The tumoral microbiome of pancreatic intraductal papillary mucinous neoplasm: A single-center retrospective cohort study.

BACKGROUND AND AIM: Pancreatic intraductal papillary mucinous neoplasm (IPMN) is one of the most common precancerous lesions of pancreatic carcinoma. Studies have found that the tumoral microbiome has an important influence on pancreatic carcinoma. However, the tumoral microbiome of IPMNs has rarely been explored. METHODS: Tumoral microbiome gene sequencing was carried out using 16 specimens of IPMN and 45 specimens of IPMN with associated invasive carcinoma (IPMN-IC) by 2bRAD sequencing for microbiome. The profile of the tumoral microbiome was summarized. Associations of the tumoral microbiome with disease grade, histological subtype, and prognosis were analyzed. RESULTS: A total of 598 species of microbes were identified, comprising 228 genera, 109 families, 60 orders, 29 classes, 14 phyla, and 2 kingdoms. The genus Pseudomonas was detected more frequently and had higher relative abundance in IPMN-ICs; Alcaligenes faecalis was detected with higher relative abundance in IPMNs. Bifidobacterium pseudolongum had a higher relative abundance in the IPMN-IC group, regardless of histological subtype. Moreover, among patients with IPMN-ICs, those with a high relative abundance of B. pseudolongum had better overall survival than those with a low relative abundance. Patients who were positive for Staphylococcus aureus or Mycolicibacillus koreensis had shorter survival. The presence of S. aureus was an independent risk factor for poor prognosis. CONCLUSIONS: There are enriching tumoral microbes in IPMN. The tumoral microbiome of IPMN is different from that of IPMN-IC.

Allocation of Eavesdropping Attacks for Multi-System Remote State Estimation.

In recent years, the problem of cyber-physical systems' remote state estimations under eavesdropping attacks have been a source of concern. Aiming at the existence of eavesdroppers in multi-system CPSs, the optimal attack energy allocation problem based on a SINR (signal-to-noise ratio) remote state estimation is studied. Assume that there are N sensors, and these sensors use a shared wireless communication channel to send their state measurements to the remote estimator. Due to the limited power, eavesdroppers can only attack M channels out of N channels at most. Our goal is to use the Markov decision processes (MDP) method to maximize the eavesdropper's state estimation error, so as to determine the eavesdropper's optimal attack allocation. We propose a backward induction algorithm which uses MDP to obtain the optimal attack energy allocation strategy. Compared with the traditional induction algorithm, this algorithm has lower computational cost. Finally, the numerical simulation results verify the correctness of the theoretical analysis.

[Clinical Application of Microwave Ablation in Potentially Resectable Colorectal Cancer With Simultaneously Multiple Liver Metastases].

Objective To analyze the clinical efficacy of microwave ablation in the colorectal cancer with simultaneously multiple liver metastases that was initially evaluated as potentially resectable. Methods The patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases treated in the Department of General Surgery of the First Affiliated Hospital of Hebei North University,the Center of Minimally Invasive Therapy in Oncology of Traditional Chinese and Western Medicine in Dongzhimen Hospital of Beijing University of Chinese Medicine,and the Second Department of General Surgery in the Fourth Hospital of Hebei Medical University from October 1,2018 to October 1,2020 were selected in this study.The general data,pathological features,treatment methods,and clinical efficacy of the patients were collected.According to the treatment methods,the patients were assigned into a surgical resection group(conversion therapy+laparoscopic primary resection+hepatectomy)and a microwave ablation group(conversion therapy+laparoscopic primary resection+microwave ablation).The surgical indicators(operation duration,time to first postoperative anal exhaust,hospital stay,etc.)and postoperative complications(anastomotic stenosis,anastomotic hemorrhage,incision infection,etc.)were compared between the two groups.The survival period was followed up,including the overall survival period and disease-free survival period,and the survival curves were drawn to analyze the clinical efficacy of the two treatment regimens. Results A total of 198 patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases were included in this study.Sixty-six patients were cured by neoadjuvant chemotherapy(FOLFOX or FOLFIRI),including 30 patients in the surgical resection group and 36 patients in the microwave ablation group(with 57 tumors ablated).After the first ablation,54(94.74%)tumors achieved complete ablation,and all of them reached no evidence of disease status after re-ablation.The microwave ablation group had shorter operation duration,less intraoperative blood loss,shorter time to first postoperative anal exhaust,shorter time of taking a liquid diet,shorter hospital stay,and lower hospitalization cost than the surgical resection group(all P<0.001).In addition,the microwave ablation group had lower visual analogue scale score(P<0.001)than the surgical resection group.The incidences of complications such as incision infection(P=0.740),anastomotic fistula(P=1.000),and anastomotic stenosis(P=1.000),the overall survival period(P=0.191),and the disease-free survival period(P=0.934)showed no significant differences between the two groups. Conclusions For patients with colorectal cancer with simultaneous multiple liver metastases initially assessed as potentially resectable,laparoscopic primary resection+surgical resection/microwave ablation after conversion therapy was safe,effective,and had similar survival outcomes.Microwave ablation outperformed surgical resection in postoperative recovery,economy,and tolerability,being worthy of clinical promotion.

Expression of PD-L1 and VISTA in Intraductal Papillary Mucinous Neoplasm With Associated Invasive Carcinoma of the Pancreas.

Early detection and treatment of invasive carcinoma arising in association with intraductal papillary mucinous neoplasm (IPMN), which is biologically and (epi)genetically distinct from conventional pancreatic ductal adenocarcinoma, provide an opportunity to improve the prognosis of this lethal disease. Despite the successful application of programmed death (ligand) 1 (PD-[L]1)-blocking strategies in numerous cancers, the immune microenvironment of IPMN with associated invasive carcinoma remains elusive. Here, we investigated CD8+ T cells, CD68+ macrophages, PD-L1, and V-domain immunoglobulin suppressor of T-cell activation (VISTA) in 60 patients with IPMN with associated invasive carcinoma using immunohistochemistry, explored their correlations with clinicopathologic variables and prognosis, and compared them with those in 76 patients with IPMN without invasive carcinoma (60 low-grade and 16 high-grade lesions). Using antibodies against CD8, CD68, and VISTA, we evaluated tumor-infiltrating immune cells in 5 high-power fields (×400) and calculated the corresponding mean counts. PD-L1 with a combined positive score of ≥1 was regarded as positive, and VISTA expression on tumor cells (TCs) was deemed positive when ≥1% of TCs showed membranous/cytoplasmic staining. A reduction of CD8+ T cells and an increase of macrophages were observed during carcinogenesis. Positive PD-L1 combined positive score and VISTA expression on TCs were 13% and 11% in the intraductal component of IPMN with associated invasive carcinoma, 15% and 12% in the associated invasive carcinoma, and 6% and 4% in IPMN without an invasive carcinoma, respectively. Interestingly, the PD-L1 positivity rate was the highest in a subset of associated invasive carcinomas (predominantly gastric-type-derived) and was associated with higher counts of CD8+ T cells, macrophages, and VISTA+ immune cells. Accumulation of VISTA+ immune cells was observed in the intraductal component of IPMN with associated invasive carcinoma compared with that of low-grade IPMN, whereas in intestinal-type IPMN with associated invasive carcinoma, the number of these cells decreased during the transition from the intraductal component to the associated invasive carcinoma. Survival analysis revealed that a higher number of macrophages predicted poorer prognosis. In conclusion, our results might help in individualized immunotherapeutic strategies for these patients.

Solid Pseudopapillary Neoplasms of the Pancreas: Clinicopathologic Analysis and a Predictive Model.

Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare. They are considered low-grade malignancies, and a small percentage of patients experience recurrence or metastasis. It is critical to investigate associated biological behavior and identify patients at a risk of relapse. This was a retrospective study of 486 patients with SPNs who were diagnosed between 2000 and 2021. Their clinicopathologic features, including 23 parameters and prognoses were analyzed. Six patients (1.2%) presented with synchronous liver metastasis. A total of 21 patients experienced recurrence or metastasis postoperatively. The overall and disease-specific survival rates were 99.8% and 100%, respectively. The 5- and 10-year relapse-free survival (RFS) rates were 97.4% and 90.2%, respectively. Tumor size, lymphovascular invasion, and the Ki-67 index were independent predictors of relapse. Furthermore, a Peking Union Medical College Hospital-SPN risk model was built to evaluate the risk of relapse and compared it with the American Joint Committee on Cancer tumor staging system (eighth edition, 2017). Risk factors included 3 parameters: tumor size (>9 cm), lymphovascular invasion status (presence), and Ki-67 index (>1%). Risk grades were available for 345 patients, who were divided into 2 groups: (1) low risk (n = 124) and (2) high risk (n = 221). The group with no risk factors was designated as low risk and had a 10-year RFS of 100%. The group associated with 1 to 3 factors was designated as high risk, with a 10-year RFS of 75.3%. Receiver operating characteristic curves were generated, and the area under the curve was 0.791 for our model and 0.630 for the American Joint Committee on Cancer with respect to the cancer staging system. We validated our model in independent cohorts and demonstrated a sensitivity of 98.3%. In conclusion, SPNs are low-grade malignant neoplasms that rarely metastasize, and the 3 selected pathologic parameters can be used to predict their behavior. A novel Peking Union Medical College Hospital-SPN risk model was proposed for routine application to guide the patient counseling in clinical practice.

Clinicopathological analysis of patients with molecularly confirmed stage I adult granulosa cell tumors and prediction of recurrence.

OBJECTIVE: Adult granulosa cell tumors (AGCTs) are rare malignancies that accounts for approximately 1% of ovarian neoplasms. As there are currently no well-recognized models for predicting relapse-free survival (RFS), we performed a clinicopathological analysis to identify risk factors for AGCT recurrence. METHODS: We investigated 130 patients with pathologically diagnosed AGCT as confirmed by the presence of the characteristic FOXL2 C402G mutation. RESULTS: Most patients had International Federation of Gynecology and Obstetrics stage I disease (n = 122, 95.3%). The 10-year RFS rate was 31.4% (22/70) and mean 10-year RFS was 74.4 (95% CI, 65.2-83.7) months. Ten patients experienced recurrence beyond the 10-year follow-up period. Undergoing fertility sparing surgery, an estrogen receptor-α (ERα) score (>0.25), and a Ki-67 index >15% were independent risk factors for recurrence in patients with stage I disease (bias-corrected C-index: 0.776). We constructed a nomogram with well-fitting calibration plots; the areas under the curve (AUCs) for 5-, and 10-year RFS prediction were 0.883 and 0.906 respectively. A simplified model with 3 predictive factors (ERα score, Ki-67 index, and primary surgical procedure) and 2 risk stratification subgroups (low- and high-risk) was constructed; its AUCs for 5-, and 10-year RFS prediction were 0.825 and 0.850 respectively. Kaplan-Meier survival curves showed significant differences in 10-year RFS between the low- and high-risk groups (p < 0.001). CONCLUSIONS: The type of primary surgical procedure, ERα score, and Ki-67 index are independent predictors of recurrence for patients with stage I AGCT. Our predictive model based on these factors showed good performance.

Comprehensive evaluation of BRCA1/2 variant interpretation ability among laboratories in China.

High-quality interpretation of BRCA1/2 variants plays a critical role in the clinical practice of precision medicine. However, a comprehensive system to evaluate the quality and accuracy of variant interpretation has yet to be established. This study investigates the performance of an interpretation system in evaluating the capacities of BRCA1/2 interpretation among distinct laboratories in China. The evaluation system is based on a reference database that contains 750 different variants in BRCA1/2 Evaluation was performed among 41 laboratories in China. We classified their performance into five levels. Only level A was considered qualified. This level allows for a 0.3% error rate for clinical decision-related misinterpretation; 26 of 41 laboratories (63%) met the qualified standard, while 7 laboratories were at levels D and E, which indicated egregious mistakes and systemic problems in variant interpretation. Due to strict quality demands, the interpretation of several variants was amended, which largely influenced the quality rate. The number of qualified laboratories would decrease from 26 to 17 if those incorrect recommended interpretations were not corrected. This evaluation system provides a potential approach for standardisation of variant interpretation and lowers the discordance of variant interpretation between different laboratories. A well-designed interpretation ability evaluation is essential to evaluate the interpretation level of laboratories before they provide service in real-world clinical settings.

High Mast Cell Density Predicts a Favorable Prognosis in Patients with Pancreatic Neuroendocrine Neoplasms.

INTRODUCTION: Mast cells are involved in allergic diseases, immune regulation, and tumor microenvironment modulation, with both pro- and anti-tumorigenic functions, and could serve as a prognostic factor in various cancers. However, their potential role in pancreatic neuroendocrine neoplasms (PanNENs) is largely unknown. Here, our aim was to investigate the presence of mast cells in PanNENs and evaluate their association with clinicopathological parameters and other common tumor-infiltrating immune cells. METHODS: Tissue microarrays containing PanNEN samples from 187 patients were constructed and stained immunohistochemically for CD117, CD15, CD68, CD3, CD4, and CD8. Immune cells were counted from four high-power fields (HPFs; ×400) at maximal concentrations, and the mean counts were calculated per HPF. The cutoff values were set by X-tile. RESULTS: The median (interquartile range) counts of CD117+ mast cells, CD15+ neutrophils, CD68+ macrophages, CD3+ T cells, and CD4+ T cells were 3.5 (2.0-6.0), 3.0 (1.3-6), 3.8 (2.5-5.8), 13 (8.0-24.0), and 2.0 (1.0-4.0)/HPF, respectively. CD8+ T cells were not detected. The cutoff values for these immune cells were 1.5/HPF, 6/HPF, 4.8/HPF, 32.5/HPF, and 2/HPF, respectively. Low mast cell density was correlated with higher grades, noninsulinoma, and advanced stages. Moreover, high mast cell infiltration was associated with elevated CD4+ T cell and CD15+ neutrophil counts. Multivariate analysis revealed that high mast cell density was an independent predictor of prolonged progression-free survival in the entire cohort; in pancreatic neuroendocrine tumors; and in intermediate-grade, noninsulinoma, and advanced stage subgroups. CONCLUSIONS: These findings suggest a protective role of mast cells in PanNENs.

Alternative Lengthening of Telomeres Phenotype Predicts Progression Risk in Noninsulinomas in a Chinese Cohort.

INTRODUCTION: Recent studies have suggested that alternative lengthening of telomeres (ALT) is associated with metastasis and poor survival in pancreatic neuroendocrine tumors (PanNETs). This study evaluated whether this association is applicable to Chinese patients as well as the potential somatic mutations associated with ALT. METHODS: We assessed the prevalence of ALT by performing telomere-specific fluorescence in situ hybridization and analyzed DAXX/ATRX expression using immunohistochemistry in 112 Chinese patients with PanNETs to evaluate the association between ALT and clinical outcomes. A subset of the noninsulinoma samples (28/60) was subjected to Sanger sequencing and targeted sequencing. RESULTS: The ALT-positive phenotype was identified in 23.2% (26/112) of the samples. The clinicopathologic factors significantly associated with progression in the noninsulinoma (n = 60) cohort were the female sex (p = 0.006), Ki-67 index (p < 0.001), World Health Organization grade (p = 0.031), and ALT positivity (p = 0.013). Patients with ALT-positive PanNETs had significantly shorter progression-free survival than those with ALT-negative PanNETs in the entire cohort (p < 0.001), noninsulinoma subgroup (p = 0.01), and G2 subgroup (p = 0.001). ALT-positive samples frequently harbored somatic mutations in DAXX, ATRX, MEN1, SETBP1, PRKDC, and GNAS. CONCLUSIONS: We confirmed that ALT positivity is an effective risk predictor, especially in the noninsulinoma and G2 subgroups. ALT is also related to somatic mutations in MEN1, SETBP1, PRKDC, and GNAS, in addition to DAXX and ATRX.

Evaluation of the diagnostic performance of the EFSUMB CEUS Pancreatic Applications guidelines (2017 version): a retrospective single-center analysis of 455 solid pancreatic masses.

OBJECTIVES: To explore the diagnostic performance of EFSUMB CEUS Pancreatic Applications guidelines (version 2017) before and after the addition of iso-enhancement and very fast/fast washout as supplementary diagnostic criteria for PDAC. METHODS: In this retrospective study, patients diagnosed with solid pancreatic lesions from January 2017 to December 2020 were evaluated. Pancreatic ductal adenocarcinoma (PDAC) is reported to show hypo-enhancement in all phases according to the EFSUMB guidelines. First, based on this definition, all lesions were categorized as PDAC and non-PDAC. Then, iso-enhancement and very fast/fast washout were added as supplementary diagnostic criteria, and all lesions were recategorized. The diagnostic performance was assessed in terms of the accuracy (ACC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV). The reference standard consisted of histologic evaluation or composite imaging and clinical follow-up findings. RESULTS: A total of 455 nodules in 450 patients (median age, 58.37 years; 250 men) were included. The diagnostic performance using the EFSUMB CEUS guidelines for PDAC had an ACC of 69.5%, SEN of 65.4%, SPE of 84%, PPV of 93.5%, NPV of 40.6%, and ROC of 0.747. After recategorization according to the supplementary diagnostic criteria, the diagnostic performance for PDAC had an ACC of 95.8%, SEN of 99.2%, SPE of 84%, PPV of 95.7%, NPV of 96.6%, and ROC of 0.916. CONCLUSION: The EFSUMB guidelines and recommendations for pancreatic lesions can effectively identify PDAC via hypo-enhancement on CEUS. However, the diagnostic performance may be further improved by the reclassification of PDAC lesions after adding iso-enhancement and very fast/fast washout mode. KEY POINTS: • In the EFSUMB guidelines, the only diagnostic criterion for PDAC is hypo-enhancement, to which iso-enhancement and very fast/fast washout mode were added in our research. • Using hypo-enhancement/iso-enhancement with very fast/fast washout patterns as the diagnostic criteria for PDAC for solid pancreatic masses on CEUS has high diagnostic accuracy. • The blood supply pattern of PDAC can provide important information, and CEUS has unique advantages in this respect due to its real-time dynamic attenuation ability.

Sphingolipids at Plasmodesmata: Structural Components and Functional Modulators.

Plasmodesmata (PD) are plant-specific channels connecting adjacent cells to mediate intercellular communication of molecules essential for plant development and defense. The typical PD are organized by the close apposition of the plasma membrane (PM), the desmotubule derived from the endoplasmic reticulum (ER), and spoke-like elements linking the two membranes. The plasmodesmal PM (PD-PM) is characterized by the formation of unique microdomains enriched with sphingolipids, sterols, and specific proteins, identified by lipidomics and proteomics. These components modulate PD to adapt to the dynamic changes of developmental processes and environmental stimuli. In this review, we focus on highlighting the functions of sphingolipid species in plasmodesmata, including membrane microdomain organization, architecture transformation, callose deposition and permeability control, and signaling regulation. We also briefly discuss the difference between sphingolipids and sterols, and we propose potential unresolved questions that are of help for further understanding the correspondence between plasmodesmal structure and function.

A Retrospective Study of Ultrasonography in the Investigation of Primary Hyperparathyroidism: A New Perspective for Ultrasound Echogenicity Features of Parathyroid Nodules.

OBJECTIVE: To identify and understand parathyroid lesions of patients with primary hyperparathyroidism (PHPT) more accurately under ultrasound. METHODS: This retrospective study involved 423 adult patients with PHPT with a single parathyroid nodule and positive parathyroid ultrasonography between 2018 and 2019. The clinical characteristics of the study patients and histopathologic sections were reviewed. RESULTS: According to the main grayscale echogenicity features of parathyroid nodules, 423 cases were divided into groups: iso-hyperechogenicity solid (61/423), hypoechogenicity solid (304/423), and mixed-echogenicity cyst-solid (58/423) groups. Comparison among the 3 groups showed that the iso-hyperechogenicity group included more asymptomatic patients with PHPT and fewer patients with severe symptoms like bone fractures (P < .05). The mixed-echogenicity group showed higher median serum parathyroid hormone (PTH) and serum calcium levels and larger lesion sizes (P < .05), and the iso-hyperechogenicity group showed the lowest median serum PTH level. No difference in lesion size was noted between the 2 solid groups, but the median serum PTH level in the hypoechogenicity group was higher than that in the iso-hyperechogenicity group (P < .05). According to histopathology, the hypoechogenic area of the samples may contain more functional components (chief cells), whereas the iso-hyperechogenic area has more nonfunctional components (eg, lipocytes and connective tissues). CONCLUSION: The PHPT nodules distinguished by ultrasound echogenicity features showed different histopathologic components, reflected by different clinical characteristics of the patients with PHPT.

Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production.

T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.

Gastric adenocarcinoma at stage IV with complete remission after neoadjuvant therapy concurrent with adenosquamous carcinoma of the ampulla of Vater: a case report and literature review.

BACKGROUND: Adenosquamous carcinoma (ASC) of the ampulla of Vater (AmV) is exceedingly rare with more aggressive behavior and worse prognosis than adenocarcinoma. The finding of ASC at the AmV in combination to the gastric adenocarcinoma has never been reported in the literature before. CASE PRESENTATION: An old lady was diagnosed as gastric adenocarcinoma at stage IV with enlargement of supraclavicular lymph nodes by gastroscopy and histopathological evaluation 3 years ago. Afterwards, the patient achieved complete remission after regular chemotherapy. However, the patient manifested yellow sclera and skin, choluria and clay colored stool 3 months ago. Preoperative contrast-enhanced CT, ERCP, MRCP, and PET/CT revealed the presence of an ampullary tumor. The patient then underwent laparoscopic radical gastrectomy and pancreaticoduodenectomy with regional lymph node dissection. Postoperative cytological analyses confirmed the diagnosis of gastric ulcer with complete response to neoadjuvant therapy and ASC at the AmV. The patient's postoperative outcome was uneventful. CONCLUSION: Drawing firm conclusions about the diagnosis of ampullary ASC is difficult because of the difficulty in acquiring both adenocarcinoma and SCC components by fine needle biopsy. The rarity of ASC of the AmV coexistent with gastric carcinoma makes it difficult to elucidate their clinicopathological characteristics, therapeutic strategies and overall prognosis. Surgical resection still remains the main treatment method.

Roles for VEGF-C/NRP-2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation.

Vascular endothelial growth factor C (VEGF-C) is an angiogenic and lymphangiogenic growth factor. Recent research has revealed the role for VEGF-C in regulating autophagy by interacting with a nontyrosine kinase receptor, neuropilin-2 (NRP-2). However, whether VEGF-C participates in regulating cell survival and autophagy in renal proximal tubular cells is unknown. To address this question, we employed a cell modal of serum deprivation to verify the role of VEGF-C and its receptor NRP-2 in regulating cell survival and autophagy in NRK52E cell lines. The results show that VEGF-C rescued the loss of cell viability induced by serum deprivation in a concentration-dependent manner. Furthermore, endogenous VEGF-C was knocked down in NRK52E cells by using specific small-interfering RNAs (siRNA), cells were more sensitive to serum deprivation-induced cell death. A similar increase in cell death rate was observed following NRP-2 depletion in serum-starved NRK52E cells. Autophagy activity in serum-starved NRK52E cells was confirmed by western blot analysis of microtubule-associated protein-1 chain 3 (LC3), immunofluorescence staining of endogenous LC3, and the formation of autophagosomes by electron microscopy. VEGF-C or NRP-2 depletion further increased LC3 expression induced by serum deprivation, suggesting that VEGF-C and NRP-2 were involved in controlling autophagy in NRK52E cells. We further performed autophagic flux experiments to identify that VEGF-C promotes the activation of autophagy in serum-starved NRK52E cells. Together, these results suggest for the first time that VEGF-C/NRP-2 axis promotes survival and autophagy in NRK52E cells under serum deprivation condition. SIGNIFICANCE OF THE STUDY: More researchers had focused on the regulation of autophagy in kidney disease. The effect of VEGF-C on cell death and autophagy in renal epithelial cells has not been examined. We first identified the VEGF-C as a regulator of cell survival and autophagy in NRK52E cell lines. And VEGF-C/NRP-2 may mediate autophagy by regulating the phosphorylation of 4EBP1 and P70S6K. VEGF-C treatment may be identified as a therapeutic target in renal injury repair due to its capacity to promote tubular cell survival in the future.

Identification of the Chemical Constituents of an Anti-Arthritic Chinese Medicine Wen Luo Yin by Liquid Chromatography Coupled with Mass Spectrometry.

Wen Luo Yin (WLY), a well-known traditional Chinese medicine formulation, has been used as a complementary therapy for the treatment of rheumatoid arthritis in clinical settings. However, the chemical constituents of WLY remain unclear. In this study, a high-performance liquid chromatography coupled with tandem mass spectrometry method was established to separate and comprehensively identify the chemical constituents of WLY. The analytes were eluted with a mobile phase of acetonitrile and 0.1% aqueous acetic acid. Mass detection was performed in both positive and negative ion mode. The MS/MS fragmentation pathways were proposed for the identification of the components. A total of 42 compounds including sesquiterpenes, alkaloids, biflavonoids, polyacetylenes, phenylpropanoids and acetylenic phenols were identified unambiguously or tentatively according to their retention times and mass behavior with those of authentic standards or literature data. The identification and structural elucidation of chemical constituents may provide important information for quality control and pharmacological research of WLY.

Congenital Infiltrating Lipomatosis of the Face: Case Report and Literature Review.

RATIONALE: Congenital infiltrating lipomatosis of the face (CILF) is a rare disorder characterized by collections of nonencapsulated mature lipocytes that infiltrate surrounding tissues. In this article, we would report a new case of CILF, which may be one of the first few cases reported in China. PATIENT CONCERNS: An 8-year-old boy presented with a hyperplasia of subcutaneous tissue of his left face, which had been gradually progressing since birth, resulting in a marked facial asymmetry. Then he underwent an operation of resection of the subcutaneous mass, and the postoperative pathological analysis reported a mature adipose tissue. DIAGNOSES AND OUTCOMES: The diagnosis of CILF was finally made according to a comprehensive consideration of the patient's situation. We then searched different databases for studies that had investigated CILF, reviewed those literatures, and gave our summaries for such a rare disease. LESSONS: Congenital infiltrating lipomatosis of the face is an extremely rare disease. There is so much unknown about it, and the gradual progress and recurrence make it even harder to cure. Besides, the psychological impact on such patients must be considered. Thus, a proper collection and analysis of the reports of such a disease are very important.

The antihelmenthic phosphate niclosamide impedes renal fibrosis by inhibiting homeodomain-interacting protein kinase 2 expression.

Renal fibrosis is the final common pathway of all varieties of progressive chronic kidney disease. However, there are no effective therapies to prevent or slow the progression of renal fibrosis. Niclosamide is a US Food and Drug Administration-approved oral antihelminthic drug used for treating most tapeworm infections. Here, we demonstrated that phosphate niclosamide, the water-soluble form of niclosamide, significantly reduced proteinuria, glomerulosclrotic lesions, and interstitial fibrosis in a murine model of adriamycin nephropathy. In addition, phosphate niclosamide significantly ameliorated established renal interstitial fibrosis a murine model of unilateral ureteral obstruction. Mechanistically, phosphate niclosamide directly inhibited TGF-ß-induced expression of homeodomain-interacting protein kinase 2 (HIPK2) by interfering with the binding of Smad3 to the promoter of the HIPK2 gene, and subsequently mitigated the activation of its downstream signaling pathways including Smad, Notch, NF-κB and Wnt/ß-catenin pathway both in vitro and in vivo. Thus, phosphate niclosamide mitigates renal fibrosis at least partially by inhibiting HIPK2 expression. Hence, phosphate niclosamide might be a potential therapeutic agent for renal fibrosis.

hsa-miR-96 and hsa-miR-217 Expression Down-Regulates with Increasing Dysplasia in Pancreatic Intraepithelial Neoplasias and Intraductal Papillary Mucinous Neoplasms.

AIM: To compare the clinicopathological features of pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs), and to investigate the role of hsa-miR-96 and hsa-miR-217 in these two lesions. Methods: Formalin-fixed paraffin-embedded pancreatic specimens were selected in this study, including 58 cases of pancreatic intraepithelial neoplasias (PanINs), 45 cases of pancreatic ductal adenocarcinomas (PDAs), and 57 cases of intraductal papillary mucinous neoplasms (IPMNs). MiRNAs hsa-miR-96 and hsa-miR-217 were detected using locked nucleic acid in situ hybridization (LNA-ISH) with the NBT/BCIP staining system. The differences in miRNA expression among sample sets were analyzed with the Chi-squared test. Results: PanIN-PDAs were inclined to present with higher rate of invasion (p=0.033), lymph node metastasis (p=0.0004) and poorer differentiation (p<0.001). Of the 45 PDAs, only 2 cases were within AJCC Ⅰstage, while there were 11 cases of IPMN associated carcinomas (p=0.0018). In PanIN-1, PanIN-2 and PanIN-3, the expression of hsa-miR-96 was 91.3% (22/23), 78.6%(12/17) and 22.2%(4/18) respectively, while the expression of hsa-miR-217 was 95.7%(22/23) , 70.6% (12/17) and 27.8% (5/18). In IPMN with low-grade, intermediate-grade, high-grade dysplasia, associated carcinoma, the expression of hsa-miR-96 was 67%(9/13), 64%(7/11), 43%(3/7) and 27%(7/26) respectively, while the expression of hsa-miR-217 was 77%(10/13), 64%(7/11), 29%(2/7) and 38%(10/26). The expression of hsa-miR-96 and hsa-miR-217 in PanIN-1 lesions was not significantly different from that in the normal pancreatic ductal epithelium. However, their expression in PanIN-2/3 lesions was significantly different from that in normal pancreatic ductal epithelium (P<0.01). No difference was observed between PanIN derived adenocarcinomas and IPMN-associated carcinomas. Conclusion: IPMN associated carcinomas were in a statistically earlier stage than PanIN- PDAs at the time of operation. Abnormal expression of hsa-miR-96 and of hsa-miR-217 was observed in premalignant lesions (PanINs and IPMNs) of pancreatic carcinoma and down-regulated with increasing grades of PanINs and IPMNs. These microRNAs may serve as potentially early biomarker and act as tumor suppressor genes.