Roles of fibroblast growth factors in the treatment of diabetes.

Diabetes affects about 422 million people worldwide, causing 1.5 million deaths each year. However, the incidence of diabetes is increasing, including several types of diabetes. Type 1 diabetes (5%-10% of diabetic cases) and type 2 diabetes (90%-95% of diabetic cases) are the main types of diabetes in the clinic. Accumulating evidence shows that the fibroblast growth factor (FGF) family plays important roles in many metabolic disorders, including type 1 and type 2 diabetes. FGF consists of 23 family members (FGF-1-23) in humans. Here, we review current findings of FGFs in the treatment of diabetes and management of diabetic complications. Some FGFs (e.g., FGF-15, FGF-19, and FGF-21) have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes, and their therapeutic roles in diabetes are currently under investigation in clinical trials. Overall, the roles of FGFs in diabetes and diabetic complications are involved in numerous processes. First, FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production. Second, modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components, promote diabetic wound healing process and bone repair, and inhibit cancer cell proliferation and migration. Finally, FGFs can regulate the activation of glucose-excited neurons and the expression of thermogenic genes.

Interleukins in liver disease treatment.

Cytokines play pleiotropic roles in human health and disease by regulating both innate and adaptive immune responses. Interleukins (ILs), a large group of cytokines, can be divided into seven families, including IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and IL-17 families. Here, we review the functions of ILs in the pathogenesis and resolution of liver diseases, such as liver inflammation (e.g., IL-35), alcohol-related liver disease (e.g., IL-11), non-alcoholic steatohepatitis (e.g., IL-22), liver fibrosis (e.g., Il-17a), and liver cancer (e.g., IL-8). Overall, IL-1 family members are implicated in liver inflammation induced by different etiologies, such as alcohol consumption, high-fat diet, and hepatitis viruses. IL-2 family members mainly regulate T lymphocyte and NK cell proliferation and activation, and the differentiation of T cells. IL-6 family cytokines play important roles in acute phase response in liver infection, liver regeneration, and metabolic regulation, as well as lymphocyte activation. IL-8, also known as CXCL8, is activated in chronic liver diseases, which is associated with the accumulation of neutrophils and macrophages. IL-10 family members contribute key roles to liver immune tolerance and immunosuppression in liver disease. IL-12 family cytokines influence T-cell differentiation and play an essential role in autoimmune liver disease. IL-17 subfamilies contribute to infection defense, liver inflammation, and Th17 cell differentiation. ILs interact with different type I and type II cytokine receptors to regulate intracellular signaling pathways that mediate their functions. However, most clinical studies are only performed to evaluate IL-mediated therapies on alcohol and hepatitis virus infection-induced hepatitis. More pre-clinical and clinical studies are required to evaluate IL-mediated monotherapy and synergistic therapies.

[Imaging findings of carcinoma ex pleomorphic adenoma in minor salivary glands].

PURPOSE: To summarize the CT and MR imaging features of carcinoma ex pleomorphic adenoma(Ca-ex-PA) in minor salivary gland, and analyze the correlation between various features and pathological classification. METHODS: Forty-three patients with Ca-ex-PA in minor salivary gland were collected. The CT and MRI findings were retrospectively analyzed and correlated with their pathological types. Fisher's exact test was used to analyze the correlation between various imaging features (tumor morphology, boundary, internal structure, bone invasion, cervical lymph node metastasis) and pathological types with SPSS 25.0 software package. RESULTS: Among the 43 patients with Ca-ex-PA, 83.7%(36/43) of the tumors were lobulated; 81.4%(35/43) showed cystic degeneration or necrosis, with heterogeneous enhancement. Coarse calcification or mixed calcification was found in 37.2%(16/43), 25.6%(11/43) had compressive absorption of adjacent bone. 75%(12/16) of type Ⅰ/Ⅱ tumors had regular morphology (round or oval), and 77.8%(21/27) of type Ⅲ tumors had irregular morphology, 93.8%(15/16) of type Ⅰ/Ⅱ tumors had well-defined margin and 66.7%(18/27) of type Ⅲ tumors had ill-defined margin. Osteolytic bone resorption occurred in 59.3%(16/27) of type Ⅲ tumors. The average maximum diameter of type Ⅰ/Ⅱ tumors was significantly shorter than that of type Ⅲ(P＜0.05). Fisher's exact test showed the characteristics of tumor morphology, boundary and osteolytic bone resorption were related to pathological grouping(P＜0.001). CONCLUSIONS: Most Ca-ex-PA in minor salivary glands is characterized by lobular and heterogeneous enhanced neoplasm on CT and MR imaging. A round or oval tumor with well-defined margin usually correlates with typeⅠ and Ⅱ, contrarily, an irregular mass with ill-defined margin and osteolytic bone destruction usually correlates with type Ⅲ. Combining the three characteristics of morphology, boundary and osteolysis is more helpful to distinguish type Ⅰ/Ⅱ and type Ⅲ tumors.

Treatment of liver fibrosis: Past, current, and future.

Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty liver disease. It is commonly associated with liver injury, inflammation, and cell death. Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins. Activated hepatic stellate cells contribute to the major population of myofibroblasts. Many treatments for liver fibrosis have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment (e.g., simtuzumab), drug (e.g., pegbelfermin and natural herbs), genetic regulation (e.g., non-coding RNAs), and transplantation of stem cells (e.g., hematopoietic stem cells). However, none of these treatments has been approved by Food and Drug Administration. The treatment efficacy can be evaluated by histological staining methods, imaging methods, and serum biomarkers, as well as fibrosis scoring systems, such as fibrosis-4 index, aspartate aminotransferase to platelet ratio, and non-alcoholic fatty liver disease fibrosis score. Furthermore, the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis. To avoid the life-threatening stage of liver fibrosis, anti-fibrotic treatments, especially for combined behavior prevention, biological treatment, drugs or herb medicines, and dietary regulation are needed. This review summarizes the past studies and current and future treatments for liver fibrosis.

Antioxidant and anti-inflammatory agents in chronic liver diseases: Molecular mechanisms and therapy.

Chronic liver disease (CLD) is a continuous process that causes a reduction of liver function lasting more than six months. CLD includes alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to liver fibrosis, cirrhosis, and cancer. Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, and peroxisome proliferator-activated receptors (PPARs) are implicated in the pathogenesis of CLD. Therefore, antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD, NAFLD, and hepatocellular carcinoma (HCC). In this review, we summarize some powerful products that can be potential applied in all the stages of CLD, from ALD/NAFLD to HCC. The selected agents such as ß-sitosterol, curcumin, genistein, and silymarin can regulate the activation of several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, and lysyl oxidase-like proteins. In addition, clinical trials are undergoing to evaluate their efficacy and safety.

Adenoid cystic carcinoma in children and young adults: A clinicopathological study of 12 cases.

OBJECTIVE: To investigate the clinicopathological characteristics, immunoprofile, and molecular alterations of adenoid cystic carcinoma (ACC) in children and young adults. MATERIALS AND METHODS: Twelve cases of ACC were included. MYB, MYBL1, Ki-67, type IV Collagen, Laminin, and LAMB1 expression were detected by immunohistochemistry. MYB and MYBL1 rearrangements were detected by fluorescence in situ hybridization. RESULTS: Among 12 patients, four were female and eight were male. Seven cases (58.3%) located in major salivary glands and eight cases (66.7%) were classified as Grade I. Ten tumors (83.3%) had collagenous and hyalinized stroma. MYB was positive in 83.3% cases, and the average Ki-67 labeling index (LI) was 8.3%. LAMB1, type IV Collagen, and Laminin were positive in 91.7%, 66.7%, and 58.3% cases, respectively. Besides, three out of eight tumors had MYB rearrangement. Cases without MYB rearrangement were negative for MYBL1 expression and MYBL1 rearrangement. The average follow-up time was 91.8 months. Four patients had recurrent diseases. CONCLUSIONS: ACC in children and young adults was seen more frequently in males and major salivary glands. Most cases had ECM and hyaline stroma. Grade III tumors, higher Ki-67 LI, negative expression of type IV Collagen, and Laminin showed a tendency of higher recurrence rate.

Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Factors including carcinogens, infection of hepatitis viruses, alcohol abuse, and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression. Immunotherapy is one of the most powerful tools for unresectable HCC treatment in patients. CD8+ T cells are a major immune component in the tumor microenvironment with cytotoxic effects against cancer cells. However, these CD8+ T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing-3, and/or lymphocyte-activation gene 3, producing low levels of perforin (PRF1) and granzyme B (GZMB), as well as anti-tumor cytokines, such as interferon gamma and tumor necrosis factor alpha. In the referenced study, the authors also showed that deprivation of glutamine decreased the antitumor function of CD8+ T cells, as well as the production of PRF1 and GZMB. However, the role of each amino acid in T cell function and exhaustion may depend on tumor type and tumor microenvironment, including the source of other nutrients. Overall, amino acids or other nutrient metabolites in the tumor microenvironment play a pivotal role in both tumor growth and immune response.

Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy.

Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma (HCC). Factors, including carcinogens, infection of hepatitis viruses, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), can induce HCC initiation and promote HCC progression. The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide. However, the benefit of current therapeutic options is still limited. Intrahepatic immunity plays critically important roles in HCC initiation, development, and progression. Regulatory T cells (Tregs) and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC. Therefore, targeting Tregs and blocking their mediated factors may prevent HCC progression. This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD, liver fibrosis, cirrhosis, and viral infections. Overall, a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.

Crosstalk between gut microbiota and COVID-19 impacts pancreatic cancer progression.

Pancreatic cancer (PC) is one of the most common causes of cancer-associated death worldwide, with a low rate of 5-year survival. Currently, the pathogenesis of PC is complicated, with no efficient therapy. Coronavirus disease 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus 2 further exacerbates the challenge of patients with PC. The alteration of gut microbiota caused by COVID-19 infection may impact PC progression in patients via immune regulation. The expression of inflammatory immune mediators such as interleukin (IL)-6, IL-8, and IL-10 has been found to increase in both PC and COVID-19 patients, which is associated with the disease severity and prognostic outcome. Gut microbiome serves as a critical connector between viral infection and PC. It can regulate host systemic immune response and impact the efficacy of immunotherapy. Here, we first demonstrated the features of inflammatory cytokines in both diseases and their impact on disease outcomes. Then, we demonstrated the importance of immunotherapeutic strategies. This includes the immune modulation that targets a single or dual receptors using a single agent or their combinations for the treatment of PC in patients who get infected with COVID-19. Additionally, we explored the possibility of managing the disease by regulating gut microbiome. Overall, modulation of the lung-gut-pancreases axis can boost anti-cancer immunotherapy and reduce adverse prognostic outcomes.

Important role of acute care surgery during pandemic time.

Pandemic impacts acute care surgery for diseases, such as gallbladder disease and acute appendicitis. At the early stage of coronavirus disease 2019 (COVID-19) pandemic, the case number of patients needing surgery decreased in hospitals from different countries. This decline was associated with the stay-home order and fear of getting COVID-19 infection. However, recent reports show that the case number for acute surgery returns to the normal level, which is comparable to that before the beginning of the pandemic. In addition, a variety of diseases show more severe than the cases before the pandemic, which might be caused by factors such as lack of regular follow-up and screening diagnosis and infection of viruses.

Functions of three ubiquitin-conjugating enzyme 2 genes in hepatocellular carcinoma diagnosis and prognosis.

BACKGROUND: Liver cancer ranks the third cause of cancer-related death worldwide. The most common type of liver cancer is hepatocellular carcinoma (HCC). The survival time for HCC patients is very limited by years due to the lack of efficient treatment, failure of early diagnosis, and poor prognosis. Ubiquitination plays an essential role in the biochemical processes of a variety of cellular functions. AIM: To investigate three ubiquitination-associated genes in HCC. METHODS: Herein, the expression levels of ubiquitin-conjugating enzymes 2 (UBE2) including UBE2C, UBE2T, and UBE2S in tumor samples of HCC patients and non-tumor controls at the Cancer Genome Atlas (TCGA) database, was comprehensively analyzed. The relationship of UBE2 gene expression level with cancer stage, prognostic outcome, and TP53 mutant status was studied. RESULTS: Our results showed that UBE2C, UBE2T, and UBE2S genes were overexpressed in HCC samples compared to non-tumor tissues. Dependent on the cancer progression stage, three UBE2 genes showed higher expression in tumor tissues at all four stages compared to non-tumor control samples. Furthermore, a significantly higher expression of these genes was found in stage 2 and stage 3 cancers compared to stage 1 cancer. Additionally, overexpression of those genes was negatively associated with prognostic outcome and overall survival time. Patients with TP53 mutation showed a higher expression level of three UBE2 genes, indicating an association between UBE2 expression with p53 function. CONCLUSION: In summary, this study shed light on the potential roles of UBE2C, UBE2T, UBE2S on diagnostic and prognostic biomarkers for HCC. Moreover, based on our findings, it is appealing to further explore the correlation of those genes with TP53 mutation in HCC and the related mechanisms.

Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options.

Pancreatic cancer (PC) is the third-leading cause of cancer deaths. The overall 5-year survival rate of PC is 9%, and this rate for metastatic PC is below 3%. However, the PC-induced death cases will increase about 2-fold by 2060. Many factors such as genetic and environmental factors and metabolic diseases can drive PC development and progression. The most common type of PC in the clinic is pancreatic ductal adenocarcinoma, comprising approximately 90% of PC cases. Multiple pathogenic processes including but not limited to inflammation, fibrosis, angiogenesis, epithelial-mesenchymal transition, and proliferation of cancer stem cells are involved in the initiation and progression of PC. Early diagnosis is essential for curable therapy, for which a combined panel of serum markers is very helpful. Although some mono or combined therapies have been approved by the United States Food and Drug Administration for PC treatment, current therapies have not shown promising outcomes. Fortunately, the development of novel immunotherapies, such as oncolytic viruses-mediated treatments and chimeric antigen receptor-T cells, combined with therapies such as neoadjuvant therapy plus surgery, and advanced delivery systems of immunotherapy will improve therapeutic outcomes and combat drug resistance in PC patients. Herein, the pathogenesis, molecular signaling pathways, diagnostic markers, prognosis, and potential treatments in completed, ongoing, and recruiting clinical trials for PC were reviewed.

Diagnostic biomarkers for pancreatic cancer: An update.

Pancreatic ductal adenocarcinoma accounts for the primary type of pancreatic cancer (PC) with a 5-year survival rate of only about 10% in the United States. Early diagnosis will improve chances for curative treatment. To date, a broadly used serum marker for PC diagnosis is carbohydrate antigen 19-9, which is the only approved biomarker currently by the United States Food and Drug Administration. However, it has low specificity; therefore, development of novel biomarkers is urgently needed. Clinical trials are ongoing to evaluate candidate biomarkers for PC diagnosis, and the use of a multi-biomarker panel with current PC diagnostic biomarkers appears promising.

Melanotic Neuroectodermal Tumor of Infancy: A Clinicopathological and BRAF V600E Mutation Study of 11 Cases.

PURPOSE: To investigate the clinicopathological features and BRAF V600E mutation of melanotic neuroectodermal tumor of infancy (MNTI). MATERIALS AND METHODS: Eleven cases of MNTI diagnosed at the Department of Oral Pathology were collected. Clinicopathological characteristics were obtained from the medical records. Immunostaining was performed by immunohistochemistry (IHC). Amplification-Refractory Mutation System-qPCR (ARMS-qPCR) and Sanger Sequencing were used to detect BRAF V600E mutation. RESULTS: Of the 11 cases, 3 cases were female and 8 cases were male. The mean age of the first symptoms was 3.2 months (range: 1 to 6 months). Ten cases (90.9%) located in maxilla but only one (9.1%) in mandible. Most of the cases demonstrated well-defined mass with lytic bone destruction and tooth germ affecting radiologically. Histologically, MNTI was consisted of large polygonal melanin-producing epithelioid cells and small round neuroblast-like cells which arranged in irregular alveolar, tubuloglandular and fissured architecture. The epithelioid cells expressed Vim, Pan-CK, NSE and HMB45, while the smalls cells expressed Syn, NSE and scattered Vim. Most cases showed low Ki-67 index (range: <1% to 50%). None of the MNTI cases showed BRAF V600E mutation. Most cases were treated with enucleation (45.4%) or curettage (36.4%). Among the 11 cases, 6 cases had follow-up information, and 2 cases had recurrence lesions after surgery. CONCLUSION: MNTI, an extremely rare tumor, mainly affects male infants with strong preference for maxilla. Distinct histopathological features and immunohistochemical profile are helpful to distinguish from other melanin-containing tumors and small round cell tumors. No BRAF V600E mutation in MNTI is detected in the present study and needs further investigations. The factors that contribute to the local recurrence of MNTI are controversial, but the close follow-up for the patients is recommended.

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment.

Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.

Analysis of Immunological Characteristics and Genomic Alterations in HPV-Positive Oropharyngeal Squamous Cell Carcinoma Based on PD-L1 Expression.

Programmed death-ligand 1 (PD-L1) expression has been approved as an immune checkpoint inhibitor (ICI) response predictive biomarker; however, the clinicopathological and molecular features of HPV-positive oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] based on PD-L1 expression are not well studied. We aimed to characterize clinicopathological, tumor immune microenvironmental, and molecular features of HPV(+)OPSCC with different PD-L1 expression scored by combined positive score (CPS). A total of 112 cases were collected from 2008-2021 and received PD-L1 and CD8 immunohistochemistry (IHC) staining. 71 samples received DNA sequencing out of which 32 samples received RNA sequencing for immune-related gene alterations or expression analysis. The 32 samples were also subjected to analysis of CD20, CD4, CD8, CD68, Foxp3 and P16 by multiplex immunofluorescence (mIF) staining, and the immune markers were evaluated in the tumor body (TB), tumor margin (TM) and normal stroma (NS) regions separately. Our results showed that of 112 HPV(+)OPSCC tumors, high(CPS≥20), intermediate(1≤CPS<20), and low(CPS<1) PD-L1 expression was seen in 29.5%, 43.8% and 26.8% cases respectively. Non-smoking patients and patients with tumors occurring at the tonsils or having rich lymphocytes infiltration had significantly higher PD-L1 expression. Patients with CPS≥20 had significantly higher tumor mutation burden (TMB, p=0.0058), and PD-L1 expression correlated significantly with CD8+ T cells infiltration, which were ample in tumor regions than in NS in mIF. CD20+, CD4+, CD68+, Foxp3+CD4+ cells were demonstrated to infiltrate higher in TM while CD20+ and CD68+ cells were also enriched in NS and TB regions respectively. However, none of them showed correlations with PD-L1 expression. ARID1A, STK11 alterations were enriched in the low PD-L1 group significantly, while anti-viral immune associated APOBEC mutation signature and immune-related genes expression such as XCL1 and IL11 were positively associated with PD-L1 expression (p<0.05). This is a comprehensive investigation revealing immune and molecular features of HPV(+)OPSCC based on PD-L1 expression. Our study suggested that 73.2% of HPV(+)OPSCC patients may benefit from immunotherapy, and high PD-L1 expression reflects immune-active status of HPV(+)OPSCC accompanied by higher immune effect factors such as TMB, CD8+ cytotoxic T cells and immune-related genomic alterations. Our study offers valuable information for understanding the immune features of HPV(+)OPSCC.

Primary pseudomyogenic hemangioendothelioma of right maxilla: a case with immunohistochemistry and FOSB rearrangement study.

OBJECTIVE: Primary pseudomyogenic hemangioendothelioma (PMH) of bone is an extremely rare vascular neoplasm. We present here a case of primary PMH occurring in the maxilla. STUDY DESIGN: A 34-year-old man was referred to our hospital for treatment because of possible recurrence after surgery and chemotherapy of a right maxillary malignant tumor. Morphologic features, immunophenotypes, and FOSB gene rearrangement status of the surgically sectioned sample were assessed by hematoxylin-eosin staining, immunohistochemistry, and fluorescence in situ hybridization, respectively. RESULTS: Morphologically, the tumor cells were arranged in a loose fascicular and sheet-like manner, with a large number of reactive woven bones forming. The most striking feature was the presence of epithelioid cells with abundant brightly eosinophilic cytoplasm, which resembled the rhabdomyoblast in appearance. The tumor was diffusely positive for AE1/AE3, CD31, erythroblast transformation-specific transcription factor, and Friend leukemia integration 1; negative for CD34, CAM5.2, epithelial membrane antigen, and desmin; and had retained expression of integrase interactor 1. The tumor harbored FOSB rearrangement. No distant metastasis was found during the follow-up period (18 months). CONCLUSIONS: To the best of our knowledge, this case represents the first report of PMH arising in the maxilla. The distinct morphologic features, immunophenotypes, and FOSB rearrangement could help achieve precise diagnosis and prevent misdiagnosis of mimics with overlapping features.

Ameloblastoma with mucous cells: A clinicopathological, BRAF mutation, and MAML2 rearrangement study.

OBJECTIVES: To investigate the clinicopathological features, BRAF V600E mutation, and MAML2 rearrangement of ameloblastoma with mucous cell differentiation. MATERIALS AND METHODS: Five cases of ameloblastoma with mucous cell differentiation were retrospectively studied. Clinicopathological features, BRAF V600E mutation, and MAML2 rearrangement were analyzed. Follow-up information was available for all cases. RESULTS: Of five cases, two cases were male and three were female, aged 18-55 years. Four cases were located in the mandible and one case in the maxilla. Histologically, four of the five cases (80%) presented with cystic features and three of the five cases (60%) with varying degrees of squamous metaplasia. The mucous cells were located in the epithelial islands or the luminal aspect of the cystic cavities. The BRAF V600E mutation was found in three of five cases (60%). All the cases showed no MAML2 rearrangement. Two cases were recurrent lesions, and one case had a local recurrence during the follow-up. CONCLUSIONS: Ameloblastoma with mucous cell differentiation is closely related to the cystic features, squamous metaplasia, and shows a high prevalence of BRAF V600E mutation. The absence of MAML2 rearrangement reveals that ameloblastoma with mucous cell differentiation and central mucoepidermoid carcinoma (MEC) are two distinct tumor entities.

Efficacy of fluoxetine for anorexia nervosa caused by chemotherapy in patients with cholangiocarcinoma.

BACKGROUND: Fluoxetine has been reported to treat anorexia nervosa (AN) caused by chemotherapy in patients with cholangiocarcinoma effectively. However, no study systematically investigated its efficacy and safety. Thus, this study will systematically assess its efficacy and safety for AN caused by chemotherapy in patients with cholangiocarcinoma. METHODS: A comprehensive literature search for relevant studies will be conducted from the following databases from inception to the present: MEDILINE, EMBASE, Cochrane Library, Web of Science, PSYCINFO, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All randomized controlled trials on assessing the efficacy and safety of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma will be considered for inclusion in this study. RevMan V.5.3 software will be used for risk of bias assessment and statistical analysis. RESULTS: This study will summarize the latest evidence of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma through assessing outcomes of weight, depression, anxiety, and quality of life. Additionally, any adverse events will also be analyzed. CONCLUSION: The findings of this study will provide most recent evidence of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019131583.

In Vitro Metabolism by Aldehyde Oxidase Leads to Poor Pharmacokinetic Profile in Rats for c-Met Inhibitor MET401.

BACKGROUND AND OBJECTIVES: MET401 is a potent and selective c-Met inhibitor with a novel triazolopyrimidine scaffold. The aim of this study was to determine the pharmacokinetic profile of MET401 in preclinical species, and to identify the metabolic soft spot and enzyme involved, in order to help medicinal chemists to modify the compound to improve the pharmacokinetic profile. METHODS: A metabolite identification study was performed in different liver fractions from various species. Chemical inhibition with selective cytochrome P450 (CYP) and molybdenum hydroxylase inhibitors was carried out to identify the enzyme involved. The deuterium substitution strategy was adopted to reduce metabolism. Pharmacokinetic studies were performed in rats to confirm the effect. RESULTS: Although M-2 is a minor metabolite in liver microsomal incubations, it became the predominant metabolite in incubations with liver S9, cytosol, hepatocytes and rat pharmacokinetic study. M-2 was synthesized enzymatically and the structure was identified as a mono-oxidation on the triazolopyrimidine moiety. The M-2 formation was ascribed to aldehyde oxidase (AO)-mediated metabolism based on the following evidence-M-2 production was NADPH independent, pan-CYP inhibitor 1-aminobenzotriazole and xanthine oxidase inhibitor allopurinol did not inhibit M-2 formation, and AO inhibitors menadione and raloxifene inhibited M-2 formation. The deuterated analog MET763 demonstrated an improved pharmacokinetic profile with lower clearance, longer terminal half-life and double oral exposure compared with MET401 in rats. CONCLUSIONS: These results indicate that the main metabolic pathway of MET401 is AO-mediated metabolism, which leads to poor in vivo pharmacokinetic profiles in rodents. The deuterium substitution strategy could be used to reduce AO-mediated metabolism liability.