Characterization of tumors of jaw:Additive value of contrast enhancement and dual-energy computed tomography

BACKGROUND Currently,the differentiation of jaw tumors is mainly based on the lesion’s morphology rather than the enhancement characteristics,which are important in the differentiation of neoplasms across the body.There is a paucity of literature on the enhancement characteristics of jaw tumors.This is mainly because,even though computed tomography(CT)is used to evaluate these lesions,they are often imaged without intravenous contrast.This study hypothesised that the enhancement characteristics of the solid component of jaw tumors can aid in the differentiation of these lesions in addition to their morphology by dual-energy CT,therefore improving the ability to differentiate between various pathologies.AIM To evaluate the role of contrast enhancement and dual-energy quantitative parameters in CT in the differentiation of jaw tumors.METHODS Fifty-seven patients with jaw tumors underwent contrast-enhanced dual-energy CT.Morphological analysis of the tumor,including the enhancing solid component,was done,followed by quantitative analysis of iodine concentration(IC),water concentration(WC),HU,and normalized IC.The study population was divided into four subgroups based on histopathological analysis-central giant cell granuloma(CGCG),ameloblastoma,odontogenic keratocyst(OKC),and other jaw tumors.A one-way ANOVA test for parametric variables and the Kruskal-Wallis test for nonparametric variables were used.If significant differences were found,a series of independent t-tests or Mann-Whitney U tests were used.RESULTS Ameloblastoma was the most common pathology(n=20),followed by CGCG(n=11)and OKC.CGCG showed a higher mean concentration of all quantitative parameters than ameloblastomas(P<0.05).An IC threshold of 31.35×100μg/cm^(3) had the maximum sensitivity(81.8%)and specificity(65%).Between ameloblastomas and OKC,the former showed a higher mean concentration of all quantitative parameters(P<0.001),however when comparing unilocular ameloblastomas with OKCs,the latter showed significantly higher WC.Also,ameloblastoma had a higher IC and lower WC compared to“other jaw tumors”group.CONCLUSION Enhancement characteristics of solid components combined with dual-energy parameters offer a more precise way to differentiate between jaw tumors.

Histopathology and Immunohistochemistry Assessments of Acute Experimental Infection by <i>Brucella melitensis</i>in Bucks

Background: Brucellosis in male goats is characterized by arthritis, orchitis and epididymitis, which may induce infertility. Nevertheless, these lesions were categorized as chronic while acute lesions had not been described. This study investigates the histopathological and immuno histochemistry reactions in organs of bucks acutely infected by Brucella melitensis. Results: Only testis and prepuce of acutely infected bucks showed significantly severe histological lesions. Other internal organs had mild to moderate lesions. However, positive immunohistochemistry stainings were observed in organs except the bulbourethral gland. There was a significant positive correlation between the distribution of B. melitensis and IHC intensity but no significant correlation between the IHC intensity and histopathology lesions. Conclusion: The results indicate that acute brucellosis did not lead to clinical presentation, although B. melitensis was well distributed in various organs of bucks.

Mucosal healing and inflammatory bowel disease:Therapeutic implications and new targets

Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.

Overview of angiogenesis and oxidative stress in cancer

Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiologically.Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress;the latter being one of the most powerful stimuli of angiogenesis.As a result of altered tumor metabolism due to hypoxia,acidosis occurs.The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers.The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers,ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies.In particular,in the treatment of patients with similar clinical tumor phenotypes but different prognoses,the new biomarkers could be useful.Moreover,they may lead to a better understanding of the mechanisms underlying drug resistance.Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells,which require a high vascular supply.

Microscopic and metabolic investigations disclose the factors that lead to skin cracking in chili-type pepper fruit varieties

The hydrophobic cuticle encasing the fruit skin surface plays critical roles during fruit development and post-harvest.Skin failure often results in the fruit surface cracking and forming a wound-periderm tissue made of suberin and lignin.The factors that make the fruit skin susceptible to cracking have yet to be fully understood.Herein,we investigated two varieties of chili peppers(Capsicum annuum L.),Numex Garnet,whose fruit has intact skin,and Vezena Slatka,whose fruit has cracked skin.Microscopical observations,gas chromatography-mass spectrometry,biochemical and gene expression assays revealed that Vezena Slatka fruit form a thicker cuticle with greater levels of cutin monomers and hydroxycinnamic acids,and highly express key cutin-related genes.The skin of these fruit also had a lower epidermal cell density due to cells with very large perimeters,and highly express genes involved in epidermal cell differentiation.We demonstrate that skin cracking in the Vezena Slatka fruit is accompanied by a spatial accumulation of lignin-like polyphenolic compounds,without the formation of a typical wound-periderm tissues made of suberized cells.Lastly,we establish that skin cracking in chili-type pepper significantly affects fruit quality during post-harvest storage in a temperature-dependent manner.In conclusion,our data highlight cuticle thickness and epidermal cell density as two critical factors determining fruit skin susceptibility to cracking in chili-type pepper fruit.

A Survey of the Major Sorghum Production Regions for Foliar and Panicle Diseases during the 2022 Growing Season in Senegal, West Africa

Sorghum is a vital commodity and greatly contributes to the daily calorie needs for millions of the inhabitants in Senegal, West Africa. Yet, sorghum productivity and profitability are impacted by diseases. In the 2022 growing season, 122 farmers’ fields across 7 regions, notably Diourbel, Fatick, Kaffrine, Kaolack, Kolda, Tambacounda, and Thies were surveyed for foliar and panicle diseases. During the survey, stops were made at 30 km intervals and at each stop, 2 - 5 fields were evaluated. In each field, 40 plants mostly at soft to early hard dough stages of development were assessed using a W-shaped pattern to cover the whole field. A total of 13 diseases, including leaf blight, anthracnose, Zonate leaf spot, Sooty stripe, rough leaf spot, oval leaf spot, long smut, grain mold, and covered kernel smut were documented. The most predominant diseases were leaf blight, anthracnose, and zonate leaf spot. The prevalence of leaf blight was 100%, while anthracnose and zonate leaf spot were found in 93 out of the 122 fields surveyed, indicating a 76% prevalence, respectively. Across the regions, the prevalence of rough leaf spot was 47%, covered kernel smut (32%), oval leaf spot (19%) and target leaf spot (19%). Mean incidence of leaf blight was high in all regions, ranging from 94% (Kaolack) to 100% (Fatick and Tambacounda). The highest mean incidence of anthracnose (62%) and covered kernel smut (16%) was noted in Tambacounda region. In the region of Thies, the highest mean incidence of zonate leaf spot (49%) was recorded. The mean severity of leaf blight (37%) was highest on plants assessed in the region of Kaffrine, followed by those in the regions of Kaolack, Tambacounda, and Kolda. Anthracnose infection was most intense on plants evaluated in Kolda, while zonate leaf spot was most severe in the region of Tambacounda. Fields with incidences of 85% and above were considered as “hotspots” to evaluate sorghum germplasm for disease resistance. This survey is significant because the information obtained will be beneficial to plant pathologists, sorghum producers, government officials, and funding agencies to prioritize research projects that ensure productivity and food security.

The arms race between Magnaporthe oryzae and rice: Diversity and interaction of Avr and R genes

Rice blast disease, caused by Magnaporthe oryzae, threatens global food security. The rice blast pathosystem is a longstanding model system for understanding plant-microbe interactions. In order to elucidate the coevolution of the host and pathogen, and provide the appropriate methods for preventing or controlling rice blast disease, researchers have focused on the evolution of virulence factors and resistance genes. Thus far, more than 30 rice blast resistance（R） genes and 12 avirulence（Avr） genes have been cloned. This review summarizes the cloned rice blast R genes, cloned Avr genes of M. oryzae and the interaction between them. This discussion also considers some of the major unanswered questions concerning this pathosystem and the opportunities for future investigations.

Alcohol metabolites and lipopolysaccharide: Roles in the development and/or progression of alcoholic liver disease

The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol-induced inflammation, ethanol metabolites, and the indirect reactions from those metabolites. Ethanol oxidation results in the production of metabolites that have been shown to bind and form protein adducts, and to increase inflammatory, fibrotic and cirrhotic responses. Lipopolysaccharide (LPS) has many deleterious effects and plays a significant role in a number of disease processes by increasing inflammatory cytokine release. In ALD, LPS is thought to be derived from a breakdown in the intestinal wall enabling LPS from resident gut bacterial cell walls to leak into the blood stream. The ability of adducts and LPS to independently stimulate the various cells of the liver provides for a two-hit mechanism by which various biological responses are induced and result in liver injury. Therefore, the purpose of this article is to evaluate the effects of a two-hit combination of ethanol metabolites and LPS on the cells of the liver to increase inflamma-tion and fi brosis, and play a role in the development and/or progression of ALD.

Gallbladder cancer: Clinical and pathological approach

Gallbladder cancer(GBC) shows a marked geographical variation in its incidence. Middle-aged and elderly women are more commonly affected. Risk factors for its development include the presence of gallstones, chronic infection and pancreaticobiliary maljunction. Controversy remains in regard to the theory of carcinogenesis from adenomyomatosis, porcelain gallbladder and adenoma of the gallbladder. The surgical strategy and prognosis after surgery for GBC differ strikingly according to T-stage. Discrimination of favorable cases, particularly T2 or T3 lesions, is useful for the selection of surgical strategies for individual patients. Although many candidate factors predicting disease progression, such as depth of subserosal invasion, horizontal tumor spread, tumor budding, dedifferentiation, Ki-67 labeling index, p53 nuclear expression, CD8+ tumor-infiltrating lymphocytes, mitotic counts, Laminin-5-gamma-2 chain, hypoxia-inducible factor-1a, cyclooxygenase-2 and the Hedgehog signaling pathway have been investigated,useful prognostic makers or factors have not been established. As GBC is often discovered incidentally after routine cholecystectomy and accurate preoperative diagnosis is difficult, close mutual cooperation between surgeons and pathologists is essential for developing a rational surgical strategy for GBC.

Duodenal gangliocytic paraganglioma with lymph node metastases: a case report and comparative review of 31 cases

Gangliocytic paraganglioma(GP) is a rare tumor of uncertain origin most often located in the second portion of the duodenum. It is composed of three cellular components: Epithelioid endocrine cells, spindlelike/sustentacular cells, and ganglion-like cells. While this tumor most often behaves in a benign manner, cases with metastasis are reported. We describe the case of a 62-year-old male with a periampullary GP with metastases to two regional lymph nodes who was successfully treated with pancreaticoduodenectomy. Using Pub Med, EMBASE, EBSCOhost MEDLINE and CINAHL, and Google Scholar, we searched the literature for cases of GP with regional lymph node metastasis and evaluated the varying presentations, diagnostic workup, and disease management of identified cases. Thirty-one cases of GP with metastasis were compiled(30 with at least lymph node metastases and one with only distant metastasis to bone), with age at diagnosis ranging from 16 to 74 years. Ratio of males to females was 19:12. The most common presenting symptoms were abdominal pain(55%) and gastrointestinal bleeding or sequelae(42%). Twenty-five patients underwent pancreaticoduodenectomy. Five patients were treated with local resection alone. One patient died secondary to metastatic disease, and one died secondary to perioperative decompensation. The remainder did well, with no evidence of disease at follow-up from the most recent procedure(except two in which residual disease was deliberately left behind). Of the 26 cases with sufficient histological description, 16 described a primary tumor that infiltrated deep to the submucosa, and 3 described lymphovascular invasion. Of the specific immunohistochemistry staining patterns studied, synaptophysin(SYN) stained all epithelioid endocrine cells(18/18). Neuron specific enolase(NSE) and SYN stained most ganglion-like cells(7/8 and 13/18 respectively), and S-100 stained all spindle-like/sustentacular cells(21/21). Our literature review of published cases of GP with lymph node metastasis underscores the excellent prognosis of GP regardless of specific treatment modality. We question the necessity of aggressive surgical intervention in select patients, and argue that local resection of the mass and metastasis may be adequate. We also emphasize the importance of pre-surgical assessment with imaging studies, as well as post-surgical follow-up surveillance for disease recurrence.

Molecular epidemiology and phylogeny of Nipah virus infection:A mini review

Nipah virus(Ni V) is a member of the genus Henipavirus of the family Paramyxoviridae,characterized by high pathogenicity and endemic in South Asia.It is classified as a Biosafety Level-4(BSL-4) agent.The case-fatality varies from 40%-70% depending on the severity of the disease and on the availability of adequate healthcare facilities.At present no antiviral drugs are available for Ni V disease and the treatment is just supportive.Phylogenetic and evolutionary analyses can be used to help in understanding the epidemiology and the temporal origin of this virus.This review provides an overview of evolutionary studies performed on Nipah viruses circulating in different countries.Thirty phylogenetic studies have been published from 2000 to 2015 years,searching on pub-med using the key words ‘Nipah virus AND phylogeny' and twenty-eight molecular epidemiological studies from 2006 to 2015 have been performed,typing the key words ‘Nipah virus AND molecular epidemiology'.Overall data from the published study demonstrated as phylogenetic and evolutionary analysis represent promising tools to evidence NiV epidemics,to study their origin and evolution and finally to act with effective preventive measure.

Formalin fixation on HER-2 and PD-L1 expression in gastric cancer:A pilot analysis using the same surgical specimens with different fixation times

BACKGROUND The needs for human epidermal growth factor receptor 2(HER-2) and/or programmed death-ligand 1(PD-L1) evaluations in gastric cancer are dramatically increasing. Although the importance of standardization of sample fixation has been widely recognized, most of the evidence regarding the fixation duration or type of fixing solution are based on breast cancer.AIM To investigate the real effects of fixation conditions on HER-2 testing or PD-L1 testing for gastric cancer using gastrectomy specimens.METHODS Thirty-two patients who underwent gastrectomy for gastric cancer were enrolled.Their resected specimens were each divided into four pieces and fixed in four strictly controlled different durations(6 h, 24 h, and 48 h, and 1 wk) by 10%formalin(n = 22) or 10% neutral buffered formalin(NBF)(n = 10).Immunohistochemistry(IHC) of HER-2 and PD-1 was performed, and a pathology examination was conducted. In the HER-2-immunoreactive cases, all four specimens were subjected to dual-color in situ hybridization(DISH). Five cases were assessed as HER-2-positive by IHC and DISH. We used the cut-off values of 1%, 10%, and 50% to assess the IHC findings of PD-L1.RESULTS No significant difference was observed in comparisons between the shorter fixation period groups(6 h, 24 h, and 48 h) and the prolonged fixation period(1 wk) group in the HER-2 and PD-L1 analyses. Although no significant difference was observed between 10% formalin and 10% NBF within 1 wk of fixation, the superiority of 10% NBF was confirmed in a long-term(> 3 mo) fixation in both the HER-2 and PD-L1 analyses.CONCLUSION In this small-numbered pilot study, prolonged fixation within 1 wk showed no inferiority in HER-2 or PD-L1 testing. However, a large-numbered prospective study is needed to obtain conclusive results.

Granulomatous reaction in hepatic inflammatory angiomyolipoma after chemoembolization and spontaneous rupture

A 77-year-old Japanese woman was transported to a nearby hospital due to sudden abdominal pain and transient loss of consciousness. Abdominal computed tomography(CT) suggested hemoperitoneum and hepatic nodule. She was conservatively treated. Contrast-enhanced CT two months later revealed an increased mass size, and the enhancement pattern suggested the possibility of hepatocellular carcinoma(HCC). Under a clinical diagnosis of HCC, transcatheter arterial chemoembolization(TACE) was performed. A subsequent imaging study revealed that most of the lipiodol used for the embolization was washed out. Therefore, surgical resection was performed. Histologically, the nodule contained numerous inflammatory cells including small lymphocytes, plasma cells and macrophages. Notably, epithelioid granulomatous features with multinucleated giant cells were observed in both the nodule and background liver. Some of the multinucleated giant cells contained oil lipid. Among the infiltrating inflammatory cells,spindle-shaped, histiocytoid or myoid tumor cells with eosinophilic cytoplasm were found. The tumor cells were positive for Melan A and HMB45. The nodule contained many Ig G4-positive plasma cells; these were counted and found to number 72.6 cells/HPF(range: 61-80). The calculated Ig G4:Ig G ratio was 33.2%. The nodule was finally diagnosed as previously ruptured inflammatory angiomyolipoma modified by granulomatous reaction after TACE.

Inverse correlation between CD8^+ inflammatory cells and E-cadherin expression in gallbladder cancer:Tissue microarray and imaging analysis

AIM To investigated the association between the tumor cells' expression of E-cadherin and the numbers of several types of inflammatory cells infiltrating into the invasive portion of gallbladder cancer(GBC).METHODS We analyzed 50 GBC cases for which a sufficient amount of tumor tissues for tissue microarray(TMA) had been saved. Three tissue cores(3.0 mm) of invasive lesion from each case were used for the TMA. The 4-μm cut sections on slides were immunostained using primary antibodies including E-cadherin for cancer cells, leukocyte common antigen for leukocyte, myeloperoxidase for neutrophils, CD3 for T cells, CD4 for helper T cells, CD8 for killer T cells, CD20 for B cells and CD68 for macrophages. The immunostained slides were digitally analyzed by imaging analysis software.RESULTS A significant inverse correlation between the number of infiltrating CD8^+ cells at invasive areas and the expression of E-cadherin by cancer cells was observed(P = 0.0001), although the degree of this correlation was relatively weak(R = 0.32). The number of CD8^+ cells and the cancer cells' E-cadherin expression were also significantly correlated with tumor differentiation(welldifferentiated vs poorly differentiated)(P = 0.0467 and P = 0.0294, respectively). Inverse correlation of T-stageand the number of CD8^+ cell infiltration was observed with statistical significance in comparison of T2 and T3 cases(P = 0.0324).CONCLUSION Our findings indicate an inverse correlation of CD8^+ T cell infiltration and cancer cells' E-cadherin expression at invasive areas of GBC. Further analyses are essential to test these findings.

FOXO3a Inhibits TNF-α-and IL-1β-Induced Astrocyte Proliferation:Implication for Reactive Astrogliosis

反应性星形胶质细胞增生是神经退行性疾病的特征性病理性改变之一。炎性细胞因子,如TNF-α和IL-1β,已被证实在神经退行性疾病中介导反应性星形胶质细胞增生,尽管其分子机制仍不清楚。本研究探讨严重反应性星形胶质细胞增生的一个主要方面——转录因子FOXO3a在星形胶质细胞增生中的作用。本研究通过Ki67和BrdU免疫染色证实TNF-α和IL-1β促进星形胶质细胞增生。本研究进一步发现细胞因子介导的星形胶质细胞增生伴有FOXO3a磷酸化的增加和核表达的下降。颅内注射TNF-α和IL-1β导致星形胶质细胞增生和肥大,这与星形胶质细胞中的Foxo3a核表达下降有关。为了确定Foxo3a在星形胶质细胞增生中的作用,在腺病毒中过表达野生型Foxo3a,引起p27Kip1及Gadd45α上调,且显著抑制细胞因子介导的星形胶质细胞增生。与之相反,负显性型FOXO3a的过表达使p27Kip1降低,下调Cyclin D1,促进星形胶质细胞增生。同样,Foxo3a敲除小鼠中分离的星形胶质细胞表现出更高的增生趋势。颅内注射细胞因子后,Foxo3a敲除小鼠在体内表现出严重的星形胶质细胞增生。综上所述,FOXO3a在促炎因子刺激时对于遏制星形胶质细胞增生发挥重要作用,FOXO3a功能的缺失可能是严重反应性星形胶质细胞增生中星形胶质细胞增生的原因。了解FOXO3a在反应性星形胶质细胞增生中的关键调节作用可能为神经炎症提供一个新的治疗靶点。

GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation

Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

Occult hepatitis B virus infection and surgical outcomes in non-B, non-C patients with curative resection for hepatocellular carcinoma

AIM To investigate the prevalence, clinicopathological characteristics and surgical outcomes of occult hepatitis B virus(HBV) infection(OBI) in patients with non-B, non-C(NBNC) hepatocellular carcinoma(HCC).METHODS This study retrospectively examined the cases of 78 NBNC patients with curative resection for HCC for whom DNA could be extracted from formalin-fixed paraffin-embedded tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqM an realtime polymerase chain reaction. Possibly carcinogenetic factors such as alcohol abuse, diabetes mellitus, obesity and non-alcoholic steatohepatitis(NASH) were examined. Surgical outcomes were evaluated according to diseasefree survival(DFS), overall survival(OS) and diseasespecific survival(DSS).RESULTS OBI was found in 27/78 patients(34.6%) with NBNC HCC. The OBI patients were significantly younger than the non-OBI cases at the time of surgery(average age 63.0 vs 68.1, P = 0.0334) and the OBI cases overlapped with other etiologies significantly more frequently compared to the non-OBI cases(P = 0.0057). OBI had no impact on the DFS, OS or DSS. Only tumorrelated factors affected these surgical outcomes.CONCLUSION Our findings indicate that OBI had no impact on surgical outcomes. The surgical outcomes of NBNC HCC depend on early tumor detection; this reconfirms the importance of a periodic medical examination for individuals who have NBNC HCC risk factors.

Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants

Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer(NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors(TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligandindependent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLCassociated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligasemediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenicprocesses. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, and introduce potential mechanisms by which altered endocytic properties of mutant EGFRs may alter signaling and vice versa as well as their implications for NSCLC therapy.

Role of angiogenesis in oral squamous cell carcinoma development and metastasis: an immunohistochemical study

Although a few studies have shown that vascularity is increased from normal mucosa to dysplasia to carcinoma suggesting that disease progression in the oral mucosa is accompanied by angiogenesis. The role in lymph node metastasis in oral squamous cell carcinoma （OSCC） is equivocal. Role of angiogenesis in OSCC development and metastasis is evaluated in this study. This retrospective study of 50 samples consisted of 9 normal buccal mucosa, 22 leukoplakias, and 19 OSCC. Polyclonal antibodies to von-Willebrand factor were used to highlight the microvessels. Images were captured and morphometric image analysis was done for microvessel density （MVD）, area, and perimeter. Highest, as well as mean values of these three parameters were compared. MVD and perimeter, but not area, are significantly different between normal mucosa and OSCC, and leukoplakia and OSCC. There were no differences between normal mucosa and leukoplakia. MVD, area, and perimeter were not significantly different between the OSCC with and without lymph node metastasis. The highest and mean values of MVD are significantly correlated. In the development of OSCC, angiogenic phenotypic change occurs in carcinomas rather than in the pre-cancerous stage, and quantification of angiogenesis in OSCC does not predict the risk of lymph node metastasis.

Phylogeny of Murray Valley encephalitis virus in Australia and Papua New Guinea

Objective:To study the genetic diversity of Murray Valley encephalitis virus(MVEV) in Australia and Papua New Guinea.Methods:MVEV envelope gene sequences were aligned using Clustal X and manual editing was performed with Bioedit.ModelTest v.3.7 was used to select the simplest evolutionary model that adequately fitted the sequence data.Maximum likelihood analysis was performed using PhyML.The phylogenetic signal of the dataset wa.s investigated by the likelihood mapping analysis.The Bayesian phylogenetic tree was built using BEAST.Results:The phylogenetic trees showed two main clades.The clade Ⅰincluding eight strains isolated from West Australia.The clade Ⅱ was characterized by at least four epidemic entries,three of which localized in Northern West Australia and one in Papua New Guinea.The estimated mean evolutionary rate value of the MVEV envelope gene wa.s0.407 × 10^(-3) substitution/site/year(95%HPD:0.623 × 10~4-0.780× 10^(-3)).Population dynamics defines a relative constant population until the year 2000.when a reduction occurred,probably due to a bottleneck.Conclusions:This study has been useful in supporting the probable connection between climate changes and viral evolution also by the vector point of view:multidisciplinary monitoring studies are important to prevent new viral epidemics inside and outside new endemic areas.