Prophylactic drainage versus non-drainage following gastric cancer surgery: a meta-analysis of randomized controlled trials and observational studies.

BACKGROUND: The role of prophylactic drainage (PD) in gastrectomy for gastric cancer (GC) is not well-established. The purpose of this study is to compare the perioperative outcomes between the PD and non-drainage (ND) in GC patients undergoing gastrectomy. METHODS: A systematic review of electronic databases including PubMed, Embase, Web of Science, the Cochrane Library, and China National Knowledge Infrastructure was performed up to December 2022. All eligible randomized controlled trials (RCTs) and observational studies were included and meta-analyzed separately. The registration number of this protocol is PROSPERO CRD42022371102. RESULTS: Overall, 7 RCTs (783 patients) and 14 observational studies (4359 patients) were ultimately included. Data from RCTs indicated that patients in the ND group had a lower total complications rate (OR = 0.68; 95%CI:0.47-0.98; P = 0.04; I2 = 0%), earlier time to soft diet (MD = - 0.27; 95%CI: - 0.55 to 0.00; P = 0.05; I2 = 0%) and shorter length of hospital stay (MD = - 0.98; 95%CI: - 1.71 to - 0.26; P = 0.007; I2 = 40%). While other outcomes including anastomotic leakage, duodenal stump leakage, pancreatic leakage, intra-abdominal abscess, surgical-site infection, pulmonary infection, need for additional drainage, reoperation rate, readmission rate, and mortality were not significantly different between the two groups. Meta-analyses on observational studies showed good agreement with the pooled results from RCTs, with higher statistical power. CONCLUSION: The present meta-analysis suggests that routine use of PD may not be necessary and even harmful in GC patients following gastrectomy. However, well-designed RCTs with risk-stratified randomization are still needed to validate the results of our study.

Mutations of 1p genes do not consistently abrogate tumor suppressor functions in 1p-intact neuroblastoma.

BACKGROUND: Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may mimic the deleterious effects of chromosomal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. METHODS: We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. RESULTS: Among patients with adverse disease characteristics, those who additionally had 1p deletion had significantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bß and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P = 0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bß I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. CONCLUSIONS: Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.

Asymmetric Aza-Claisen Rearrangement between Enantioenriched α-Chiral Allylamines and Allenones.

An unprecedented asymmetric aza-Claisen rearrangement between enantioenriched α-chiral allylamines and allenones was found to proceed in the absence of catalysts and additives at room temperature. The rearrangement, followed by hydrolysis, provides convenient access to structurally diverse δ-chiral ß-diketones in good to excellent yields with excellent retention of enantiopurity. This protocol proved powerful for the construction of an all-carbon quaternary stereocenter with high enantiopurity.

Biological characteristics of renal cancer cells after CTP-mediated cancer suppressor gene NPRL2 protein treatment.

Nitrogen permease regulator like-2 (NPRL2) has been proved to be a useful suppressor gene in treating many cancers containing renal cancer based on experiments. Transgenic technology which transfect exogenous NPRL2 gene into cancer cell was used in these experiments. However, this technology has defects, such as gene mutation and loss. Cytoplasmic transduction peptide (CTP) can be used to avoid these defects because it can directly mediate proteins to penetrate cell membrane and specifically locate in cytoplasm. In this article, CTP was used to directly mediate NPRL2 protein into the renal cancer cell line 786-O, then cell proliferation was detected by the CCK-8 method, cell cycle and apoptosis were detected by flow cytometry, cell invasion and migration ability were detected by the Transwell assay. Bcl-xl, Cyt-c and caspase-3 were detected by real-time fluorescent quantitative PCR and Western blot for the analysis of the related mechanism. The result showed that CTP successfully mediated NPRL2 protein into renal cancer cells and the growth of cells was significantly inhibited. The mechanism may be NPRL2 down-regulating the expression of Bcl-xl which can up-regulate Cyt-c and further activate caspase-3, and then a cascade reaction is caused for cell apoptosis on the classic mitochondrial apoptosis pathway.

Exosomal mRNA Cargo are biomarkers of tumor and immune cell populations in pediatric osteosarcoma.

Osteosarcoma is the commonest malignant bone tumor of children and adolescents and is characterized by a high risk of recurrence despite multimodal therapy, especially in metastatic disease. This suggests the presence of clinically undetected cancer cells that persist, leading to cancer recurrence. We sought to evaluate the utility of peripheral blood exosomes as a more sensitive yet minimally invasive blood test that could aid in evaluating treatment response and surveillance for potential disease recurrence. We extracted exosomes from the blood of pediatric osteosarcoma patients at diagnosis (n=7) and after neoadjuvant chemotherapy (n=5 subset), as well as from age-matched cancer-free controls (n=3). We also obtained matched tumor biopsy samples (n=7) from the cases. Exosome isolation was verified by CD9 immunoblot and characterized on electron microscopy. Profiles of 780 cancer-related transcripts were analysed in mRNA from exosomes of osteosarcoma patients at diagnosis and control patients, matched post-chemotherapy samples, and matched primary tumor samples. Peripheral blood exosomes of osteosarcoma patients at diagnosis were significantly smaller than those of controls and overexpressed extracellular matrix protein gene THBS1 and B cell markers MS4A1 and TCL1A. Immunohistochemical staining of corresponding tumor samples verified the expression of THBS1 on tumor cells and osteoid matrix, and its persistence in a treatment-refractory patient, as well as the B cell origin of the latter. These hold potential as liquid biopsy biomarkers of disease burden and host immune response in osteosarcoma. Our findings suggest that exosomes may provide novel and clinically-important insights into the pathophysiology of cancers such as osteosarcoma.

Ratiometrically homogeneous electrochemical biosensor based on the signal amplified strategy of dual DNA nanomachines for microRNA analysis.

Precise and sensitive microRNA (miRNA) analysis is very significant for early disease diagnosis. In this work, a dual DNA nanomachines-based homogeneous electrochemical biosensor was constructed for the sensitively ratiometric detection of miRNA by a nicking enzyme (Nt.AlwI)-assisted cycling signal amplification strategy. The Co-based metal organic frameworks (Co-MOFs) and toluidine blue (TB) were employed as signal probes and internal reference probes, respectively. The introduction of internal reference probes can actually calibrate the interferent factors of the analytical system to improve the stability in detection procedure. In addition, with the help of the magnetic separation technique, the homogeneous electrochemical biosensor provides a more simpler way for the development of immobilization-free electrochemical miRNA biosensors, avoiding the complex modification procedure of traditional electrochemical biosensing interfaces. Consequently, taking advantages of this proposed dual DNA nanomachines-based homogeneous electrochemical biosensor, the highly sensitive and selective detection of miRNA-141 as model could be accomplished in ranging from 1 fM to 10 nM with detection limit of 0.46 fM. This strategy exhited good sensitivity and stability to integrate the nicking enzyme-powered dual DNA nanomachines with the ratiometric electrochemical output modes, which open new opportunities for the sensitive and reliable diagnosis of miRNA-related diseases.

Comparisons of perioperative and long-term outcomes of laparoscopic versus open gastrectomy for advanced gastric cancer after neoadjuvant therapy: an updated pooled analysis of eighteen studies.

BACKGROUND: Outcomes of laparoscopic surgery in advanced gastric cancer patients who received neoadjuvant therapy represent a controversial issue. We performed an updated meta-analysis to evaluate the perioperative and long-term survival outcomes of laparoscopic gastrectomy (LG) versus conventional open gastrectomy (OG) in this subset of patients. METHODS: Electronic databases including PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure were comprehensively searched up to May 2023. The short-term and long-term outcomes of LG versus OG in advanced gastric cancer patients undergoing neoadjuvant therapy were evaluated. Effect sizes with 95% confidence intervals were always assessed using random-effects model. The prospective protocol was registered with PROSPERO (CRD42022359126). RESULTS: Eighteen studies (2 randomized controlled trials and 16 cohort studies) involving 2096 patients were included. In total, 933 patients were treated with LG and 1163 patients were treated with OG. In perioperative outcomes, LG was associated with less estimated blood loss (MD = - 65.15; P < 0.0001), faster time to flatus (MD = - 0.56; P < 0.0001) and liquid intake (MD = - 0.42; P = 0.02), reduced hospital stay (MD = - 2.26; P < 0.0001), lower overall complication rate (OR = 0.70; P = 0.002) and lower minor complication rate (OR = 0.69; P = 0.006), while longer operative time (MD = 25.98; P < 0.0001). There were no significant differences between the two groups in terms of proximal margin, distal margin, R1/R2 resection rate, retrieved lymph nodes, time to remove gastric tube and drainage tube, major complications and other specific complications. In survival outcomes, LG and OG were not significantly different in overall survival, disease-free survival and recurrence-free survival. CONCLUSION: LG can be a safe and feasible technique for the treatment of advanced gastric cancer patients receiving neoadjuvant therapy. However, more high-quality randomized controlled trials are still needed to further validate the results of our study.

Clinical significance of the advanced lung cancer inflammation index in gastrointestinal cancer patients: a systematic review and meta-analysis.

Background: The advanced lung cancer inflammation index (ALI) has been identified as a scientific and clinical priority in multiple malignancies. The aim of this study is to investigate the value of the ALI before treatment in evaluating postoperative complications (POCs) and survival outcomes in patients with gastrointestinal (GI) cancer. Methods: Electronic databases including PubMed, Embase and Web of Science were comprehensively reviewed up to June 2022. The endpoints were POCs and survival outcomes. Subgroup analyses and sensitivity analyses were also performed. Results: Eleven studies including 4417 participants were included. A significant heterogeneity in the ALI cut-off value among studies was observed. Patients in the low ALI group showed increased incidence of POCs (OR=2.02; 95%CI:1.60-2.57; P<0.001; I2 = 0%). In addition, a low ALI was also significantly associated with worse overall survival (HR=1.96; 95%CI: 1.58-2.43; P<0.001; I2 = 64%), which remained consistent in all subgroups based on country, sample size, tumor site, tumor stage, selection method and Newcastle Ottawa Scale score. Moreover, patients in the low ALI group had an obviously decreased disease-free survival compared to these in the high ALI group (HR=1.47; 95%CI: 1.28-1.68; P<0.001; I2 = 0%). Conclusion: Based on existing evidence, the ALI could act as a valuable predictor of POCs and long-term outcomes in patients with GI cancer. However, the heterogeneity in the ALI cut-off value among studies should be considered when interpreting these findings.

Targeted Degradation of XIAP is Sufficient and Specific to Induce Apoptosis in MYCN-overexpressing High-risk Neuroblastoma.

XIAP, the most potent mammalian inhibitor of apoptosis protein (IAP), critically restricts developmental culling of sympathetic neuronal progenitors, and is correspondingly overexpressed in most MYCN-amplified neuroblastoma tumors. Because apoptosis-related protein in the TGFß signaling pathway (ARTS) is the only XIAP antagonist that directly binds and degrades XIAP, we evaluated the preclinical effectiveness and tolerability of XIAP antagonism as a novel targeting strategy for neuroblastoma. We found that antagonism of XIAP, but not other IAPs, triggered apoptotic death in neuroblastoma cells. XIAP silencing induced apoptosis while overexpression conferred protection from drug-induced apoptosis. From a screen of IAP inhibitors, first-in-class ARTS mimetic A4 was most effective against high-risk and high XIAP-expressing neuroblastoma cells, and least toxic toward normal liver- and bone marrow-derived cells, compared with pan-IAP antagonists. On target engagement assays and nuclear magnetic resonance spectroscopy, A4 was observed to degrade rather than inhibit XIAP, catalyzing rapid degradation of XIAP through the ubiquitin-proteasome pathway. In MYCN-amplified neuroblastoma patient-derived xenografts, A4 significantly prolonged survival as a single agent, and demonstrated synergism with standard-of-care agents to reduce their effective required doses 3- to 6-fold. Engagement and degradation of XIAP by ARTS mimetics is a novel targeting strategy for neuroblastoma that may be especially effective against MYCN-amplified disease with intrinsically high XIAP expression. First-in-class ARTS mimetic A4 demonstrates preclinical efficacy and warrants further development and study. SIGNIFICANCE: XIAP degradation is sufficient to kill MYCN-amplified neuroblastoma which overexpresses and relies on XIAP as a brake against cell death, without affecting normal cells.

Elemene-containing hyperthermic intraperitoneal chemotherapy combined with chemotherapy for elderly patients with peritoneal metastatic advanced gastric cancer.

BACKGROUND: Almost all elderly patients with peritoneal metastatic gastric cancer (PGC) are unlikely to tolerate cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and adjuvant chemotherapy. However, determining how to optimize the treatment strategy for such patients has always been a clinical problem. Both HIPEC and palliative adjuvant chemotherapy can benefit patients with PGC. Therefore, optimizing HIPEC and chemotherapy regimens has potential clinical value in reducing side effects, and improving treatment tolerance and clinical effectiveness. AIM: To explore the effect of HIPEC containing elemene, which is an anti-cancer component extracted in traditional Chinese herbal medicine, combined with reduced capecitabine and oxaliplatin (CapeOx) chemotherapy regimens, in elderly patients with PGC. METHODS: In the present study, 39 of 52 elderly PGC patients were included and assigned to different HIPEC treatment groups [lobaplatin group (group L) and mixed group (group M)] for analysis. Lobaplatin was used for all three HIPECs in group L. In group M, lobaplatin was used in the middle of the three HIPECs, and elemene was used for the first and third HIPEC. After HIPEC, patients received CapeOx chemotherapy. The incidence of complications (abdominal infection, lung infection, and urinary tract infection), myelosuppression, immune function (CD4/CD8 ratio), average length of hospital stay, and prognosis were compared between these two groups. RESULTS: There was no significant difference in the incidence of complications between the two groups during hospitalization (P > 0.05). Compared to patients in group M, patients in group L exhibited severe myelosuppression (P = 0.027) and increased length of hospital stay (P = 0.045). However, no overall survival benefit was observed in group M. Furthermore, the immune function of patients in group M was less affected (P < 0.001), when compared to that of patients in group L. The multivariate analysis suggested that the cycles of chemotherapy after perfusion significantly affected the prognosis of patients in both groups. CONCLUSION: Compared to the lobaplatin-based HIPEC regimen, the administration of elemene reduced the myelosuppression incidence in elderly PGC patients. The present study sheds light on the implementation of this therapeutic strategy for this set of patients.

Detection of asymptomatic recurrence following curative surgery improves survival in patients with gastric cancer: A systematic review and meta-analysis.

Background: To date, there is no evidence that intensive follow-up provides survival benefit in gastric cancer patients undergoing curative gastrectomy. The aim of this study is to investigate the efficacy of detection of asymptomatic recurrence using intensive surveillance strategy in long-term survival after curative gastric cancer surgery. Methods: A systematic review of electronic databases including PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure, Clinical Trials Registry and Google Scholar was performed up to April 2022. The primary outcomes were survival outcomes: overall survival, recurrence-free survival and post-recurrence survival. The secondary endpoints were clinicopathological features, recurrence patterns and treatment after recurrence. The registration number of this protocol is PROSPERO CRD42022327370. Results: A total of 11 studies including 1898 participants were included. In the pooled analysis, the detection of asymptomatic recurrence was significantly associated with an improved overall survival compared to patients showing symptoms of recurrence (HR=0.67; 95%CI: 0.57-0.79; P<0.001), which was primarily driven by the prolongation of post-recurrence survival (HR=0.51; 95%CI: 0.42-0.61; P<0.001), since there was no significant difference observed in recurrence-free survival (HR=1.12; 95%CI: 0.81-1.55; P=0.48) between the two groups. Meanwhile, male sex and advanced T stage were more frequently observed in the symptomatic recurrence group. Furthermore, patients in the symptomatic recurrence group had a higher proportion of peritoneal relapse but lower proportion of distant lymph node metastasis. Additionally, patients in the symptomatic recurrence group were less likely to receive surgery treatment and post-recurrence chemotherapy. Conclusion: The detection of asymptomatic recurrence using intensive follow-up was associated with an appreciable improvement in overall survival. However, more robust data from high-quality studies are still required to verify this issue. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327370, identifier CRD42022327370.

Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse.

Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes via NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.

Golgi Phosphoprotein 3 Represents a Novel Tumor Marker for Gastric and Colorectal Cancers.

BACKGROUND: Early diagnosis is very important for the clinical treatment of gastric cancer (GC) and colorectal cancer (CRC). We aimed to detect Golgi phosphoprotein 3 (GOLPH3) and evaluate its diagnostic value. MATERIALS AND METHODS: Serum concentrations of GOLPH3 were detected by ELISA in 136 CRC patients, 102 GC patients, and 50 healthy controls at the Second Affiliated Hospital of Fujian Medical University from June 2016 to December 2019. Serum concentrations of CEA and CA19-9 were detected by ECLIA. RESULTS: Serum concentrations of GOLPH3, CEA, and CA19-9 were higher in GC and CRC patients than in healthy controls (P < 0.001). Serum GOLPH3 concentrations were increased in GC and CRC patients with tumors greater than 5 cm, poor differentiation, greater depth of tumor invasion, and increased lymphatic and distant metastases (P < 0.05). In the GC and CRC groups, the AUCs of GOLPH3 were higher than those of CEA and CA19-9 (P < 0.05), while the AUCs of the marker combination were higher than those of GOLPH3 (P < 0.05), and postoperative serum GOLPH3 levels were lower than preoperative levels (P < 0.001). Serum GOLPH3 concentrations in CRC patients correlated positively with CEA and CA19-9 concentrations (P < 0.05). CONCLUSION: Serum GOLPH3 concentrations in GC and CRC patients are related to TNM stage. GOLPH3 may represent a novel biomarker for the diagnosis of GC and CRC. The combination of serum GOLPH3, CEA, and CA19-9 concentrations can improve diagnostic efficiency for GC and CRC. GOLPH3 is expected to become an indicator for the early diagnosis and evaluation of surgical effects.

Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma.

Neuroblastoma is the commonest extracranial pediatric malignancy. With few recurrent single nucleotide variations (SNVs), mutation-based precision oncology approaches have limited utility, but its frequent and heterogenous copy number variations (CNVs) could represent genomic dependencies that may be exploited for personalized therapy. Patient-derived cell culture (PDC) models can facilitate rapid testing of multiple agents to determine such individualized drug-responses. Thus, to study the relationship between individual genomic aberrations and therapeutic susceptibilities, we integrated comprehensive genomic profiling of neuroblastoma tumors with drug screening of corresponding PDCs against 418 targeted inhibitors. We quantified the strength of association between copy number and cytotoxicity, and validated significantly correlated gene-drug pairs in public data and using machine learning models. Somatic mutations were infrequent (3.1 per case), but copy number losses in 1p (31%) and 11q (38%), and gains in 17q (69%) were prevalent. Critically, in-vitro cytotoxicity significantly correlated only with CNVs, but not SNVs. Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Predictive Markov random field models constructed from CNVs alone recapitulated the true z-score-weighted associations, with the strongest gene-drug functional interactions in subnetworks involving PI3K and JAK-STAT pathways. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers.

mitoEnergetics and cancer cell fate.

The critical role of mitochondria in cell fate decisions has been well documented over the years. These observations have highlighted the way mitochondrial physiology controls cell survival and growth in the normal settings, the critical role of mitochondrial outer membrane permeabilization and altered mitoenergetics in cell death execution, and most importantly the association of altered mitochondrial metabolism with pathological states, in particular cancer. Reprogramming of cell metabolism, an invariable finding in cancer cells, is tightly linked to mitoenergetics as is evidenced by up-regulation of nutrient uptake and a pro-oxidant tilt in the intracellular milieu. The latter has also been demonstrated in oncogene-induced carcinogenesis models, notably as a functional outcome of Bcl-2 overexpression. Interestingly, even in that model, mitochondria appear to be the target as well. Thus the association of metabolic re-circuiting and altered mitoenergetics with the process of transformation has resulted in a paradigm shift in the way cancer development and progression is viewed today, which has tremendous implications for the development of novel and strategic therapeutic modalities.

Patients' and healthcare professionals' perspectives towards technology-assisted diabetes self-management education. A qualitative systematic review.

INTRODUCTION: Diabetes self-management education is a key aspect in the long-term management of type 2 diabetes. The patient and healthcare professional (HCP) perspective on the use of technology-assisted DSME has yet to be studied. Hence, the objective of this study was to better understand the factors that facilitate or hinder the adoptions of such education by adults with type 2 diabetes and their HCPs. METHODS: We systematically searched five databases (Medline, Embase, CINAHL, Web of Science Core Collection, and PsycINFO) until August 2019. The search included qualitative and mixed-method studies that reported the views of patients and HCPs regarding features, uses, and implementations of technology-assisted DSME. Data were synthesized through an inductive thematic analysis. RESULTS: A total of 13 articles were included, involving 242 patients, ranging from 18 to 81 years and included web-based, mobile application, digital versatile disc (DVD), virtual reality or telehealth interventions. Patients and HCPs had mixed views towards features of the technology-assisted interventions, with patients' personal qualities and HCPs' concerns affecting uses of the interventions. Patients generally preferred technologies that were easy to access, use, and apply and that had reliable information. Patients' ambitions motivated them, and personal attributes such as poor competence with technology, poor literacy, and language barriers acted as barriers. Patients especially liked the peer support that they received but did not like it when there was no regulation of advice on these platforms. HCPs believed that while the interventions were useful to patients, they faced difficulties with integration into their clinical workflows. CONCLUSION: This review explored the features of technology-assisted diabetes self-management education interventions that enhanced positive patient engagements and the negative aspects of both the platforms and the target groups. Technical support and training will be effective in managing these concerns and ensuring meaningful use of these platforms.

Destined to Die: Apoptosis and Pediatric Cancers.

Apoptosis (programmed cell death) is a systematic and coordinated cellular process that occurs in physiological and pathophysiological conditions. Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies. This review dissects the apoptosis pathways implicated in pediatric tumors. Understanding these pathways not only unraveled key molecules that may serve as potential targets for drug discovery, but also molecular nodes that integrate with other signaling networks involved in processes such as development. This review presents current knowledge of the complex regulatory system that governs apoptosis with respect to other processes in pediatric cancers, so that fresh insights may be derived regarding treatment resistance or for more effective treatment options.

GOLPH3 expression promotes the resistance of HT29 cells to 5­fluorouracil by activating multiple signaling pathways.

The novel proto­oncogene Golgi phosphoprotein (GOLPH)3 is overexpressed in a variety of tumor tissues and is associated with poor prognosis. The authors previously demonstrated that GOLPH3 gene is overexpressed in colorectal cancer tissues and promotes the proliferation of colonic cancer cells by activating the phosphatidylinositol­3­kinase/protein kinase B/the mammalian target of rapamycin and Wnt/ß­catenin signaling pathways. However, to the best of the authors' knowledge, if and how the GOLPH3 gene is involved in inducing resistance to colonic cancer chemotherapy has not been reported. In the present study, the association between the overexpression of the GOLPH3 gene and resistance of HT29 colonic cancer cells to 5­fluorouracil (5­FU) was investigated. Following confirmation of the effective silencing of the GOLPH3 gene, proliferation and apoptosis of colonic cancer cells were detected by MTT assay, colony formation assay and flow cytometry, and then the mechanism of GOLPH3­induced resistance to 5­FU chemotherapy in colonic cancer cells was investigated by western blotting. The results demonstrated that the expression of phosphorylated (p)­glycoprotein and GOLPH3 was increased in HT29 cells following treatment with 5­FU, which resulted in the development of drug resistance. Silencing GOLPH3 increased the sensitivity of HT29 cells to 5­FU, reduced their tumorigenicity and partly reversed their resistance to 5­FU. The expression of p­extracellular signal­regulated kinase (pERK)1/2 and ß­catenin was decreased, which indicated that its mechanism was associated with the activation of the mitogen­activated protein kinase/ERK and Wnt/ß­catenin signaling pathways. Therefore, GOLPH3 may be a potential, novel target for reversing chemotherapy resistance in colon cancer.

Silencing GOLPH3 gene expression reverses resistance to cisplatin in HT29 colon cancer cells via multiple signaling pathways.

Golgi phosphorylated protein (GOLPH)3 is overexpressed in colorectal cancer tissues and promotes the proliferation of colon cancer cells. A previous study by the authors demonstrated that GOLPH3 was associated with poor prognosis in colorectal cancer. However, the association between GOLPH3 gene overexpression and resistance to platinum-based drugs in colon cancer remains unknown. In the present study, the association between GOLPH3 overexpression and resistance of HT29 colon cancer cells to cisplatin and the mechanism underlying the development of chemoresistance were investigated. HT29 cells were divided into five groups. The expression of GOLPH3 mRNA was measured in the control and siRNA transfection groups. Reverse transcription-quantitative polymerase chain reaction analysis, cell proliferation, colony formation assay, tumor sphere formation and apoptosis (Annexin V) assays, western blotting and a nude mouse tumorigenicity assay were performed. HT29 cells were resistant to 10 µM cisplatin treatment, whereas the expression of GOLPH3, P-glycoprotein, phosphorylated extracellular signal-regulated kinase (pERK)1/2 and ß-catenin protein was significantly upregulated compared with the control group. With cisplatin treatment, silencing GOLPH3 gene expression downregulated the expression of these proteins, reduced cell proliferation and tumorigenicity, induced apoptosis and reversed the resistance of HT29 cells to cisplatin. In addition, the change in pERK1/2 and ß-catenin expression demonstrated that the mechanism of GOLPH3 overexpression involved in cisplatin resistance was associated with activation of the mitogen-activated protein kinase/ERK and Wnt/ß­catenin signaling pathways in HT29 cells. The tumorigenicity experiment in nude mice also demonstrated that silencing GOLPH3 expression increased the sensitivity of HT29 cells to cisplatin in vivo. Therefore, overexpression of GOLPH3 may be involved in the resistance of HT29 colon cancer cells to cisplatin chemotherapy by activating multiple cell signaling pathways.

KIF1Bß increases ROS to mediate apoptosis and reinforces its protein expression through O 2- in a positive feedback mechanism in neuroblastoma.

Relapse-prone, poor prognosis neuroblastoma is frequently characterized by deletion of chr1p36 where tumor suppressor gene KIF1Bß resides. Interestingly, many 1p36-positive patients failed to express KIF1Bß protein. Since altered cellular redox status has been reported to be involved in cell death and protein modification, we investigated the relationship between reactive oxygen species (ROS) and KIF1Bß. Here, we showed that wild-type KIF1Bß protein expression positively correlates with superoxide (O2-) and total ROS levels in neuroblastoma cells, unlike apoptotic loss-of-function KIF1Bß mutants. Overexpression of KIF1Bß apoptotic domain variants increases total ROS and, specifically O2-, whereas knockdown of endogenous KIF1Bß decreases ROS and O2-. Interestingly, O2- increases KIF1Bß protein expression, independent of the proteasomal degradation pathway. Scavenging O2- or ROS decreases KIF1Bß protein expression and subsequent apoptosis. Moreover, treatment with investigational redox compound Gliotoxin increases O2-, KIF1Bß protein expression, apoptosis and colony formation inhibition. Overall, our findings suggest that ROS and O2- may be important downstream effectors of KIF1Bß-mediated apoptosis. Subsequently, O2- produced may increase KIF1Bß protein expression in a positive feedback mechanism. Therefore, ROS and, specifically O2-, may be critical regulators of KIF1Bß-mediated apoptosis and its protein expression in neuroblastoma.