Efficacy of Raw Corn Starch in Insulinoma-Related Hypoglycemia: A Promising Supportive Therapy.

Objective To investigate the efficacy of raw corn starch (RCS) in clinical management of insulinoma-induced hypoglycemia.Methods We retrospectively collected clinical data of insulinoma patients who received RCS-supplemented diet preoperatively, and analyzed the therapeutic effects of the RCS intervention on blood glucose control, weight change, and its adverse events.Results The study population consisted of 24 case of insulinoma patients, 7 males and 17 females, aged 46.08 ± 14.15 years. Before RCS-supplemented diet, all patients had frequent hypoglycemic episodes (2.51 ± 3.88 times/week), concurrent with neuroglycopenia (in 83.3% of patients) and autonomic manifestations (in 75.0% of patients), with the median fasting blood glucose (FBG) of 2.70 [interquartile range (IQR): 2.50-2.90] mmol/L. The patients' weight increased by 0.38 (IQR: 0.05-0.65) kg per month, with 8 (33.3%) cases developing overweight and 7 (29.2%) cases developing obesity. All patients maintained the RCS-supplemented diet until they underwent tumor resection (23 cases) and transarterial chemoembolization for liver metastases (1 case). For 19 patients receiving RCS throughout the day, the median FBG within one week of nutritional management was 4.30 (IQR: 3.30-5.70) mmol/L, which was a significant increase compared to pre-nutritional level [2.25 (IQR: 1.60-2.90) mmol/L; P = 0.000]. Of them, 10 patients receiving RCS throughout the day for over four weeks had sustained improvement in FBG compared to pre-treatment [3.20 (IQR: 2.60-3.95) mmol/L vs. 2.15 (IQR: 1.83-2.33) mmol/L; P = 0.000). Five patients who received RCS only at night also had a significant increase in FBG within one week of nutritional management [3.50 (IQR: 2.50-3.65) mmol/L vs. 2.20 (IQR:1.80-2.60) mmol/L; P = 0.000], but only one patient who continued to receive RCS for over 4 weeks did not have a significant improvement in FBG. No improvement in weight gain was observed upon RCS supplementation. Mild diarrhea (2 cases) and flatulence (1 case) occurred, and were relieved by reduction of RCS dose.Conclusion The RCS-supplemented diet is effective in controlling insulinoma-induced hypoglycemia.

Efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil monotherapy for refractory metastatic colorectal cancer: a retrospective cohort study.

Background: Several studies demonstrated trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) had better efficacy than the monotherapy of TAS-102 in refractory metastatic colorectal cancer (mCRC). However, it remains unclear whether Chinese population can benefit from this combination or not. Hence, we conducted this retrospective cohort study to compare the efficacy and safety between TAS-102 plus BEV with TAS-102 monotherapy in refractory mCRC. Methods: This retrospective cohort study enrolled patients (any age) with refractory mCRC from Hunan Cancer Hospital. The main inclusion criteria were histopathologically and/or radiographically confirmed refractory mCRC, World Health Organization (WHO) performance status of 0 to 2, adequate organ function, and initial treatment of TAS-102 with or without BEV between November 2020 and October 2022. Previous therapy with fruquintinib or regorafenib was allowed but not mandatory. Baseline demographic and clinical characteristics were collected appropriately. Every 2 or 3 treatment cycles, the patients were assessed by computed tomography (CT) scans and clinical assessments until disease progression or loss to follow-up. The National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 (NCI-CTCAE 5.0) were presented as n (%). The primary endpoint was investigator-evaluated overall survival (OS). As this is a retrospective cohort study, sample size calculation was not performed. Eligible patients would be enrolled as many as possible. Results: A total of 90 patients were enrolled, including 58 patients who received TAS-102 plus BEV and another 32 patients who received TAS-102 monotherapy. The known baseline characteristics were comparable (P<0.05). With a median follow-up of 4.60 months (range, 0.20-22.80), the median OS (mOS) time in the TAS-102 plus BEV group was longer than that in the TAS-102 monotherapy group (10.83 vs. 7.43 months), but the difference was not significant (P=0.79). The median progression-free survival (mPFS) time was comparable between the two groups (4.67 vs. 4.30 months, P=0.96). Multivariate Cox regression analysis demonstrated that undergoing therapy after TAS-102 either with or without BEV was an independent risk factor for OS [hazard ratio (HR) =0.25; 95% confidence interval (CI): 0.09-0.71, P<0.01], and previous treatment with cetuximab was an independent protective factor for PFS (HR =0.17; 95% CI: 0.03-0.91, P=0.04). Of the 70 patients who were evaluated, those receiving TAS-102 plus BEV showed trend of a higher objective response rate (ORR) and disease control rate (DCR) than those who received TAS-102 monotherapy (P=0.16 and P=0.29, respectively). Adverse events (AEs) were similar between the two groups, except that the incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group. Conclusions: There was a trend in favor of the combination of BEV plus TAS-102 regarding OS and DCR, without reaching statistical significance, and it means that there was no clear advantage of one over the other in terms of efficacy. Further prospective studies are still necessary to draw a definite conclusion.

Validity of the modified versions of SARC-F+EBM for sarcopenia screening and diagnosis in China: the PPLSS study.

BACKGROUND AND OBJECTIVES: It is recommended by Asian Working Group for Sarcopenia to early identify people at risk for sarcopenia using simple screening tools like SARC-F. The modified version SARC-F+EBM showed higher diagnostic performance. However, this cut-off value of body mass index (BMI) remained uncertain to be used in Chinese population. In this study, we used appropriate BMI recommended for Chinese older population and further modified SARC-F+EBM by combining calf circumference. METHODS AND STUDY DESIGN: Diagnostic tests were performed and the receiver operating characteristics analyses were conducted between the SARC-F, SARC-F+EBM (cut-off of BMI: ≤ 21 kg/m2), SARC-F+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2), SARC-CalF and SARC-CalF+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2) in 1660 community-dwelling participants aged ≥ 65 years from China. RESULTS: The participants had an average age of 71.7±5.1 years, of which 56.8% were women. All the modified models could enhance the areas under the receiver operating characteristic curve (AUC) of original SARC-F (all p<0.001). The SARC-F+EBM (CN) also showed a significantly higher sensitivity of 47.4% (p<0.001) and an AUC of 0.809 (p=0.005) than SARC-F+EBM. SARC-CalF+EBM (CN) was validated to be of great diagnostic value of the highest AUC of 0.88 among these sarcopenia screening tools, including SARC-F, SARC-CalF and SARC-F+EBM (CN) (all p<0.001). Using this study population as a reference, the optimal cut-off value of SARC-CalF+EBM (CN) is ≥12 points, with a sensitivity of 79.3% and a specificity of 80.7%. CONCLUSIONS: The SARC-F+EBM (CN) and SARC-CalF+EBM (CN) could enhance the diagnostic performance of SARC-F and SARC-F+EBM and are suitable sarcopenia screening tools for Chinese population.

Evodiamine inhibits EPRS expression to regulate glutamate metabolism and proliferation of oral squamous cell carcinoma cells.

The effects of evodiamine (EVO) on oral squamous cell carcinoma (OSCC) are not yet understood. Based on our earlier findings, we hypothesized that evodiamine may affect OSCC cell proliferation and glutamate metabolism by modulating the expression of EPRS (glutamyl-prolyl-tRNA synthetase 1). From GEPIA, we obtained EPRS expression data in patients with OSCC as well as survival prognosis data. An animal model using Cal27 cells in BALB/c nude mice was established. The expression of EPRS was assessed by immunofluorescence, Western blotting, and quantitative PCR. Glutamate measurements were performed to evaluate the impact of evodiamine on glutamate metabolism of Cal27 and SAS tumor cells. transient transfection techniques were used to knock down and modulate EPRS in these cells. EPRS is expressed at higher levels in OSCC than in normal tissues, and it predicts poor prognosis in patients. In a nude mouse xenograft model, evodiamine inhibited tumor growth and the expression of EPRS. Evodiamine impacted cell proliferation, glutamine metabolism, and EPRS expression on Cal27 and SAS cell lines. In EPRS knockdown cell lines, both cell proliferation and glutamine metabolism are suppressed. EPRS's overexpression partially restores evodiamine's inhibitory effects on cell proliferation and glutamine metabolism. This study provides crucial experimental evidence supporting the potential therapeutic application of evodiamine in treating OSCC. Evodiamine exhibits promising anti-tumor effects by targeting EPRS to regulate glutamate metabolism.

The role of serum metrics in anti- VEGF treatment for macular edema induced by retinal vein occlusion.

AIM: To evaluate association between pretreatment serum metrics and best corrected visual acuity ( BCVA) of patients with macular edema secondary to retinal vein occlusion and its subtypes after intravitreal ranibizumab or conbercept implant. METHODS: This prospective research included 201 patients(201 eyes) who were diagnosed with macular edema secondary to retinal vein occlusion at Heibei Eye Hospital between January 2020 and January 2021, who all received intravitreal anti- vascular endothelial growth factor treatment. Serum metrics were measured before the first treatment, and correlations between BCVA and each of four parameters- platelets, neutrophil- to- lymphocyte ratio(NLR), platelet- to- lymphocyte ratio(PLR) and monocyte- to- lymphocyte ratio(MLR)- were analyzed to identify predictors of effective intravitreal injection treatment outcomes. RESULTS: The mean platelets was significantly different in the effective and ineffective group for RVO-ME (273.02 ± 41.49 × 109/L,214.54 ± 44.08 × 109/L P < 0.01),BRVO-ME (269.43 ± 49.52 × 109/L,214.72 ± 40.42 × 109/L P < 0.01), and CRVO-ME (262.32 ± 32.41 × 109/L,209.27 ± 42 0.91 × 109/L P < 0.01). The cutoff value of the platelets was 266.500, the area under the curve was 0.857,and the sensitivity and specificity were 59.8% and 93.6%, respectively. The mean PLR was significantly different in the effective and ineffective group for RVO-ME (154.66 ± 49.60, 122.77± 44.63 P < 0.01),BRVO-ME (152.24 ± 54.99, 124.72 ± 41.46 P = 0.003), and CRVO-ME (152.06±44.23, 118.67 ± 41.80 P = 0.001). The cutoff value of the platelets was 126.734, the area under the curve was 0.699, and the sensitivity and specificity were 70.7% and 63.3%, respectively. There were no statistical differencies between the effective and ineffective group(RVO- ME and its subtypes) in NLR and MLR. CONCLUSION: Higher pretreatment platelets and PLR were associated with BCVA in patients with RVO- ME and its subtypes who were treated with anti- VEGF drugs. The platelets and PLR may be used as predictive and prognostic tools for effective intravitreal injection treatment outcomes.

Efficacy and safety of anti-PD-1 antibody plus regorafenib in refractory microsatellite stable metastatic colorectal cancer: a retrospective single-arm cohort study.

Background: Managements for refractory proficient mismatch repair (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC) were still challenging and controversial. Our study sought to investigate the efficacy and safety of anti-programmed cell death protein 1 (anti-PD-1) antibodies plus regorafenib in refractory pMMR/MSS mCRC. Methods: We retrospectively analyzed the efficacy and safety of 103 pMMR/MSS mCRC patients treated with at least one dose of anti-PD-1 antibodies plus regorafenib (80 mg once daily for 21 days on/7 days off 28 days as a cycle) between July 2019 and June 2021 at the Hunan Cancer Hospital. All patients had previously received at least second-line treatment. The patients were evaluated by computed tomography every 2 or 3 treatment cycles until progression or being lost to follow-up. The primary end point was overall survival (OS). Results: The median follow-up period was 5.30 (range, 0.50-22.50) months. The median OS (mOS) and medical progression-free survival (mPFS) were 8.40 and 2.50 months for the entire cohort, respectively. The mOS and mPFS were 16.07 and 3.10 months in patients who received >1 cycle of anti-PD-1 antibodies and regorafenib (n=55), which were significantly longer than 4.37 and 1.11 months in those received only 1 cycle (n=48) (both P<0.001, respectively). The Cox multivariate regression analysis demonstrated that the number of cycles of regorafenib plus PD-1 and previously undergone surgery were independent risk factors for OS, whereas Sintilimab was confirmed to have a significant better PFS compared to other anti-PD-1 antibodies. Of the 55 patients who were evaluated, 7 were diagnosed with a partial response (PR) and another 16 were diagnosed with stable disease (SD), but no patient showed a complete response (CR). Thus, the objective response rate (ORR) was 12.7% and the disease control rate was 41.8%. Treatment-related adverse events (TRAEs) of grade 3 or higher occurred in 13 (12.6%) patients. Conclusions: The combination of regorafenib plus anti-PD-1 antibodies has a manageable safety profile and may improve prognosis for pMMR/MSS mCRC patients, especially those who received >1 cycle. Compared to the other anti-PD-1 antibodies, sintilimab may be more efficacious; however, further prospective studies need to be conducted to confirm our findings.

The post-translational modification of Fascin: impact on cell biology and its associations with inhibiting tumor metastasis.

The post-translational modifications (PTMs), which are crucial in the regulation of protein functions, have great potential as biomarkers of cancer status. Fascin (Fascin actin-bundling protein 1, FSCN1), a key protein in the formation of filopodia that is structurally based on actin filaments (F-actin), is significantly associated with tumor invasion and metastasis. Studies have revealed various regulatory mechanisms of human Fascin, including PTMs. Although a number of Fascin PTM sites have been identified, their exact functions and clinical significance are much less explored. This review explores studies on the functions of Fascin and briefly discusses the regulatory mechanisms of Fascin. Next, to review the role of Fascin PTMs in cell biology and their associations with metastatic disease, we discuss the advances in the characterization of Fascin PTMs, including phosphorylation, ubiquitination, sumoylation, and acetylation, and the main regulatory mechanisms are discussed. Fascin PTMs may be potential targets for therapy for metastatic disease.

Nutrition Risk Screening and Related Factors Analysis of Non-hospitalized Cancer Survivors: A Nationwide Online Survey in China.

Purposes: This study investigated the nutritional problems and risks of Chinese non-hospitalized cancer survivors through an online survey. Methods: The survey included nutritional and clinical questions distributed to non-hospitalized cancer survivors. All data were screened and analyzed with strict quality control. Nutrition Risk Screening-2002 (NRS-2002) was adopted and the related factors were analyzed. Results: Six thousand six hundred eighty-five questionnaires were included. The prevalence of nutritional risk was 33.9%, which varied according to age, sex, cancer type, TNM staging, oncologic treatment, time interval since last treatment, etc. In the regression analysis, nutritional risk was associated with age, TNM staging, and nutrition support. Patients with leukemia and digestive cancer had the highest NRS-2002 score (3.33 ± 1.45 and 3.25 ± 1.61); the prevalence of nutritional risk (NRS-2002 ≥ 3) was 66.7 and 55.1%, respectively. Patients with a higher TNM stage had higher NRS-2002 scores in non-digestive cancer, which was not seen in digestive cancer. Among digestive, bone, nervous, and respiratory cancer patients, the NRS-2002 score mainly consisted of "impaired nutritional status," which coincided with the "disease severity score" in leukemia patients. Nutrition intervention was achieved in 79.7 and 15.2% of patients with nutritional risk and no risk. Of the patients, 60.3% exhibited confusion about nutritional problems, but only 25.1% had professional counseling. Conclusions: Regular nutritional risk screening, assessment, and monitoring are needed to cover non-hospitalized cancer survivors to provide nutrition intervention for better clinical outcome and quality of life. By online survey, the nutritional risk of non-hospitalized cancer survivors was found high in China, but the nutrition support or professional consultation were not desirable. The composition of nutritional risk should also be aware of.

hsa_circ_0067514 suppresses gastric cancer progression and glycolysis via miR-654-3p/LATS2 axis.

Gastric cancer is the third most frequent cancer with high prevalence and mortality globally. Circular RNAs (circRNAs) play a key role in cancer regulation, including gastric cancer. Nevertheless, only a few circRNAs have been well elucidated in gastric cancer. Hence, we investigated the action of circ_0067514 on gastric cancer and clarified the underlying mechanism. Here, we found that circ_0067514 was decreased in gastric cancer patients and cancer cells. The circ_0067514 expression was correlated with gastric cancer overall survival, lymph node metastasis, tumor, node, metastasis (TNM) stage, and histological differentiation. Overexpression of circ_0067514 blocked proliferation, invasion, and glycolysis of gastric cancer cells. Besides, circ_0067514 regulated large tumor suppressor kinase 2 (LATS2) expression by absorbing microRNA (miR)-654-3p. Furthermore, circ_0067514 modulated gastric cancer aggressive behaviors and glycolysis via miR-654-3p/LATS2 axis. Moreover, circ_0067514 constrained tumor growth in vivo. Together, this study showed that circ_0067514 suppressed gastric cancer aggressive development and glycolysis via miR-654-3p/LATS2 axis, making circ_0067514 a valuable target for preventing gastric cancer progression.

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1.

In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene­knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low­density lipoprotein cholesterol (LDL­C) and high­density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of ß­cell islets was evaluated by using the insulin resistance index (HOMA­IR) and pancreatic ß­cell secretion index (HOMA­ß). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA­IR decreased since VEGFB was knocked down. Western blotting and RT­qPCR results revealed that the expression levels of VEGFR1 and neuropilin­1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid metabolism was detected, which provided a theoretical and experimental basis for VEGFB to affect the regulation of glucose and lipid metabolism balance.

Analysis on short-term change of macular function and the correlates after intravitreal conbercept for CRVO-ME.

AIM: To study the short-term change of macular function and the correlates after intravitreal conbercept for CRVO-ME. STUDY DESIGN: Prospective, clinical study. METHODS: Twenty Three patients(23 eyes) were recruited, who were non-ischemia central retinal vein occlusion diagnosed by FFA (fundus fluorescein angiography) and treated with intravitreal conbercept for macular edema, best - corrected visual acuity ( BCVA), central macular thickness(CMT), amplitude density of P1 wave and implicit time of P1,N1 wave from ring 1 and ring 2 of mf-ERG were measured before and 1 week、2 month after treatment. RESULTS: Compared to the baseline, BCVA、CMT、amplitude density of P1 wave and implicit time of P1,N1 wave from ring 1 and ring 2 were greatly improved at 1 W、2 M after treatment; better results were gained at 2 M compared to 1 W; Pearson correlation analysis shows no significantly correlation between the improvement of mf-ERG with the change of BCVA、CMT. CONCLUSION: The BCVA、the structure and the function of macular were greatly improved after intravitreal conbercept for central retinal vein occlusion induced macular edema; however no significantly correlation between the improvement of the function of macular with the strcture of macular and BCVA.

Pyroglutamate Aminopeptidase I Promotes Hepatocellular Carcinoma via IL-6/STAT3 Activation as Revealed by a Specific Biosensor.

As a global health challenge, hepatocellular carcinoma (HCC) is strongly associated with chronic inflammation. Targeting inflammation, particularly inflammatory factors, is regarded as an important strategy for HCC diagnosis and treatment. Pyroglutamic aminopeptidase I (PGP-I), a common exopeptidase, was recently identified as a novel inflammatory cytokine in cells. However, whether PGP-I is involved in HCC development and can be regarded as a biomarker remains unclear. To address this issue, endogenous PGP-I was imaged in live cells and in vivo, and the related biochemical and pathological processes were analyzed accordingly with a newly developed fluorogenic PGP-I biosensor. Bioimaging with the specific biosensor demonstrated the aberrant expression of PGP-I in HCC cell lines and tumor-bearing nude mice. Moreover, overexpression of PGP-I in HCC cells promoted tumor progression, whereas knockdown of PGP-I significantly suppressed tumor cell growth and migration. The activity of PGP-I was further identified to be highly related to the phosphorylation of STAT3, which could be impeded by the natural product parthenolide. Collectively, these findings suggest that PGP-I, which can promote hepatocellular tumor progression through the classical inflammation-/tumor-related IL-6/STAT3 pathway, may serve as a potential HCC biomarker and therapeutic target.

The effects and mechanism of α-mangostin on chemosensitivity of gastric cancer cells.

This work investigated the effect of α-mangostin (α-M) on gastric cancer (GC) cell chemoresistance and its underlying mechanisms. Different concentrations of α-M and CDDP were applied to treat GC cells (SGC7901) and CDDP-resistant GC cells (SGC7901/CDDP) for 24 or 48 h. CCK-8 assays were used to measure the inhibitory effect of CDDP or α-M on SGC7901 and SGC7901/CDDP cells as well as the half-maximal inhibitory concentrations (IC50) of α-M for SGC7901 and SGC7901/CDDP cells. The optimal concentration and induction time of CDDP or α-M were determined. SGC7901/CDDP cells were treated with CDDP or/and α-M, where some of them were transfected with pcDNA3.1 or pcDNA3.1-EBI3. Cell proliferation and apoptosis were assessed as well as the levels of EBI3, STAT3, p-STAT3, autophagy-related proteins, and apoptosis-related proteins. CDDP inhibited SGC7901 cell proliferation in a dose-dependent manner. The IC50 of α-M for SGC7901 cells was 12.86 µM and that for SGC7901/CDDP cells was 13.69 µM. The optimal concentrations of CDDP and α-M for SGC7901/CDDP cells were 2 and 15 µM, respectively, and the optimal time was 48 h. The SGC7901/CDDP cells in the CDDP+/α-M+ group had elevated inhibition of proliferation and apoptosis rates. Western blot analysis revealed enhanced levels of LC3-II/I and Beclin1, reduced p62 level, decreased Bcl2 level, and increased levels of Bax and cleaved caspase-3/9. The EBI3/STAT3 pathway was implicated in the effect of α-M on SGC7901/CDDP cell development. α-M increases the chemosensitivity of GC cells by facilitating autophagy and inactivating the EBI3/STAT3 pathway.

Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca2+ and cyclic adenosine monophosphate levels through PI3K/AKT pathway.

BACKGROUND: Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic ß-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic ß-cell dysfunction and is an important factor affecting ß-cell secretion of insulin. As an in vitro model of normal pancreatic ß-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects. AIM: To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation. METHODS: The MIN6 mouse pancreatic islet ß-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca2+ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway. RESULTS: Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca2+ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca2+ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins. CONCLUSION: VEGF-B can regulate insulin secretion by modulating the levels of Ca2+ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity.

The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer.

An Activity-Based Fluorogenic Probe Enables Cellular and in Vivo Profiling of Carboxylesterase Isozymes.

Carboxylesterases (CEs) exist as multiple types of isomers in humans, and two major types are CE1 and CE2. They are widely distributed in human tissues and well-known for their important roles in drug metabolism and pathology of various diseases. Thus, the detection of CEs in living systems could provide efficient proof in disease diagnostics, as well as important information regarding chemotherapeutic effects of antitumor drugs and prognosis. To develop a specific probe to discriminate CEs from other hydrolases, especially cholinesterases, is quite challenging due to their structural similarities and substrate specificity. To date, almost all of the fluorescent probes developed for CEs have been constructed with an acetyl group as the recognition unit. Herein we proposed a new design strategy of probe-cavity matching, which led to the identification of a new fluorogenic substrate (termed as HBT-CE) with high specificity toward both CE isomers and improved sensitivity, considering the higher binding affinity and catalysis efficiency. The promising capability of HBT-CE was further demonstrated for endogenous CEs imaging in living cells, zebrafish, and nude mice. In addition, HBT-CE was successfully applied in kinetically monitoring drug-induced CE regulation in cancer cells. All of these findings suggest that HBT-CE is a valuable tool for tracking and imaging endogenous CEs in complex biological systems.

Human Neutrophil Elastase Activated Fluorescent Probe for Pulmonary Diseases Based on Fluorescence Resonance Energy Transfer Using CdSe/ZnS Quantum Dots.

There is an increasing demand for effective noninvasive diagnosis against common pulmonary diseases, which are rising sharply due to the serious air pollution. Human neutrophil elastase (HNE), a typical protease highly involved in pulmonary inflammatory diseases and lung cancer, is a potential predictor for disease progression. Currently, few of the HNE-targeting probes are applicable in vivo due to the limitation in sensitivity and biocompatibility. Herein, we reported the achievement of in vitro detection and in vivo imaging of HNE by incorporating the HNE-specific peptide substrate, quantum dots (QDs), and organic dyes into the fluorescence resonance energy transfer (FRET) system. The refined nanoprobe, termed QDP, could specifically measure the HNE with excellent sensitivity of 7.15 pM in aqueous solution and successfully image the endogenous and exogenous HNE in living cells. In addition, this nanoprobe enabled HNE imaging in mouse models of lung cancer and acute lung injury, and the HNE activity at high temporal and spatial resolution was continuously monitored. Most importantly, QDP successfully discriminated the serums of patients with lung diseases from those of the healthy controls based on the HNE activity determination. Overall, this study demonstrates the advantages of a FRET-system-based nanoprobe in imaging performance and provides an applicable tool for in vivo HNE detection and pulmonary disease diagnosis.

[Correlation between nutritional status before radiotherapy and dietary intake in patients with oral cancers].

PURPOSE: To explore the correlation between dietary nutrient intake and PG-SGA score in patients with oral cancers before radiotherapy. METHODS: Sixty-five patients with oral cancers treated in Shanghai Ninth People's Hospital were selected. The 72-hour dietary survey method was used to understand the food intake of the patients. PG-SGA was used to make quantitative scoring of the nutritional status of the patients. SPSS 23.0 software package was used for data analysis. RESULTS: The number of severe malnutrition cases in male patients was significantly higher than that in female patients (P＜0.05). Energy, fat and fat energy ratio, carbohydrate and carbohydrate energy ratio from diet in good nutrition/mild malnutrition group, moderate malnutrition, severe malnutrition patients were over reference intake of dietary nutrients for Chinese residents; protein intake and protein energy ratio were greater than reference intake of nutrients for Chinese people. There was no significant difference among the three groups. The selenium intake of the well-nourished/mildly malnourished, moderately malnourished and severely malnourished groups was 67.15, 81.04 and 81.59 µg; vitamin E was 27.81, 30.88, 26.40 mg α-TE; vitamin C was 150.19, 159.81, 183.71 mg; retinol was 904.65, 1401.51, and 1373.81 µg RAE, respectively. Niacin was 12.97, 18.76 and 14.27 mg NE, respectively, reaching or exceeding the reference intake. There was no significant difference among the three groups. In male patients, dietary energy and niacin intake were negatively correlated with PG-SGA score (P<0.05). CONCLUSIONS: Patients with oral cancers have a high incidence of malnutrition before radiotherapy, and the average intake of dietary energy, protein, fat, carbohydrates and micronutrients such as selenium, vitamin E, vitamin C, retinol and niacin reached or exceeded the reference intake. Energy and niacin intake were negatively correlated with PG-SGA score in male patients.

Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention.

BACKGROUND: Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing-related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons. METHODS: A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non-sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty-two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre-intensive and post-intensive lifestyle interventions, were measured. RESULTS: The sarcopenic group was significantly older (72.05 ± 6.54 years; P < 0.001), more likely to be inactive and female (57.1% of all sarcopenic patients), and had a higher prevalence of type 2 diabetes (16% higher risk). Compared with non-sarcopenic subjects, serum interleukin (IL)-6, IL-18, tumour necrosis factor-α (TNF-α), TNF-like weak inducer of apoptosis (TWEAK), and leptin were significantly higher, while insulin growth factor 1, insulin, and adiponectin were significantly lower in sarcopenic patients (all P < 0.05). Logistic regression analyses revealed that high levels of TNF-α (>11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6-fold and 14.3-fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4-fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF-α, IL-18, insulin, and adiponectin (all P < 0.05). CONCLUSIONS: High levels of the inflammatory cytokines TWEAK and TNF-α are associated with an increased risk of sarcopenia, while the metabolic hormones insulin growth factor 1, insulin, and adiponectin are associated with a decreased risk of sarcopenia in our Chinese patient cohort. Intensive lifestyle interventions could significantly improve muscle mass, reduce inflammation, and restore metabolic hormone levels in sarcopenic patients. This trial was registered at clinicaltrials.gov as NCT02873676.

Activity-Based Near-Infrared Fluorogenic Probe for Enabling in Vitro and in Vivo Profiling of Neutrophil Elastase.

Neutrophil elastase (NE), a typical hematopoietic serine protease, has significant roles in inflammatory and immune responses, and thus is highly associated with various diseases such as acute lung injury (ALI) and lung cancer. Rapid and accurate measurement of NE activity in biological systems is particularly important for understanding the role of NE in inflammatory diseases, as well as clinical diagnosis. However, the specific detection and noninvasive imaging of NE in vivo remains a challenge. To address this issue, a small-molecule substrate based near-infrared fluorogenic probe (NEP) for NE was constructed via incorporating pentafluoroethyl as the recognition group with a hemicyanine dye-based fluorophore. This initially quenched probe possesses more than 25-fold red fluorescence enhancement upon the catalysis of human NE, and the detection limit is about 29.6 ng/mL. In addition, the high specificity and the long emission wavelength (λemmax = 700 nm) of NEP allowed the direct monitoring of NE-trafficking, exogenous NE uptake, and endogenous NE upregulation at the cellular level. Moreover, the successful spatiotemporal imaging of NE in ALI model mice also made it a promising new tool in clinical diagnosis for ALI and other lung diseases.