell cancer (ESCC) who underwent definitive radiotherapy remained unclear. The present study aimed to determine the impact of sex on the prognosis of patients with ESCC underwent definitive radiotherapy. Methods Between January 2009 and December 2015, patients with ESCC underwent definitive radiotherapy in Shantou Central Hospital were included in this study. The Progression-free survival (PFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. The PFS and OS were compared between female and male patients. The Cox regression model was used to identify prognostic factors. Propensity score-matched analysis was performed to balance baseline characteristics between female and male patients. Results A total of 683 ESCC patients treated with definitive radiotherapy were included, with 497 male and 186 female patients. In the whole cohort, female patients had a significantly longer median PFS (14.0 months vs 10.6 months, P = 0.0001, HR = 0.688, 95% CI, 0.567–0.836) and OS (20.8 months vs 15.9 months, P = 0.0005, HR = 0.702, 95% CI, 0.575–0.857). In the matched cohort, female patients still had a significantly longer median PFS (13.5 months vs 11.6 months) and OS (19.6 months vs 16.1 months). Multivariate analysis showed that sex was an independent prognostic factor for PFS (HR = 0.746, 95% CI, 0.611–0.910, P = 0.004) and OS (HR = 0.755, 95% CI, 0.615–0.926, P = 0.007). Conclusions This present study indicated that sex was an independent prognostic factor in Chinese patients with ESCC underwent definitive radiotherapy, with better survival outcome for women than men. Efforts should be made to investigate the underlying biological mechanism. Electronic supplementary material The online version of this article (10.1186/s13014-019-1278-0) contains supplementary material, which is available to authorized users.

Genetic alterations have been attributed to the abnormal immune microenvironment in cancer. However, the relationship between the KrasG12D mutation and regulatory T cells (Tregs) in pancreatic cancer remains unclear. In this study, we found that KrasG12D mutation status as determined by ddPCR correlated with high levels of Treg infiltration in resectable pancreatic cancer tissues. Compared to wild-type tumour cells, tumours cells with the KrasG12D mutation were associated with higher levels of Tregs, and knockout of the KrasG12D mutation reversed this effect. In addition, overexpression of the KrasG12D mutation in wild-type Kras tumour cells resulted in conversion of CD4+CD25− T cells into Tregs. We also found that in tumour cells, the KrasG12D mutation activated the MEK/ERK pathway, thereby up-regulating the levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which induced Treg conversion. In summary, KrasG12D mutation plays a critical role in Treg conversion and contributes to an immunosuppressive tumour microenvironment in pancreatic cancer. These results provide new insights into the relationship between gene mutation and immune escape.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers worldwide. Little progress has been made in recent years concerning its diagnosis and treatment. Genetic alterations can be found in approximately 97% of PDAC cases. Mutations in the KRAS gene, which encodes the KRAS protein that regulates cell proliferation, differentiation, and apoptosis via activation of downstream signal transduction pathways, occur most frequently. KRAS plays a pivotal role in modulating the tumor microenvironment in PDAC patients. Additionally, KRAS can regulate metabolic changes in PDAC cells in a variety of ways. Although previous studies have shown that KRAS mutation detection can be used for early diagnosis and to predict the prognosis of PDAC patients, and many paths have been proposed to suppress the effects of KRAS , there is still no single pathway that leads to effective treatment of KRAS -mutant PDAC. This review summarizes the role of KRAS mutation in PDAC and examines the association between KRAS mutation and clinical applications.

Background Carbohydrate antigen 19-9 (CA19-9) is the best-validated biomarker for pancreatic cancer. The National Comprehensive Cancer Network (NCCN) guideline asserts that “CA19-9 will be undetectable in Lewis antigen-negative individuals”. However, reports of CA19-9 secretion and its significance in Lewis (-) patients with pancreatic cancer have been inconsistent. This study was to examine serum CA19-9 levels in patients with pancreatic cancer according to Lewis status. Methods Patients with pancreatic cancer (1482 cases) were retrieved from a prospectively maintained database. Patients with benign pancreatic disease (210 cases) and normal subjects (315 cases) were used as controls. Lewis genotypes were examined by fucosyltransferase 3 (FUT3) sequencing. Results In patients with pancreatic cancer, 8.4% of subjects were Lewis (-), but only 41.9% of Lewis (-) subjects had CA19-9 values ≤ 2 U/mL. CA19-9 was even elevated (>37 U/mL) in 27.4% of Lewis (-) patients. The area under the receiver operating characteristic (ROC) curve for CA19-9 as a diagnostic biomarker was 0.842 in Lewis (-) patients with pancreatic cancer, which is closing to that of CA19-9 applied in all of patients with pancreatic cancer (0.898). Lewis (-) status was an independent prognostic factor for shorter survival in a multivariable analysis (hazard ratio (HR), 1.30, 95% confidence interval (CI), 1.03–1.64; P = 0.028). Conclusions Not all Lewis (-) patients with pancreatic cancer are non-secretors of CA19-9. Contrary to general understanding, CA19-9 can retain its utility as a biomarker in these patients in spite of Lewis (-) genotype.

Background The prognostic value of supra-clavicular lymph node (SCLN) metastases in esophageal cancer (EC) is still not clear. Method From January 2009 to December 2015, a survival analysis was performed to retrospectively identify the prognostic value of SCLN metastasis on survival on 751 patients with EC treated with definitive chemo-radiotherapy (dCRT). Results The median follow-up duration for living patients was 56.6 months. The median overall survival (OS) for all patients was 16.6 months. Patients with SCLN metastasis had a much poorer prognosis for OS (χ 2 = 17.342, P

N-n-Butyl haloperidol iodide (F(2)) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F(2) against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl(4)) or thioacetamide (TAA). The mice received F(2) (0.75, 1.5 or 3 mg·kg(−1)·d(−1), ip) for 4 weeks of fibrosis induction. We showed that F(2) administration dose-dependently ameliorated CCl(4)- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-β receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F(2) (0.1, 1, 10 μM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F(2) inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-β signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-β1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-β signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F(2) suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-β signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F(2) against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1. F(2) may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

Nowadays, the hospital layout in China is commonly characterized by a large number of crowds on each floor of the inpatient department, a large mobility of patients in and out of hospital, and a complex patient composition. Because of the special composition of crowd and the general particularity of behavior, patients not only have certain physical defects, but also bear greater psychological pressure than normal people. For example, some patients with cardiovascular disease would be nervous when they encounter sudden accidents, and they would not get help for a long time, which is more likely to lead to their aggravation of disease, or even a sudden death. It is assumed that most people will subconsciously show herd behavior when an accident occurs on the inpatient floor. Due to their physiological and psychological defects, patients are more likely to have herd behavior, especially some patients with poor ability of action are relatively weak in escape. Therefore, more professional medical staff are needed to help patients with dysfunction and need to assist in evacuation. In order to optimize the layout of the inpatient department, make the evacuation more smooth and efficient, reduce the overall evacuation time of the inpatient department, and improve the survival rate of patients, this paper mainly studies the single floor of the oncology department of a TCM hospital, draws up the evacuation stairs and fire elevator as the evacuation exit, and uses the Pathfinder model to construct the layout according to the particularity of the inpatient floor and finally obtains a general optimal layout.

Shengming Deng,1– 4,* Zhiyao Fan,1– 4,* Huanyu Xia,1– 4,* Yitao Gong,1– 4 Yunzhen Qian,1– 4 Qiuyi Huang,1– 4 He Cheng,1– 4 Kaizhou Jin,1– 4 Zhiwen Xiao,1– 4 Guopei Luo,1– 4 Xianjun Yu,1– 4 Chen Liu1– 4 1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Pancreatic Cancer Institute, Shanghai, People’s Republic of China; 4Pancreatic Cancer Institute, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen Liu; Xianjun YuShanghai Pancreatic Cancer Institute, 270 Dong an Road, Shanghai 200032, People’s Republic of ChinaTel/Fax +86-21-6403-1446Email liuchen@fudanpci.org; yuxianjun@fudanpci.orgBackground: The fibrinogen/albumin ratio (FAR) has been widely reported to be a possible biomarker for predicting prognosis in several types of tumors, but the prognostic value of the FAR in pancreatic neuroendocrine neoplasms (Pan-NENs) has not been systematically studied.Patients and Methods: In total, 324 patients with Pan-NENs were recruited. The patients were divided into 2 subgroups according to the FAR cutoff value, and clinicopathological characteristics of the 2 subgroups were compared. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The prognostic value of the FAR was analyzed in univariate and multivariate analyses.Results: The optimal cutoff value for the FAR was calculated to be 0.08 for OS. The patients with a FAR ≥ 0.08 had higher proportions of nonfunctioning tumors, Pan-NECs, grade 3 tumors, and stage IV tumors than those with a FAR < 0.08. In the univariate analysis, a FAR ≥ 0.08 was associated with poor OS (hazard ratio (HR) = 2.37, P < 0.001) and PFS (HR = 2.37, P < 0.001). In the multivariate analysis, a FAR ≥ 0.08 was an independent risk factor for poor OS (HR = 4.70, P < 0.001) and PFS (HR = 1.80, P = 0.006).Conclusion: The pretreatment FAR, which includes fibrinogen and albumin, was a feasible and predictive biomarker for prognosis in patients with Pan-NENs. An elevated FAR, based on a cutoff value of 0.08, was an independent risk factor for poor OS and PFS.Keywords: pancreatic neuroendocrine neoplasms, survival, fibrinogen/albumin ratio

Background: Pancreatic cancer is a highly fatal disease and is becoming an increasingly common cause of cancer mortality. The extent of pancreatoduodenectomy for pancreatic head cancer is still controversial, and more high-level clinical evidence is needed. We compared the outcomes of standard pancreatoduodenectomy (SPD) with those of radical pancreatoduodenectomy (RPD) with retroperitoneal nerve resection in pancreatic head cancer patients in this multicentre randomized controlled trial. Methods: RAPNER was open-label, multicentre randomised trial, patients aged 18–80 years with stage I or II pancreatic head cancer undergoing curative resection were enrolled at 6 centres from China. Patients were allocated (1:1) by use of a computer-based randomisation service to assigned to receive standard pancreatoduodenectomy (PD) or radical PD, with the latter followed by the combined dissection of additional lymph nodes (LNs), nerves and soft tissues 270° on the right side surrounding the superior mesenteric artery and celiac axis. This trial is registered with Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR-TRC-12002548. Findings: Between October 3, 2012, and February 15, 2017, 468 patients were enrolled; of these, 400 were randomly assigned to the RPD group (n=201) or the SPD group (n=199). The operation time was longer with RPD than with SPD, but the R1 resection rate was slightly higher in the SPD group (12·56%) than in the RPD group (8·46%). Both the total number of retrieved LNs and number of positive LNs were significantly higher in the RPD group (20 (7-63) and 1 (0-29)) than in the SPD group (15 (7-63) and 1 (0-11)). Both the morbidity and inpatient mortality rates were comparable between the two groups. The median overall survival (OS) of the RPD and SPD groups were 23·0 months and 20·2 months (p=0·100), and the disease-free survival (DFS) were 15·6 months and 13·5 months (p=0·060). In the subgroup with a preoperative CA19-9 level less than 200 U/ml, the median OS in the RPD group was 30·8 months, which was significantly longer than that in the SPD group (20·9 months; p=0·009), and the median DFS was significantly longer in the RPD group than in the SPD group (22·3 months vs. 15·0 months, p=0·002). Furthermore, clinical benefit could be found in the RPD group in the subgroup of well & moderate histological differentiation, preoperative CEA level less than 5·00 ng/ml, R0 resection and postoperative adjuvant chemotherapy based on DFS analysis. A multivariate Cox proportional hazards model showed that initial CA19-9≥200 U/ml, N1 stage and poor differentiation suggested poor OS. Radical resection achieved equivalent prognosis regardless of perineural invasion except for aortic nerve plexus invasion. The RPD group exhibited significantly lower locoregional and mesenteric LN recurrence rates but a higher peritoneal seeding frequency. The RPD group also exhibited significantly less back pain intensity 6 months after surgery than the SPD group. Interpretation: This study suggests that in pancreatic head cancer patients, RPD with retroperitoneal nerve resection does not provide a significant survival benefit compared with SPD. RPD can be performed safely, and be considered a treatment option with improving prognosis for patients with a low chance of systemic metastasis in pancreatic head cancer. Trial Registration: ChiCTR-TRC-12002548. Funding Statement: Sun Yat-sen University Clinical Research 5010 Program (Grant No. 2012007), China; National Natural Science Foundation of China (Grant No. 81871945). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This study was approved and overseen by the clinical ethics committee of each participating hospital.

Background Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which plays a pivotal role in the progression of pancreatic ductal adenocarcinoma (PDAC). Therefore, we investigated the prognostic significance of GFPT1 expression in patients with resectable PDAC. Methods We analyzed public datasets to compare GFPT1 expression in tumor tissues and normal/adjacent pancreatic tissues. We measured the relative GFPT1 expression of 134 resected PDAC specimens in our institution, using real-time polymerase chain reaction (PCR). Survival was compared between high and low GFPT1 expression groups using Kaplan-Meier curves and log-rank tests. Multivariate analyses were estimated using Cox regression and logistic regression models. Results GFPT1 is generally upregulated in PDAC tissues, according to the analysis of public datasets. The data from our institution shows that high GFPT1 expression was correlated with a high rate of lymph node (LN) metastasis (p = 0.038) and was an independent risk factor for LN metastasis (odds ratio (OR) = 3.14, 95% confidence interval (CI) = 1.42 to 6.90, P = 0.005). High GFPT1 expression was significantly associated with poor overall survival (OS; P = 0.019) in patients with resected PDAC. The multivariable-adjusted hazard ratio (HR) for mortality when comparing patients with high and low GFPT1 expression was 2.54 (95% CI = 1.35 to 4.79, P = 0.004). Conclusions GFPT1 is generally upregulated in PDAC tissue and is associated with a high risk of LN metastasis and an unfavorable outcome in patients with resectable PDAC, suggesting its crucial role in PDAC progression.

Objective: To investigate the effectiveness of pain coping skills training in pain, function, and psychological outcomes for patients with osteoarthritis, compared to the control group; and to compare the effectiveness of pain coping skills training between the intervention involving and without involving exercise. Data sources: PubMed, Embase, the Cochrane Library, PEDro, Clinical Trials, and the WHO Clinical Trials Registry Platform (to 30 September 2020). Review methods: To calculate the results, we used standardized mean difference, and mean difference for the outcomes of continuous variables, risk difference for the risk of adverse events. Heterogeneity was identified with I2 test, and publication bias was identified with Egger’s test. Results: A total of 1195 patients with osteoarthritis underwent ten trials were included. The intervention group had significant differences in pain (SMD = −0.18; 95% CI −0.29 to −0.06), function (SMD = −0.19; −0.30 to −0.07), coping attempts (SMD = 0.37; 0.24 to 0.49), pain catastrophizing (SMD = −0.16; −0.29 to −0.02), and self-efficacy (SMD = 0.27; 0.07 to 0.46) than the control group. Between-group differences measured by the McMaster Universities Osteoarthritis Index subscales of pain (MD = −0.62; −1.48 to 0.24) or function (MD = −3.01; −6.26 to 0.24) were not statistically significant and did not reach the minimal clinically important differences that have been established. Subgroup analyses revealed no significant subgroup differences. Besides, no specific intervention-related adverse events were identified. Conclusion: Our results supported the effectiveness and safety of pain coping skills training for managing osteoarthritis in pain, function, and psychological aspects. Besides, exercise could not add benefits when combined with pain coping skills training.

Psittacosis is a zoonotic disease caused by Chlamydia psittaci (C. psittaci), leading to high risk for animal industry and human health. Lack of reliable commercial kits and effective vaccines is hampering control of C. psittaci infection. Polymorphic outer membrane protein Gs (PmpGs) are enriched in diverse C. psittaci, and its role are unclear during C. psittaci infection. In the present study, pmp20G gene was cloned into pET-28a vector and then the constructed plasmid was transferred into Escherichia coli Rossetta (DE3). After denaturation and renaturation, the recombinant Pmp20G-N was identified by SDS-PAGE and Western blot. Afterwards Pmp20G-N was used as the coating antigen to develop an indirect ELISA (I-ELISA) assay. Both the specificity and sensitivity of Pmp20G-N ELISA were 100%, while the MOMP-ELISA had 93.65% sensitivity and 98.94% specificity, respectively. The concordance between MOMP-ELISA and Pmp20G-N ELISA assay was 98.1%. Hence, Pmp20G-N ELISA has the potential to be a diagnostic antigen for detection C. psittaci antibody. However, further studies are needed to be done for differentiating C. psittaci from Chlamydia spp. and other C.psittaci-specific serovars using Pmp20G-N ELISA.

Mucinous cystic neoplasms (MCNs) of the pancreas have malignant potential. Carbohydrate antigen 125 (CA125) is a common widely used biomarker for cancers. However, the role of CA125 in predicting the malignant change of MCNs is currently unidentified. Patients with resected and pathologically confirmed MCN were identified from a prospectively maintained database. The predictive role of serum CA125 in assessing malignant change of MCNs was analyzed and compared with serum carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). This study included 164 patients with MCN (low/moderate grade, 153 cases; high grade and invasive, 11 cases). The serum levels of CA125 in the high grade and invasive group (45.1±42.1 U/ml) was significantly higher than those in the low/moderate grade group (21.0±46.2 U/ml, P=0.006). The area under the receiver operating characteristic (ROC) curve of CA125 (0.75) for predicting malignancy of MCNs was higher than that of CA19-9 (0.68) or CEA (0.72). The prediction value of CA125 was improved when combined with CEA (CA125 alone, sensitivity 36.4%, specificity 90.6%, accuracy 86.6%; combined with CEA, sensitivity 45.5%, specificity 88.2%, accuracy 85.0%). It was concluded that serum CA125 shows value in predicting the malignant change of MCNs, especially when combined with serum CEA.

Introduction: Increasing evidence suggests that borderline and exercise pulmonary hypertension (PH), bPH and ePH respectively, are associated with increased mortality. bPH and ePH may represent early stages of PH. Micro-RNAs (miRNAs) have been shown to play a key role in the pathophysiology of PH. We sought to identify miRNA signatures for early detection of PH, bPH and ePH. Methods: 245 plasma samples were collected at rest from PH (mPAP >25 mmHg, n=75), bPH (mPAP 21-24 mmHg, n=27), ePH (mPAP 30mmHg with exercise, n=39) and non-PH dyspnea patients (DC, n=104)) and assayed for N-terminal pro b-type natriuretic peptide (NTproBNP) and 600 miRNAs. Samples were randomly partitioned into training and validation sets. MiRNA signatures were generated with or without NTproBNP from the training set for distinguishing DC from PH, bPH, “bPH+ePH”, and “PH+bPH+ePH” and tested on a naive (split-sample) validation set. Results: The average Area Under the Curve (AUC) for miRNA vs. NTproBNP was 0.71 vs. 0.59, 0.60 vs. 0.56, 0.75 vs. 0.70, and 0.74 vs. 0.81 for distinguishing “DC” from “bPH+ePH”, “bPH”, “PH+bPH+ePH”, and “PH”, respectively. Conclusion: miRNA signatures can discriminate early stage disease (bPH and ePH) from DC better than NTproBNP, suggesting that miRNA signatures are capable of identifying the pulmonary vascular disease phenotype before disease progression to PH with significant RV dysfunction.

Objectives Type 2 diabetes mellitus (T2DM) has been associated with several types of cancers, but the role of T2DM in pancreatic neuroendocrine tumors (pNETs) has not been systematically studied. Methods In this study, 299 patients with pNETs were recruited, and the clinicopathologic characteristics and prognosis of the diabetic and nondiabetic patients were compared. The association between metformin use and survival was assessed to examine whether metformin impacts the prognosis of pNETs patients. Results The prevalence of T2DM in the cohort was 20.7% (n = 62). The proportions of grade 3 tumors, distant metastases, and nerve invasion in pNET patients with T2DM were higher than those in patients without T2DM, and as a result, the survival was worse in patients with T2DM. After adjusting for the tumor stage, diabetic status was not associated with poor survival in the univariate analysis. The results of logistic regression showed that pNET patients with T2DM were at high risk for tumor metastasis (odds ratio [OR], 2.81; P = 0.001), nerve invasion (OR, 2.43; P = 0.029), and grade 3 tumors (OR, 4.97; P = 0.010). Conclusions Type 2 diabetes mellitus is associated with pNET metastasis and not an independent risk factor for poor prognosis in pNETs.

Carbohydrate antigen 19-9 (CA19-9) is the best validated biomarker and an indicator of aberrant glycosylation in pancreatic cancer. CA19-9 functions as a biomarker, predictor, and promoter in pancreatic cancer. As a biomarker, the sensitivity is approximately 80%, and the major challenges involve false positives in conditions of inflammation and nonpancreatic cancers and false negatives in Lewis-negative Individuals. Lewis antigen status should be determined when using CA19-9 as a biomarker. CA19-9 has screening potential when combined with symptoms and/or risk factors. As a predictor, CA19-9 could be used to assess stage, prognosis, resectability, recurrence, and therapeutic efficacy. Normal baseline levels of CA19-9 are associated with long-term survival. As a promoter, CA19-9 could be used to evaluate the biology of pancreatic cancer. CA19-9 can accelerate pancreatic cancer progression by glycosylating proteins, binding to E-selectin, strengthening angiogenesis, and mediating the immunological response. CA19-9 is an attractive therapeutic target for cancer, and strategies include therapeutic antibodies and vaccines, CA19-9-guided nanoparticles, and inhibition of CA19-9 biosynthesis.

Hyperglycaemia has been indicated as a pro-tumoural factor; however, the prognostic role of diabetes mellitus (DM) in pancreatic neuroendocrine tumours (panNETs) remains ambiguous, partly due to the effects of anti-diabetic drugs. We hypothesise that the blood sugar level per se affects the outcome of panNETs, and thus, we investigated the prognostic significance of the fasting blood glucose (FBG) level in resected panNET patients with no pre-existing DM. A retrospective cohort study comprising 201 patients with radically resected non-functional panNETs was conducted. A total of 164 patients without pre-existing DM were further studied. An FBG level greater than 5.6 mmol/L was defined as high (otherwise, normal). Survival was evaluated using Kaplan–Meier methods and log-rank tests. Multivariate analyses for survival were performed using the Cox regression model. High FBG levels were significantly associated with poor overall survival (OS; p = 0.019) and recurrence-free survival (RFS; p = 0.011) in resected patients with panNET who had no pre-existing DM. The multivariable-adjusted hazard ratios (HRs) for mortality and recurrence comparing patients with high and normal FBG levels were 12.19 (95% confidence interval (CI) = 1.15–128.78, p = 0.038) and 2.43 (95% CI = 1.03–5.72, p = 0.042), respectively. A pre-operative FBG level greater than 5.6 mmol/L is associated with poor OS and RFS metastasis for patients with panNET who undergo radical surgical resection.

Purpose To explore the clinical significance of perioperative CTCs counts, EMT-CTCs and CTC- white blood cells (WBCs) in renal cancer patients.Materials and Methods A total of 131 patients with renal cancer who underwent operation from the Second Affiliated Hospital of Xi’an Jiaotong University were enrolled. 20 patients with benign renal diseases were used as control. 5 mL Peripheral blood was extracted from 131 patients with renal cancer before operation and about 3 months after operation. Control patients took blood at the corresponding time. CanPatrol CTC detection technique was used to enrich and identify CTCs, EMT-CTCs and CTC-WBCs simultaneously.Results All patients enrolled were T1-3N0M0. 52 renal cancer patients received radical resection, while other 79 patients underwent nephron-sparing surgery. The positive rate of CTC, mesenchymal CTCs (MCTC) and CTC-WBC before surgery were 95.4% (125/131), 61.1% (80/131) and 11.5% (15/131), respectively. Preoperative total CTCs, mesenchymal CTCs or CTC-WBCs were poorly correlated with patients’ parameters. Preoperative CTC, MCTC or CTC-WBC showed little association with progression-free survival (PFS), while post-operation total CTC (≥ 6), positive mesenchymal CTCs and positive CTC-WBC significantly correlated with early recurrence and metastasis, and remained independent indicators for worse PFS. In addition, the elevation of CTC and MCTC after operation were also correlated with unfavourable PFS.Conclusions With the detection of CTCs in peripheral blood, better risk stratification of renal cancer patients might therefore help to identify a subset of patients that might have higher recurrent risk than the overall population of patients.

Carbohydrate antigen 19-9 (CA19-9) is the most important biomarker for pancreatic cancer. Approximately 5-10% of individuals are Lewis antigen negative with scarce secretion of CA19-9 and fucosylation deficiency. However, the characteristics of Lewis-negative pancreatic cancer are unidentified. Clinicopathological characteristics of 853 patients with pancreatic cancer were examined. Pancreatic cancer cell lines were sequenced for Lewis status. Morphological and molecular features of pancreatic cancer cells were compared. Orthotopic animal modes were established. Lewis-negative patients had poorer outcome (P

Highlights • Longitudinal sera were globally analyzed for identification of surgery-associated serum biomarker for the first time. • Autoantibody repertories are stable for a single individual at different time points but highly variable among individuals. • Surgery-associated serum biomarkers are prevalent in lung adenocarcinoma patients., Background Autoantibodies against tumor associated antigens are highly related to cancer progression. Autoantibodies could serve as indicators of tumor burden, and have the potential to monitor the response of treatment and tumor recurrence. However, how the autoantibody repertoire changes in response to cancer treatment are largely unknown. Methods Sera of five lung adenocarcinoma patients before and after surgery, were collected longitudinally. These sera were analyzed on a human proteome microarray of 20,240 recombinant proteins to acquire dynamic autoantibody repertoire in response to surgery, as well as to identify the antigens with decreased antibody response after tumor excision or surgery, named as surgery-associated antigens. The identified candidate antigens were then used to construct focused microarray and validated by longitudinal sera collected from a variety of time points of the same patient and a larger cohort of 45 sera from lung adenocarcinoma patients. Findings The autoantibody profiles are highly variable among patients. Meanwhile, the autoantibody profiles of the sera from the same patient were surprisingly stable for at least 3 months after surgery. Six surgery-associated antigens were identified and validated. All the five patients have at least one surgery-associated antigen, demonstrating this type of biomarkers is prevalent, while specific antigens are poorly shared among individuals. The prevalence of each antigen is 2%–14% according to the test with a larger cohort. Interpretation To our knowledge, this is the first study of dynamically profiling of autoantibody repertoires before/after surgery of cancer patients. The high prevalence of surgery-associated antigens implies the possible broad application for monitoring of tumor recurrence in population, while the low prevalence of specific antigens allows personalized medicine. After the accumulation and analysis of more longitudinal samples, the surgery-associated serum biomarkers, combined as a panel, may be applied to alarm the recurrence of tumor in a personalized manner. Funding Research supported by grants from National Key Research and Development Program of China Grant (No. 2016YFA0500600), National Natural Science Foundation of China (No. 31970130, 31600672, 31670831, and 31370813), Open Foundation of Key Laboratory of Systems Biomedicine (No. KLSB2017QN-01), Science and Technology Commission of Shanghai Municipality Medical Guidance Science &Technology Support Project (16411966100), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20172005), Shanghai Municipal Commission of Health and Family Planning Outstanding Academic Leaders Training Program (2017BR055) and National Natural Science Foundation of China (81871882).

Objectives We aimed to evaluate whether carboplatin has a comparable efficacy with cisplatin as part of weekly concurrent chemoradiotherapy for cervical cancer (Car-RT vs. Cis-RT). Methods A literature search was conducted and both prospective and retrospective studies that evaluated the efficacy of Car-RT for cervical cancer were included. The primary endpoints were complete response (CR) rate, progression-free survival (PFS)/disease-free survival (DFS), overall survival (OS), reported as odds ratios (ORs) and 95% confidence intervals (CIs). The estimated CR rate and survival of patients treated with Car-RT were pooled. Acute toxicity was also summarized. Results Twelve studies consisting of 1698 patients were eligible for meta-analysis. A lower CR rate (OR, 0.53; 95% CI, 0.34–0.82, I2 = 0%) and a trend toward poorer 3-year PFS/DFS (OR, 0.71; 95% CI, 0.49–1.02, I2 = 0%) and 3-year OS (OR, 0.70; 95% CI, 0.46–1.05, I2 = 36%) were found in Car-RT compared with Cis-RT. For the Car-RT groups, the pooled overall CR rate was 81% (95% CI 0.74–0.89). The pooled 3-year PFS/DFS rate was 64% (95% CI 0.52–0.78). The pooled 3-year OS rate was 73% (95% CI 0.62–0.87). Acute toxic events ≥ grade 3 were infrequent in the Car-RT groups. Conclusions Car-RT showed a poorer tumor response and a trend toward inferior survival compared with Cis-RT in the treatment of cervical cancer. However, this evidence was limited by the imbalance among studies. Due to the encouraging efficacy and low toxicity, carboplatin is a suitable concurrent agent for patients with contraindications to cisplatin.