Identification of sudden cardiac death from human blood using ATR-FTIR spectroscopy and machine learning.

OBJECTIVE: The aim of this study is to identify a rapid, sensitive, and non-destructive auxiliary approach for postmortem diagnosis of SCD, addressing the challenges faced in forensic practice. METHODS: ATR-FTIR spectroscopy was employed to collect spectral features of blood samples from different cases, combined with pathological changes. Mixed datasets were analyzed using ANN, KNN, RF, and SVM algorithms. Evaluation metrics such as accuracy, precision, recall, F1-score and confusion matrix were used to select the optimal algorithm and construct the postmortem diagnosis model for SCD. RESULTS: A total of 77 cases were collected, including 43 cases in the SCD group and 34 cases in the non-SCD group. A total of 693 spectrogram were obtained. Compared to other algorithms, the SVM algorithm demonstrated the highest accuracy, reaching 95.83% based on spectral biomarkers. Furthermore, by combing spectral biomarkers with age, gender, and cardiac histopathological changes, the accuracy of the SVM model could get 100%. CONCLUSION: Integrating artificial intelligence technology, pathology, and physical chemistry analysis of blood components can serve as an effective auxiliary method for postmortem diagnosis of SCD.

Single-cell RNA-seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer.

Lymph node metastasis is the common metastasis route of gastric cancer. However, until now, heterogeneities of tumor cells and tumor microenvironment in primary tumors (PT) and metastatic lymph nodes (MLN) of gastric cancer (GC) remains uncharacterized. In our study, single cell RNA sequencing was performed on tissues from PT and MLN of gastric cancer. Trajectory analysis and function enrichment analyses were conducted to decode the underlying mechanisms contributing to LN metastasis of gastric cancer. Heterogeneous composition of immune cells and distinct intercellular interactions in PT and MLN were analyzed. Based on the generated single cell transcriptome profiles, dynamics of gene expressions in cancer cells between PT and MLN were characterized. Moreover, we reconstructed the developmental trajectory of GC cells' metastasis to LN and identified two subtypes of GC cells with distinct potentials of having malignant biological behaviors. We characterized the repression of neutrophil polarization associated genes, like LCN2, which would contribute to LN metastasis, and histochemistry experiments validated our findings. Additionally, heterogeneity in neutrophils, rather than macrophages, was characterized. Immune checkpoint associated interaction of SPP1 was found active in MLN. In conclusion, we decode the dynamics of tumor cells during LN metastasis in GC and to identify a subtype of GC cells with potentials of LN metastasis. Our data indicated that the disordering the neutrophils polarization and maturation and the activation of immune checkpoint SPP1 might contribute to LN metastasis in GC, providing a novel insight on the mechanism and potential therapeutic targets of LN metastasis in GC.

Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors.

BACKGROUND: Imatinib is the standard treatment for patients with gastrointestinal stromal tumors (GISTs), but there is significant variation in imatinib plasma trough concentrations (Cmin ) among patients. The imatinib Cmin distribution at different doses and the correlation of adverse reactions with Cmin in Chinese patients with GIST from a high-volume center were evaluated. METHODS: From July 1, 2017 to December 31, 2018, patients who were receiving imatinib treatment for GIST were prospectively enrolled. Steady-state blood samples were obtained from patients who had received same-dose imatinib treatment for ≥1 month with good compliance. Adverse reactions were recorded during regular follow-up, and blood samples were collected 24 ± 2 hours after dosing. Liquid chromatography-tandem mass spectrometry was used to measure drug concentrations. RESULTS: In total, 307 patients who received 367 dose levels were investigated. The imatinib Cmin was 1315 ± 716 ng/mL, 2117 ± 597 ng/mL, and 3844 ± 987 ng/mL in patients who were receiving imatinib 400 mg, 600 mg, and 800 mg daily, respectively. The Cmin was significantly correlated with periorbital and limb edema (P < .001), anemia (P < .001), and rash (P = .037). Nausea and vomiting, diarrhea, and conjunctival hemorrhage also were correlated, but not significantly. A much higher Cmin was observed with severe adverse reactions. There was no correlation between the imatinib Cmin and leukopenia, muscle cramps, or hepatobiliary dysfunction. CONCLUSIONS: In Chinese patients with GIST, the imatinib Cmin was higher than that reported for Western populations, especially at higher doses. The Cmin was correlated with periorbital and limb edema, anemia, and rash, suggesting that monitoring the imatinib Cmin should be considered when patients develop severe adverse reactions caused by excessive imatinib plasma concentrations.

Decreased MT1-MMP in gastric cancer suppressed cell migration and invasion via regulating MMPs and EMT.

Membrane type 1-matrix metalloproteinase (MT1-MMP) has been identified to play a significant role in several types of cancers, but little is known about the significance of MT1-MMP in gastric cancer patients. The purpose of this study is to investigate the involvement of MT1-MMP in tumor progression of gastric cancer. MT1-MMP expression levels were examined in gastric cancer tissues and cells, and normal gastric tissues and cells. The effects and molecular mechanisms of MT1-MMP expression on cell proliferation, migration, and invasion were also explored. In our results, MT1-MMP messenger RNA (mRNA) and protein expression levels were significantly increased in gastric cancer tissue. Moreover, the overexpression of MT1-MMP was positively associated with the status of clinical stage and lymph node metastasis through real-time PCR. Furthermore, knocking down MT1-MMP expression significantly suppressed the cell migration and invasion in vitro and regulated the expression of MMPs and epithelial-mesenchymal transition (EMT)-associated genes. In conclusions, our study demonstrates that MT1-MMP was overexpressed in gastric cancer tissue, and reduced expression of MT1-MMP suppressed cell migration, invasion, and through regulating the expression of MMPs and the process of EMT in gastric cancer.

Dual effects of atmospheric pressure plasma jet on skin wound healing of mice.

Cold plasma has become an attractive tool for promoting wound healing and treating skin diseases. This article presents an atmospheric pressure plasma jet (APPJ) generated in argon gas through dielectric barrier discharge, which was applied to superficial skin wounds in BALB/c mice. The mice (n = 50) were assigned randomly into five groups (named A, B, C, D, E) with 10 animals in each group. Natural wound healing was compared with stimulated wound healing treated daily with APPJ for different time spans (10, 20, 30, 40, and 50 seconds) on 14 consecutive days. APPJ emission spectra, morphological changes in animal wounds, and tissue histological parameters were analyzed. Statistical results revealed that wound size changed over the duration of the experimental period and there was a significant interaction between experimental day and group. Differences between group C and other groups at day 7 were statistically significant (p < 0.05). All groups had nearly achieved closure of the untreated control wounds at day 14. The wounds treated with APPJ for 10, 20, 30, and 40 seconds showed significantly enhanced daily improvement compared with the control and almost complete closure at day 12, 10, 7, and 13, respectively. The optimal results of epidermal cell regeneration, granulation tissue hyperplasia, and collagen deposition in histological aspect were observed at day 7. However, the wounds treated for 50 seconds were less well healed at day 14 than those of the control. It was concluded that appropriate doses of cold plasma could inactivate bacteria around the wound, activate fibroblast proliferation in wound tissue, and eventually promote wound healing. Whereas, over doses of plasma suppressed wound healing due to causing cell death by apoptosis or necrosis. Both positive and negative effects may be related to the existence of reactive oxygen and nitrogen species (ROS and RNS) in APPJ.

Age determination of Chrysomya megacephala (Diptera: Calliphoridae) using lifespan patterns, gene expression, and pteridine concentration under constant and variable temperatures.

Chrysomya megacephala (Fabricius, 1794) (Diptera: Calliphoridae), is a blowfly species widely studied in medical, veterinary, and entomological research. Our study examined the impact of constant (15, 20, 25, 30, and 35 °C) and variable (ranging from 21.0 to 25.4 °C, with an average of 23.31 °C) temperatures on the development and larval body length of C. megacephala. Additionally, we analyzed the age of the adult C. megacephala through pteridine content and related metabolic genes analysis. Our findings revealed three distinct growth patterns: isomorphen diagram, isomegalen diagram, and thermal accumulated models. At constant temperatures of 15, 20, 25, 30, and 35 °C, egg-hatching times were 44.5 ± 8.9, 26.7 ± 4.6, 12.6 ± 1.1, 11.0 ± 1.0, and 9.9 ± 1.9 h, respectively, while it was 15.3 ± 5.9 h at variable temperatures. The total development times from oviposition to adult eclosion in C. megacephala required 858.1 ± 69.2, 362.3 ± 5.9, 289.6 ± 17.8, 207.3 ± 9.3, and 184.7 ± 12.1 h at constant temperatures of 15, 20, 25, 30, and 35 °C, respectively. This duration was extended to 282.0 ± 64.1 h under variable temperatures. However, no significant differences were found in hatching times and the total developmental durations between 25 °C and variable temperatures. A developmental threshold temperature (D0) of 9.90 ± 0.77 °C and a thermal summation constant (K) of 4244.0 ± 347.0° hours were ascertained. Pteridine content patterns varied significantly across constant temperatures, but not between 25 °C and variable temperatures. Sex and temperature were identified as the primary factors influencing pteridine levels in the head of C. megacephala. Gene expression associated with pteridine metabolism decreased following adult eclosion, matching with increased pteridine concentration. Further investigations are needed to explore the use of pteridine cofactors for age-grading adult necrophagous flies. These findings provide valuable insights into the lifespan of C. megacephala, thereby offering valuable groundwork for forthcoming investigations and PMImin determination.

Age Determination of Chrysomya megacephala Pupae through Reflectance and Machine Learning Analysis.

Estimating the age of pupa during the development time of the blow fly Chrysomya megacephala (Diptera: Calliphoridae) is of forensic significance as it assists in determining the time of colonization (TOC), which could help to determine the postmortem interval (PMI). However, establishing an objective, accurate, and efficient method for pupa age inference is still a leading matter of concern among forensic entomologists. In this study, we utilized hyperspectral imaging (HSI) technology to analyze the reflectance changes of pupa development under different temperatures (15 °C, 20 °C, 25 °C, and 30 °C). The spectrograms showed a downtrend under all temperatures. We used PCA to reduce the dimensionality of the spectral data, and then machine learning models (RF, SVR-RBF, SVR-POLY, XGBR, and Lasso) were built. RF, SVR with RBF kernel, and XGBR could show promise in accurate developmental time estimation using accumulated degree days. Among these, the XGBR model consistently exhibited the most minor errors, ranging between 3.9156 and 7.3951 (MAE). This study has identified the value of further refinement of HSI in forensic applications involving entomological specimens, and identified the considerable potential of HSI in forensic practice.

Analysis of the Influence of Changing and Fixed Temperatures on the Growth and Pteridine Content in the Head of Adults Sarcophaga crassipalpis (Diptera: Sarcophagidae).

Flesh flies (Diptera: Sarcophagidae) are regarded as significant in medical and veterinary entomology, and their development models can be utilized as considerable markers to ascertain the minimum postmortem interval (PMImin). In this research, we explored the growth cycle and larval body length of Sarcophaga crassipalpis Macquart 1839 (Diptera: Sarcophagidae) reared under variable temperatures ranging from 15.7 to 31.1 °C, with an average of 24.55 °C and relative humidity ranges from 31.4 to 82.8% and at six fixed temperatures of 15, 20, 25, 30, 32, and then 35 °C. Moreover, pteridine from the head was used to assess adult age grading. Our results allowed us to provide three development models: the isomorphen chart, the isomegalen chart, and the thermal summation models. The time taken for S. crassipalpis to complete its development from larviposition to adult emergence at constant temperatures of 15, 20, 25, 30, 32, and 35 °C was 1256.3 ± 124.2, 698.6 ± 15.1, 481.8 ± 35.7, 366.0 ± 13.5, and 295.8 ± 20.5 h, respectively, except 35 °C, where all pupae were unable to attain adulthood. They lasted 485.8 ± 5.4 h under variable temperatures. The minimum developmental limit (D0) temperature and the thermal summation constant (K) of S. crassipalpis were 9.31 ± 0.55 °C and 7290.0 ± 388.4 degree hours, respectively. The increase in pteridine content exhibited variations across different temperatures. There was quite a considerable distinction in the pteridine contents of male and female S. crassipalpis at 15 °C (p = 0.0075) and 25 °C (p = 0.0213). At 32 °C and variable temperatures, the pteridine content between female and male S. crassipalpis was not statistically divergent. However, temperature and gender remain the main factors influencing the pteridine content in the head of S. crassipalpis. We aim to provide detailed developmental data on S. crassipalpis that can be used as a valuable resource for future research and PMI estimation.

High Expression of ATP6V1C2 Predicts Unfavorable Overall Survival in Patients With Colon Adenocarcinoma.

Aims: Colon adenocarcinoma (COAD) is responsible for 90% of all colorectal cancer cases and is one of the most common causes of cancer-related deaths worldwide. ATP6V1s (cytosolic V1 domain of vacuolar adenosine triphosphatase) participate in the biological process of transporting hydrogen ions and are implicated in tumor growth and metastasis. ATP6V1C2 as a family member has been documented to associate with esophageal carcinoma and renal clear cell carcinoma, while its roles in COAD remain elusive. Methods: The expression status, potential molecular mechanism, and prognostic value of ATP6V1C2 in COAD were investigated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. In addition, its biological roles in COAD were explored through in vitro studies. Results: ATP6V1C2 showed a significantly higher expression level in COAD compared with matched non-cancerous tissues. High expression of ATP6V1C2 predicted a shorter overall survival both in TCGA and GEO COAD datasets, and ATP6V1C2 was identified as an independent factor associated with overall survival in COAD. Bioinformatic analyses showed that high expression of ATP6V1C2 was associated with high epithelial-mesenchymal transition (EMT) score and Wnt signaling pathway was significantly enriched from differentially expressed genes between ATP6V1C2-high and -low group. We also found that high expression of ATP6V1C2 could decrease pathway activity of CD8 T effector implicated in tumor microenvironment (TME). In vitro study revealed that ATP6V1C2 knockdown resulted in aberrant expression of Wnt- and EMT-related genes and inhibited COAD cell proliferation and growth. Conclusion: This is the first study to reveal the molecular functions of ATP6V1C2 in COAD. Our study suggests that overexpressed ATP6V1C2 might promote EMT by activating Wnt signaling pathway, resulting in cancer metastasis and poor prognosis. This study paves the way for understanding potential molecular mechanisms and therapeutic perspectives in COAD.

Combination of Type I and II tyrosine kinase inhibitors-avapritinib and sunitinib-in refractory gastrointestinal stromal tumor after failure to multi-line therapy: a case report.

Background: Tyrosine kinase inhibitors (TKIs) are currently the main treatment choice for gastrointestinal stromal tumors (GISTs). However, the long-term use of TKIs can lead to drug resistance. There is no study or clinical report of combination therapies of TKIs that have been approved for marketing. Combination pharmacotherapy is a new approach for patients who do not respond to monotherapy. This case provides a reference value for selective combination of TKIs in treating advanced GIST. Case Description: In this article, we report the case of a 55-year-old female who was diagnosed with duodenal GIST in April 2018 and underwent R0 resection. KIT exon 9 mutation was detected. The patient had disease recurrence with multiple abdominal metastases during imatinib adjuvant therapy after 27 months, and failure to 2nd-line sunitinib treatment after 6 months. She underwent a cytoreductive surgery (R1), and the postoperative mutation analysis suggested KIT exon 9 mutation, with newly found secondary KIT_exon16_p. L783V mutation and other mutations on TP53, POT1, and SETD2, etc. The patient experienced short-term tumor control of standard 3rd-line therapy of regorafenib and the rapid progression of the 4th-line of ripretinib afterwards. Different TKI combination therapies (i.e., ripretinib plus sunitinib, ripretinib plus avapritinib and avapritinib plus sunitinib) were administered to the patient sequentially. Ripretinib plus sunitinib led to stable disease but was discontinued due to intolerable adverse effects. Finally, the patient received a combination regimen of avapritinib plus sunitinib. The patient's tumor showed continuous shrinking in 2 consecutive computed tomography scan evaluations within 4 months with acceptable side effects. Conclusions: Combined type I and type II TKIs of avapritinib combined with sunitinib therapy achieved tumor regression for a heavily multi-line treated patient. Our case provides a reference for a savage treatment choice in refractory GISTs after failure to all standard treatment.

Genotyping guided ripretinib directly after the progression of first-line imatinib therapy in advanced gastrointestinal stromal tumor: a case report.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery and tyrosine kinase inhibitor (TKI) therapy are the main choices of treatment. However, the long-term use of TKIs is prone to drug resistance. Herein, we report the case of a 47-year-old female with primary gastric GIST with liver metastases since June 2015. The patient achieved disease control under imatinib therapy and underwent primary lesion resection. She took postoperative imatinib maintenance therapy, but discontinued imatinib for 10 months about 2 years after surgery. The patient suffered from disease progression in May 2019, with recurrence of liver metastases and new abdominal metastases. From then on, imatinib was resumed and partial response (PR) persisted for another 2 years. The patient subsequently experienced tumor progression due to secondary KIT exon 17 mutation confirmed by tissue biopsy and circulating tumor DNA (ctDNA) detection. After multidisciplinary team discussion, the patient received ripretinib as a second-line therapy, and ctDNA monitoring demonstrated that the KIT mutations turned negative. After disease control from ripretinib for 2+ months, she underwent cytoreductive surgery (R0/1) and received ripretinib maintenance treatment postoperatively. We believe that this case provides a reference value for individualized ripretinib precise therapy according to mutational analysis after the progression of first-line GIST treatment, and ctDNA can predict effectiveness to guide treatment.

A high performance lithium metal anode enabled by CF4 plasma treated carbon paper.

To substantially boost the energy density of secondary batteries, research studies on lithium metal anodes are booming to develop technologies on lithium metal batteries. However, suffering from lithium dendritic growth and volume expansion, the batteries are still far from practical applications. Herein, carbon paper (CP) is superficially fluorinated by CF4 plasma to endow the obtained composite lithium metal anode with both high areal capacity and long lifespan. The decreasing intensity of plasma from the upper surface to the bottom in the CP matrix achieves a higher F content and a lower conductivity on the top side, thus guiding more lithium to deposit inside the matrix. Besides, the fluorinated carbon paper (FCP) possesses flatter lithium plating in contrast to typical dendrites. As a result, the cells employing FCP as the anode achieve stable cycling over 350 cycles at a high areal capacity of 3 mA h cm-2 and a current density of 1 mA cm-2.

Comprehensive Analysis and Identification of Prognostic Biomarkers and Therapeutic Targets Among FAM83 Family Members for Gastric Cancer.

Background: Gastric cancer (GC) is one of the most common and poor prognosis malignancy in the world. The Family with sequence similarity 83 (FAM83) comprises of eight members of A-H. Accumulating evidence confirmed important roles for FAM83 family in tumorigenesis and progression. However, the prognostic values of FAM83 family in GC still have not been clarified. Methods: ONCOMINE, UALCAN, GEPIA, THE HUMAN PROTEIN ATLAS, Kaplan-Meier Plotter, cBioPortal, DAVID, STRING and TIMER databases and R software were adopted in this study. Results: In this study, we demonstrated that the mRNA levels of FAM83 B/C/D/H were significantly up-regulated in stomach adenocarcinoma (STAD), but the protein level of FAM83G/H were remarkable lowly in STAD. Next, FAM83C/D/G/H were significantly associated with tumor stages in STAD patients. Then, the mutation rate of FAM83 family members in STAD patients was 46%, and the highest mutation rate was FAM83H (23%). Furthermore, the functions of FAM83 family and their 259 co-expression genes were primarily related to Shigellosis, RNA degradation and Ribosome biogenesis in eukaryotes pathway. Besides, we have established the prognostic model of FAM83 family in STAD, including the prognostic model of STAD patients (FAM83C/D/G), STAD with lymph node metastasis (FAM83C/D/G/H) and STAD with ERBB2 high expression (FAM83G/H). FAM83C/D high expression with a poor prognosis, while FAM83G/H high expression with a favorable prognosis of STAD. Additionally, we found that the expression of FAM83C/D/G/H were significantly correlated with the infiltration of six types of immune cells [B cells, CD8+T cells, CD4+T cells, macrophages and Myeloid dendritic cells (DC)], whereas CD4+T cells and Macrophage cells have higher risk scores (HR > 1) when FAM83C lowly expression and FAM83D highly expression. The risk score of NK cells was significantly reduced when FAM83G lowly expression and FAM83H highly expression (HR < 1). Conclusion: These findings suggested that FAM83C/D/G/H might play key roles in STAD tumorigenesis and progression, and FAM83C/D might be risk factors but FAM83G/H might be favorable prognostic factors for STAD patients. In addition, CD4+T cells and Macrophage cells may be the promoters of FAM83D in progression of STAD, while NK cells may promote the protective effect of FAM83H on STAD patients.

A Substage Increase in The AJCC Classification System Improves Prognostic Prediction in Stage III Gastric Cancer With Insufficient Lymph Nodes Removed.

BACKGROUND: The impact of lymph nodes (LNs) removed on the survivals of patients with stage III gastric cancer, especially on that of those who undergo the adjuvant chemotherapy as a compensation for a possibly insufficient lymphadenectomy, is still unclear. METHODS: Consecutive patients (n = 488) with stage III gastric cancer under R0 curative resection followed by adjuvant chemotherapy were analyzed. The overall survival (OS) was compared between patients with insufficient LNs removed (ILNr, <16 LNs) and sufficient LNs removed (SLNr, ≥16 LNs). Performance of the prediction systems was evaluated using the Likelihood ratio χ2 test, Akaike information criterion (AIC), Harrell's concordance index (C-index), and area under the receiver operating characteristic curves (AUC). RESULTS: The OS of patients were significantly longer in those with SLNr relative to those with ILNr (for stage IIIA, 68.2 vs. 43.2 months, P = 0.042; for stage IIIB, 43.7 vs. 24.9 months, P < 0.001; for stage IIIC, 23.9 vs. 8.3 months, P < 0.001; and for total stage III, 37.7 vs. 21.7 months, P < 0.001). However, the OS were similar between stage IIIA patients with ILNr and stage IIIB patients with SLNr (P = 0.928), between IIIB patients with ILNr and IIIC patients with SLNr (P = 0.962), and IIIC patients with ILNr and stage IV (P = 0.668), respectively. A substage increase in the AJCC classification system, from IIIA to IIIB, from IIIB to IIIC, and from IIIC to IV in patients with ILNr, enhanced the accuracy of prognostic prediction in patients with stage III gastric cancer compared to the current TNM system (Likelihood ratio χ2, 188.6 vs. 184.8; AIC, 4336.4 vs. 4340.6; C-index, 0.695 vs. 0.679, P = 0.002). The ROC curves revealed that the performance of prognostic prediction was better in the new prediction system (AUC = 0.699) compared with the current TNM system (AUC = 0.676). CONCLUSIONS: ILNr (LNs <16) impairs the long-term outcomes of stage III gastric cancer underwent adjuvant chemotherapy. The status of LNs removal adds values to the current TNM system in prognostic prediction of stage III gastric cancer.

Clinicopathological features and lymph node metastatic patterns of gastric mixed adenoneuroendocrine carcinoma.

AIMS: Mixed adenoneuroendocrine carcinoma (MANEC), also known as high- grade mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) in the World Health Organization (WHO) classification of tumors of the endocrine organs (2017), is a rare gastric malignancy. Here, we present 10 cases of gastric MANEC and analyse their clinicopathological features and lymph node metastatic patterns. METHODS AND RESULTS: Six patients were male, and four were female. The mean age of the patients was 67.9 years. Grossly, most tumors presented as ulcerative mass, located in gastric fundus or/and cardia. Microscopically, the neuroendocrine component, large cell neuroendocrine carcinoma in most cases (8/10), constituted 30-70% of the whole tumor. It was diffusely positive for CD56 or/and synaptophysin in all cases, but negative for chromogranin A in 9 cases. Ki-67 index was 50-80% in neuroendocrine component. The glandular component was moderately (6/10) or poorly (4/10) differentiated adenocarcinoma. Nine of 10 cases were positive for lymph node metastasis, with pure neuroendocrine component (6/9), or pure glandular component (1/9), or mixed components (2/9). The patients were treated with surgery, combining with chemotherapy (4/10), radiotherapy (2/10) and immunotherapy (1/10). Five patients died from tumor progress, with an average survival time of 18.6 months. The dead cases had predominant neuroendocrine component in primary tumor or in metastatic lymph nodes. CONCLUSIONS: Neuroendocrine component may determine the clinical behavior and outcome in gastric MANEC. Different metastatic component makes the selection of chemotherapy protocol more challenging.

A Systematic Review and Meta-Analysis of Laparoscopic and Open Distal Pancreatectomy of Nonductal Adenocarcinomatous Pancreatic Tumor (NDACPT) in the Pancreatic Body and Tail.

BACKGROUND: Currently, laparoscopic distal pancreatectomy is regarded as a safe and effective surgical approach for lesions in the body and tail of the pancreas. This review examined the evidence from published data of comparative studies of laparoscopic versus open distal pancreatectomy of nonductal adenocarcinomatous pancreatic tumor in pancreatic body and tail. METHODS: A systematic review of the studies comparing laparoscopic and open distal pancreatectomy was conducted. Comparative studies published between January 1996 and June 2016 were included. Studies were selected on the basis of specific inclusion and exclusion criteria. These 2 techniques were compared regarding several outcomes of interest, which were divided into preoperative, operative, postoperative, and pathologic characteristics, postoperative biomarker, and hospital stay cost. Sensitivity and subgroup analysis partially confirmed the robustness of these data. RESULTS: Ten comparative case-control studies involving 712 patients (53.7% laparoscopic and 46.3% open), who underwent a distal pancreatectomy were included. The results favored laparoscopy with regard to intraoperative blood loss (P=0.0001), the rate of blood transfusion (P=0.02), total hospital stay (P=0.004), postoperative hospital stay (P<0.0001), overall morbidity (P=0.0002), the rate of wound infection (P=0.05), time to initial feeds (P<0.0001), first flatus time (P=0.008), duration of pain-killer intake (P=0.0003), and C-reactive protein on postoperative day 1 (P=<0.0001). In the subgroup analysis, excluding western country studies, operation time changed to have a statistically significant difference between these 2 groups (P=0.02). CONCLUSIONS: Laparoscopic resection results in improved operative and postoperative outcomes compared with open surgery according to the results of the present meta-analysis. It may be a safe and feasible option for nonductal adenocarcinomatous pancreatic tumor patients in pancreatic body and tail. However, randomized controlled trials should be undertaken to confirm the relevance of these findings.

Prognostic and Predictive Value of p21-activated Kinase 6 Associated Support Vector Machine Classifier in Gastric Cancer Treated by 5-fluorouracil/Oxaliplatin Chemotherapy.

To determine whether p21-activated Kinase (PAK) 6 is a prognostic and predictive marker in gastric cancer (GC) and to construct a classifier that can identify a subset of patients who are highly sensitive to 5-fluorouracil/oxaliplatin chemotherapy. We retrospectively analyzed the expression levels of PAK6, cyclooxygenase 2, p21WAF1, Ki-67, excision repair cross-complementing gene 1, and thymidylate synthase in 242 paraffin-embedded GC specimens of the training cohort by immunohistochemistry. Then, we used support vector machine (SVM)-based methods to develop a predictive classifier for chemotherapy (chemotherapy score - CS-SVM classifier). Further validation was performed in an independent cohort of 279 patients. High PAK6 expression was associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy. The CS-SVM classifier distinguished patients with stage II and III GC into low- and high-CS-SVM groups, with significant differences in the 5-year disease-free survival (DFS) and overall survival (OS) in chemotherapy patients. Moreover, chemotherapy significantly prolonged the DFS and OS of the high CS-SVM patients in the training and validation cohorts. In conclusion, PAK6 was an independent prognostic factor and increased chemoresistance. The CS-SVM classifier distinguished a subgroup of stage II and III patients who would highly benefit from chemotherapy, thus facilitating patient counseling and individualizing the management.

VEGF promotes gastric cancer development by upregulating CRMP4.

This study aimed to investigate the precise role of CRMP4 in gastric tumor growth and patient survival. The mRNA and protein expression levels of CRMP4, VEGF and VEGFR2 were validated by qRT-PCR and immunohistochemistry. We investigated the effects on tumor growth of overexpression and knockdown of CRMP4 both in vitro and in vivo by constructing stable gastric cell lines using lentiviral-mediated transduction and shRNA interference-mediated knockdown of CRMP4 expression. We further validated the role of the ERK/AKT signaling pathways in VEGF and CRMP4 expression using ERK and PI3K inhibitors. Increased expression of VEGF and CRMP4 were observed in gastric cancer tissues compared with tumor-adjacent tissue. We found that higher CRPM4 expression was associated with lymph node metastasis, TNM stage, tumor differentiation and poorer prognosis in gastric cancer patients. In HGC27 and SGC7901 gastric cancer cells, VEGF upregulated CRMP4 in time and dose-dependent manners. Overexpression of CRMP4 increased cell proliferation, migration and invasion, whereas knockdown of CRMP4 expression had opposite effects. VEGF activated CRMP4 expression in gastric cancer cells, and this effect was significantly inhibited by MAPK and PI3K inhibitors (PD98059 and LY294002). In mice, CRMP4 overexpression also resulted in increased tumor growth. These results suggest that increased CRMP4 expression mediated by the activation of VEGF signaling facilitates gastric tumor growth and metastasis, which may have clinical implications associated with a reduced survival rate in gastric cancer patients.

Targeting CRMP-4 by lentivirus-mediated RNA interference inhibits SW480 cell proliferation and colorectal cancer growth.

The aim of the present study was to investigate the expression level of collapsin response mediator protein 4 (CRMP-4) in human colorectal cancer (CRC) tissue and to evauluate its impact on SW480 cell proliferation, in addition to tumor growth in a mouse xenograft model. Clinical CRC tissue samples were collected to detect the CRMP-4 protein expression levels using western blot and immunohistochemistry analyses. A specific small interfering RNA sequence targeting the CRMP-4 gene (DPYSL3) was constructed and transfected into an SW480 cell line using a lentivirus vector to obtain a stable cell line with low expression of CRMP-4. The effectiveness of the interference was evaluated using western blot and reverse transcription-quantitative polymerase chain reaction, and the cell proliferation was determined using MTT and BrdU colorimetric methods. Tumor growth was assessed by subcutaneously inoculating the constructed cells into BALB/c nude mice. The protein expression levels of CRMP-4 were markedly increased in colon tumor tissue of the human samples. The proliferation of SW480 cells and the tumor growth rate in nude mice of the si-CPMR-4 group were evidently depressed compared with the si-scramble group. Thus, the present results suggest that CRMP-4 may be involved in the pathogenesis of CRC.

Survival prognosis and clinicopathological features of the lymph nodes along the left gastric artery in gastric cancer: implications for D2 lymphadenectomy.

The Japanese Gastric Cancer Treatment Guidelines (third edition) have assigned No. 7 station left gastric artery lymph nodes (LNs) to the D1 range of lymphatic dissection. We investigated the clinicopathological characteristics, survival impact, and appropriateness of ascribing No. 7 station LNs to D1 lymphadenectomy in gastric cancer. Patients (n=608) undergoing radical resection with No. 7 station LN dissection were recruited between January 1997 and June 2008. They were subdivided into four groups: N0, no LN metastasis; D1, LN without No. 7 station LN metastasis in the D1 lymphadenectomy region; No. 7, No. 7 station LN without LN metastasis in the D2 lymphadenectomy region; and D2, LN without No. 7 station LN metastasis in the D2 lymphadenectomy region. Of these, 17.2% (n=105) were positive for No. 7 LN metastasis, an important, independent prognostic factor associated with poor clinicopathological parameters, advanced tumor stage, and reduced survival. Tumor behavior in the No. 7 group was similar to that in the D2 group, but poorer than in the D1 group in terms of advanced tumor stage, with 5-year survival rates of 34.3%, 25.9% and 54.6%, respectively. Five-year survival rates in the No. 7 group were comparable to those in the D2 group (P>0.05), but significantly lower than in the D1 group (P<0.05). Logistic multivariate regression analysis established No. 3 and 9 station LN metastasis, node classification, and tumor-node-metastasis stage as independent risk factors for No. 7 station LN metastasis. Thus, No. 7 station LNs should be ascribed to D2 lymphadenectomy in gastric cancer.