6. 蚊の中腸と唾液腺におけるアルボウイルス増殖の比較(第56回日本衛生動物学会西日本支部大会講演要旨)

The objective of this study was to compare the shear-peel band strength of 5 orthodontic cements using both factory and in-office micro-etched bands. The 5 orthodontic cements evaluated were a zinc phosphate (Fleck's Cement), 2 resin-modified glass ionomer cements (RMGI)(3M Multicure glass ionomer and Optiband), and 2 polyacid-modified composite resin cements (PMCR)(Transbond Plus and Ultra Band Lok). Salivary contamination was examined with a polyacid-modified composite resin (Transbond Plus). Two hundred and eighty extracted human molar teeth were embedded in resin blocks and each was randomly assigned to the following 7 groups: 6 groups with factory etched bands, 5 cement groups and salivary contaminated group, and 1 in-office micro-etched group. The cemented teeth were put in deionized water at 37 degrees C for 30 days and thermocycled for 24 hours. The force required to break the cement bond was used as a measure of shear-peel band retention. With the use of an Instron testing machine, a shear-peel load was applied to each cemented band. Data were analyzed with a one-way analysis of variance (ANOVA) with a Tukey test for the multiple comparisons. The RMGIs and PMCRs demonstrated significantly greater shear-peel band strengths compared to the zinc phosphate cement. No statistically significant differences were noted between the RMGI cement and PMCR cements and within the RMGI groups, however, there was a statistically significant difference within the PMCR groups. Significantly lower band strengths were noted with the saliva contaminated PMCR cement group (Transbond Plus) and the inpractice sandblasted PMCR group. Both RMGIs and PMCRs were found to demonstrate favorable banding qualities. The lower band strength with saliva-contaminated bands suggests that moisture control is critical when using a PMCR. The variability noted in the in-office micro-etched bands might be technique related.

Salivary glands are composed of several types of cells, and each cell type is predicted to be involved in the carcinogenesis of different types of cancers including Adenoid cystic carcinoma (ACC), Acinic cell carcinoma (AciCC), salivary duct carcinoma (SDC), myoepithelial carcinoma (MECA) and other histology. In this study, we performed single nucleus RNA-seq on three human salivary gland samples to clarify the gene expression profile of each complex cellular component of the salivary glands and related these expression patterns to expression found in salivary gland cancers (SGC) to infer cell of origin. By single nucleus RNA-seq, total 13,643 salivary gland cells were stratified into four clusters: acinar cells, ductal cells 1, ductal cells 2, and myoepithelial cells/stromal cells, with differentially expressed genes of each group. The localization of each cell group was anatomically validated by IHC of each cluster marker gene, and one group of ductal cells was found to represent intercalated ductal cells labeled with HES1. Gene ontology analysis for this group included “epithelial cell differentiation” confirming the intercalated duct. Furthermore, to elucidate the potential etiologic relationship between normal salivary glands cell type and salivary gland carcinoma histology, we compared the expression of each cluster marker to SGC public RNA-seq data. In comparison between AciCC and ACC, we used normalized RNA-seq data of 54 ACC and 21 AciCC. ACC had significantly less expression of acinar cells markers (STATH, CST2, and LPO) compared to other markers expression(***P = 4 × 10−51), unlike AciCC (P = 0.54), suggesting a possible contribution of acinar cells to the carcinogenesis of AciCC. In another cohort, we compared 16 SDC, and 38 MECA with publicly available RNA-seq data. Remarkably, HES1 and ELF3, each of two different ductal cell markers, were significantly upregulated in SDC consistent with origin of SDC from ductal cells (P=0.001, P=0.0007, respectively). Consistent with bulk RNA-seq results, expression of HES1 in IHC using clinical human SDC and MECA samples was higher in SDC than MECA, suggesting that the expression of the derived cells is involved in salivary gland carcinogenesis. Cell type expressions in specific SGC histology are similar to those found in normal salivary gland populations, indicating a potential etiologic relationship. On the other hand, there was no significant difference in myoepithelial marker ACTA2 expression between SDC and MECA, suggesting that the markers of origin are not always highly expressed, depending on cancer subtypes. Although publicly available SGC RNA-seq data used in this study are limited, the results remarkably reflect the diverse modes of carcinogenesis of SGC. These findings might provide a better understanding of the molecular basis of SGC and treatment strategies for SGC. Citation Format: Takuya Nakagawa, Chanond Nasamran, Jingjing Hu, Prakriti Sen, Theresa Guo, Kathleen Fisch, Joseph Califano. Single nucleus RNA-sequencing using normal human salivary glands revealed a potential etiologic relationship between each salivary gland cell and salivary gland malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1076.

Recently, unique activating mutations in PRKD1 were observed in salivary gland polymorphous low-grade adenocarcinoma (PLGA). PRKD1 is a serine-threonine kinase that participates in important cell functions such as survival, adhesion, and migration. PLGA is a salivary gland tumor that usually shows indolent clinical presentation. Due to morphological similarities within different subtypes of salivary gland neoplasms, differential diagnosis may be puzzling. Although salivary gland cancer is a rare disease (around 3,000 new cases per year in the USA), the gravity of the disease should not be undermined. Currently, the salivary gland cancer biology is poorly understood. Comprehending the molecular biology of this cancer is instrumental in improving the diagnosis and prognostic prediction of this disease. Our goal is to assess the incidence of c.2130A>T and c.2130A>C PRKD1 mutations in different salivary gland tumors by a high throughput mutation detection technique. We first assessed the c.2130 PRKD1 point mutations in 8 PLGA cases using conventional Sanger sequencing. Hotspot mutations were present in 75% (6/8) of the samples. Subsequently, we built tissue microarrays slides that included the following: 5 PLGA, 54 adenoid cystic carcinomas, 30 mucoepidermoid carcinomas, 14 acinic cell carcinomas, 6 adenocarcinomas not otherwise specified, 34 pleomorphic adenocarcinomas, 3 mammary analogue secretory carcinomas, and 1 salivary duct carcinoma. Additional sample collection is ongoing. We optimized a recently described in situ mutation detection to directly visualize single mutations with microscopy in fixed cells and tissue sections. The technique is based on in situ proximity ligation assays that utilize sequence specific probes. Ligation of the padlock probe will only occur if there is a perfect match between the probe and the target. The probes are labeled with fluorophores that allow generated signals to be visualized as bright spots with a fluorescence microscope. This technique allows exact quantification of the detected target molecules while identifying each individual signal (mutant or wild type) within the tissue sections. Once the methodology is validated to detect these mutations, it will allow us to quickly analyze a cohort of salivary gland neoplasms which have been already prepared as tumor microarrays. Additionally, this technique will open new avenues to analyze other mutations in different tumor cohorts already prepared as tumor microarray slides. In the context of salivary gland tumors, differentiating distinct primary tumors subtypes and/ or metastasis from primary tumors with other sites of origin would be invaluable for clinical decisions. Citation Format: Piotr T. Wysocki, William H. Westra, Shahnaz Begum, David Sidransky, Mariana Brait. High throughput detection of PRKD1 mutations in salivary gland tumors using in situ mutation detection in tissue microarrays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4844. doi:10.1158/1538-7445.AM2015-4844

Background: Vascular endothelial growth factor (VEGF) has two prominent biological effects of inducing mitogenesis and migration of vascular endothelial cells and to produce permeability on the microvasculature. Epidermal growth factor (EGF), known by its mitogenic activity on different types of cells, could induce the proliferation and differentiation of the epithelial cells and stimulate its regeneration. Doxorubicin (DXR) is a widely used anticancer drug and is one of most commonly used chemotherapeutic drugs, however it may cause some serious complications such as toxicity in various tissues in the body.Aims: The present study aims to investigate the effect of EGF on the VEGF immunoexpression in submandibular salivary gland tissue of rats receiving Doxorubicin (DXR).Methods and Material: 30 male Albino rats, two months old and weighing 200-250 gm body weight, were divided equally into three groups as follows: Group I (control group). Group II: rats received 20 mg/kg body weight DXR as a single intra peritoneal injection. Whereas, group III: rats received the same dose of DXR and on the next day they were injected intraperitoneally with EGF in a daily dose of 10μg/kg body weight for 7 consecutive days.Submandibular salivary glands were dissected out and processed for histological investigation and immunohistochemical localization of VEGF in the glandular tissue.Statistical analysis used: ANOVA was used to compare the mean area percentage of VEGF immunostaining among the specimens of different groups followed by Tukey’s Multiple Comparison Test.Results: VEGF expression in submandibular salivary glands of rats significantly decreased after DXR injection. However, daily intraperitoneal injections of EGF restored normal levels of VEGF expression in the glandular tissue.Conclusions: EGF preserved glandular architecture after DXR injection and consequently the immunohistochemical expression of VEGF in the glands to approximately the normal level.

Introduction: Dual checkpoint inhibitor therapy with nivolumab and ipilimumab has been FDA-approved for a number of different cancers including melanoma, recurrent NSCLC, and hepatocellular carcinoma. However, their role in the treatment of ACC and other salivary gland carcinomas is not well established. Methods: We performed a Simon’s two-stage prospective single-institution phase II clinical trial of nivolumab (240 mg intravenously every 2 weeks for 16 weeks, then 480 mg every 4 weeks) with ipilimumab (1 mg/kg intravenously every 6 weeks), both of which were provided until intolerable toxicity or disease progression. Two cohorts were analyzed: patients with metastatic/recurrent ACC and patients with other salivary gland cancers. The primary endpoint was median progression-free survival (PFS) based on RECIST and immune-related RECIST (irRECIST) criteria; secondary endpoints were overall response rate (ORR), overall survival (OS), and toxicity. Results: Patients with ACC (n=19) and other salivary gland carcinomas (total n=5; parotid gland adenocarcinoma (n=3), salivary duct carcinoma (n=1), and myoepithelial carcinoma (n=1)) were enrolled between May 2017 and July 2019. Among the patients with ACC, the median OS was 30.0 months (95% confidence interval (CI) 15.3 months to not reached), the median PFS was 8.3 months (95% CI 5.5 - 30.0 months), and the disease control rate (DCR) was 53% (10/19). The ORR in the ACC group was 5% (CR 0%, n=0; confirmed PR 5%, n=1) using both RECIST and irRECIST criteria, with one patient having continued stable disease at the time of trial conclusion. In the salivary gland tumor cohort, the median OS was 10.4 months (95% CI 6.21 months to not reached), the median PFS time was 6.21 months (95% CI 2.83 months to not reached), and the DCR was 40% (2/5). The ORR in this cohort was 0% using both RECIST and irRECIST criteria. Across both cohorts, platelet counts above the joint cohort’s median were significantly associated with better OS (p=0.032) and PFS (p=0.046). Additionally, although not significant, there was a trend for improved OS and PFS among patients with neutrophil-to-lymphocyte ratios >5 (OS p=0.42, PFS p=0.25) and above median neutrophil counts (OS p=0.24, PFS p=0.18). Four patients with ACC underwent circulating tumor DNA sequencing, resulting in the identification of two MYB-NFIB translocations, one NOTCH1 Cys1383 frameshift mutation, one MTOR N1760K mutation, and one PDGFRA copy number gain. Common immune-related toxicities include fatigue (54%), lymphocytopenia (46%), and anemia (42%) with lymphocytopenia being the most common grade III/IV adverse event. Conclusion: In patients with recurrent or metastatic ACC and other salivary gland neoplasms, combination nivolumab with ipilimumab resulted in moderate disease control. Further studies are warranted to validate our findings. Citation Format: Young Kwang Chae, Richard Duan, Liam Il-Young Chung, Youjin Oh, Maria Matsangou, Mark Agulnik, Victoria Villaflor, Devalingam Mahalingam. Phase II study of nivolumab and ipilimumab for treatment of metastatic/recurrent adenoid cystic carcinoma (ACC) of all anatomic sites of origin and other malignant salivary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT165.

Background: The expression of the inhibitor of apoptosis protein survivin is shown to be a significant prognostic indicator in various human cancers. Its role in cancer of the major salivary glands remains unclear. Methods: We analysed the survivin expression in 171 patients with malignant parotid gland cancer (12 different histological subtypes) by means of immunohistochemistry. The experimental findings were correlated with clinicopathological and survival parameters. The mean follow-up time was 42 months. Results: There was no significant correlation of cytoplasmic survivin expression levels with the patients’ clinicopathological characteristics. A strong cytoplasmic expression of survivin was found in 25% of the examined tumors. High cytoplasmic survivin expression was an independent prognostic indicator for a significant poorer 5-year disease-free survival rate (31% versus 67%, p<0.0005) and overall survival (45% versus 62%, p=0.048). In the multivariate analysis survivn expression and distant metastasis were significant predictors for patient outcome (p=0.001, p<0.0005). Conclusions: The correlation between cytoplasmic survivin expression and survival probabilities of salivary gland malignancies might make this an effective tool in patient follow-up, prognosis and targeted therapy in future. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1729.

Sporozoites were labeled in vivo. Mosquitoes (Anopheles stephensi) infected with the NK-65 strain of P. berghei were allowed to feed ad lib. for 14 days subsequent to an infective blood meal on 5% Karo syrup solution containing different levels of tritium-labled purines and pyrimidines. Sporozoites were harvested on day 16 by dissection of mosquito salivary glands. Isotope incorporation in sporozoites was determined by autoradiography. Each of the purines tested, including adenine-8-3H, adenosine-3H (G), deoxyadenosine-3H (G), and deoxyguanosine-3H (G), was incorporated into both nuclear and cytoplasmic regions of sporozoites when fed to mosquitoes at 5 to 100 ,uCi/ml. Similar levels of the pyrimidines tested, including thymine-methyl-3H, thymidine-methyl-3H, or orotic-5-3H acid, failed to label sporozoites. The incorporation of preformed purines, but not pyrimidines, by developing sporozoites suggests that the parasite may require exogenous sources of purine during its development in the mosquito but relies on de novo synthesis of pyrimidines. The adenine8-3H-labeled sporozoites were shown to be infective by intravenous inoculation into A/J mice. These results demonstrate the feasibility of labeling developing sporozoites and should provide a means for further studies on the developmental cycle of malaria in the vertebrate host. After the discovery of exoerythrocytic bodies of malaria in the liver of monkeys and man (Shortt and Garnham, 1948) it was generally assumed that relapses were caused by a continual cycling of histiotrophic merozoites in the liver. More recently, Garnham (1967) has proposed that relapses may be caused by sporozoites which remain latent in parenchymal cells of the liver for various periods of time before undergoing development. To date, these latent forms have not been demonstrated, possibly because of their small size and similarity to the cytoplasm of liver cells in stained preparations. Radionuclide labeling of sporozoites would provide a means for recognizing these latent forms in tissue if, indeed, they exist. In the present study a method for labeling sporozoites in vivo with tritiated purines was developed. In addition, the labeled sporozoites were shown to retain their infectivity when inoculated into susceptible hosts. MATERIALS AND METHODS Anopheles stephensi mosquitoes were allowed to feed on hamsters infected with the NK-65 strain of Plasmodium berghei and maintained at Received for publication 18 September 1973. * This work was presented in part at the 57th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlantic City, New Jersey (1973, Fed. Proc. 32: 704). 21 C as described by Yoeli et al. (1965). Subsequent to the infective blood meal, mosquitoes were allowed to feed from the mouth of a plastic dropping pipette that contained tritium-labeled purines or pyrimidines in 5% Karo syrup solution. The mouth of the pipette was mounted in contact with the mesh on top of the cage. Fresh isotope solution was supplied every other day for a period of 16 days. Sporozoites were harvested on day 18 by dissection of mosquito salivary glands into a 1:1 mixture of saline and mouse plasma. The glands were gently homogenized in a 3-ml tissue grinder fitted with a Teflon pestle in an ice bath. Sporozoite yield was estimated from counts in a Neubauer hemocytometer. Viability of adenine-8-3H-labeled sporozoites was evaluated by the intravenous inoculation of approximately 10,000 sporozoites into 6to 8-weekold A/J mice (Jackson Laboratories, Bar Harbor, Maine) within 1 hr after dissection of salivary glands. Infectivity and prepatent period were determined by daily Giemsa-stained blood films. Isotope incorporation by sporozoites was determined by autoradiography using Kodak NTB-2 nuclear track emulsion (Eastman Kodak Co.). Infected salivary glands were crushed with a glass cover slip on slides previously coated by dipping in 1% bovine serum albumin. Sporozoites were then fixed with methanol and allowed to air-dry. Slides were coated by dipping into undiluted photographic emulsion at 40 C. After exposure to the emulsion for various intervals at 4 C, slides were processed with Kodak D-19 developer and fixer. The preparation was then stained through the emulsion with 7.5% Giemsa for 1 hr at pH 7.2. The degree of labeling was determined microscopically under oil immersion by counting silver grains associated with individual sporozoites.

08.16 Mir200B-5p expression in minor salivary glands (msg): a possible predictor of lymphoma development in sjögren’s syndrome (ss)

Two western equine encephalomyelitis virus (WEEV) strains have been isolated in China. Our previous studies have verified that the mosquito Culex pipiens pallens Coquillett (Diptera: Culicidae) infected with WEEV was capable of transmitting this arbovirus, but it was not clear how the sequential multiplication and spread of virus occurred within the mosquito. In this study, we observed the distribution of WEEV antigen in orally-infected Cx. p. pallens by immunohistochemistry in order to better understand the initial infection, dissemination, and transmission of WEEV in the potential vector. Orally-infected WEEV dissemination varied within the different tissues of Cx. p. pallens, with virus antigen consistently observed in the salivary glands, foregut, midgut epithelial cells, Malpighian tubules, hindgut, and ovarian follicles of some individuals after various days of extrinsic incubation. We suggest that Cx. p. pallens, the potential vector of WEEV, has the ability to harbor the virus through the alimentary system, and the midgut epithelial cell may be the initial site of WEEV replication after ingestion of a viremic blood meal.

Aedes vigilax mosquitoes, collected from the south coast of New South Wales, were fed on a blood-meal containing the T48 strain of Ross River virus. Viral infection and multiplication in this major vector were studied, together with dissemination of the virus in organs and tissues as determined by immunofluorescence. Individuals of this field mosquito population were highly susceptible to infection (ID50 = 10(3.4) BHK-21 TCID50 per mosquito) and virus replicated rapidly, reaching a maximum level 5-6 days after feeding. Specific viral antigens were detected in sections of abdominal midgut, abdominal fat bodies, thoracic fat bodies, cerebral ganglia and head fat bodies 2-4 days after ingestion of the virus-containing bloodmeal. Antigens were also detected 5-7 days after feeding in abdominal ganglia, thoracic ganglia, salivary glands and foregut. Antigens were demonstrated in sections of eggs from the ovary of one mosquito, which provided further evidence of transovarial transmission of Ross River virus in Ae. vigilax.

Electron microscopic evidence for wound-tumor virus accumulation in various organs of an inefficient leafhopper vector, Agalliopsis novella

Mucoepidermoid carcinoma (MEC) is the most common type of malignant salivary gland tumor. MECs frequently exhibit a recurrent t(11;19)(q21;p13) chromosomal translocation that fuses the transcriptional coactivators CRTC1 (CREB-Regulated Transcription Coactivator 1; C1) and MAML2 (Mastermind-Like 2; M2). Though many C1/M2-positive tumors are easily resected, some do progress to advanced, metastatic disease accompanied by poor 5-year survival rates. Thus, it is critical to understand the mechanisms by which C1/M2 drives tumor growth and progression in order to identify therapeutic vulnerabilities. Our lab recently identified a correlation between C1/M2 expression and increased levels of the growth hormone IGF-1. This hormone plays critical roles in the development and homeostasis of normal salivary glands, and its dysregulation has been implicated in several cancers including colon and lung cancers. Interestingly, we demonstrate that IGF-1 is not directly upregulated by C1/M2. Rather, we have discovered a novel C1/M2-driven signaling circuit whereby constitutive CREB activation drives the increased production of a minor PGC-1α (PPARγ Coactivator 1α) splice variant, PGC-1α4, which is responsible for the high IGF-1 levels observed in C1/M2-positive MEC cells. Notably, the PGC-1α4 splice variant is minimally expressed in normal tissues and C1/M2-negative cell lines but is selectively upregulated in C1/M2-positive cell lines. We show that C1/M2 directly binds CREB at the PGC-1α4 promoter to induce expression of this variant, resulting in increased IGF-1 expression. IGF-1 promoter analysis revealed a significant enrichment of PPARγ binding motifs and functional studies confirm that this promoter is regulated by PPARγ. Consequently, we demonstrate that a novel PPARγ inverse agonist is capable of repressing IGF-1 promoter activity and reducing growth and clonogenic potential of C1/M2-positive cell lines that exhibit high PGC-1α4 expression. Collectively, our results reveal a novel therapeutic vulnerability in salivary MEC cells that may extend more broadly to other cancers that exhibit dysregulated CREB activity. Citation Format: Adele M. Musicant, Kshitij P. Sharma, Erin C. Henry, Jason Tasoulas, Ricardo Padilla, Monideepa Sengupta, Colin Flaveny, Antonio L. Amelio. The CRTC1/MAML2 oncogene induces a PGC-1a splice variant that sensitizes mucoepidermoid carcinoma cells to PPARg inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 874.

Salivary gland tumors are a heterogeneous group of lesions, being mucoepidermoid carcinoma (MEC) the malignant neoplasm with the highest incidence, occurring mainly in the parotid gland. Characterization of its histological grade (high, intermediate, and low) is important for determining patient prognosis. Metastasis is more common high-grade tumors and can occur at regional lymph nodes or distant sites. Although the mechanisms underlying the metastatic process are largely unknown, large-scale microRNA expression profiling studies of human cancers have demonstrated that dysregulation of miRNA is frequently associated with many cancer types. The aim of this study is to validate the use of microRNA expression for the discrimination of the metastatic potential of MEC samples. Using Real Time RT-PCR (qPCR) we have analyzed the expression of 384 miRNAs and controls in 4 non-metastatic MECs, 3 MECs with lymph node metastasis, 3 MECs with distant metastasis, and 2 non-neoplastic human salivary gland samples. Comparing the expression among these groups we identified 45 differentially expressed miRNAs that may be related with the metastatic potential of these tumors. To validate the microRNA expression associated with the metastatic potential, we selected 7 out of the 45 differentially expressed microRNAs and 7 MEC samples from the different groups of samples. Considering the 7 microRNAs evaluated, we validated that the expression of miR-191 was increased in non-neoplastic samples when compared to MECs with lymph node metastasis and the expression of miR-494 was increased in non-neoplastic samples when compared to MECs with distant metastasis, suggesting that loss of these microRNAs might be involved in the development of metastasis in mucoepidermoid carcinoma. The determination of a miRNA expression profile could provide a better understanding of the molecular basis of MEC and facilitate the determination of diagnosis and prognosis of patients. Citation Format: Maria E. Trevizani, Katia K. Oliveira, Fabio A. Marchi, Daniela Bizinelli, Fernanda V. Mariano, Cibele P. Nagano, Felipe A. Costa, Clovis A. Pinto, Luiz P. Kowalski, Silvia V. Lourenço, Cláudia M. Coutinho-Camillo. Evaluation of microRNA expression in metastatic and non-metastatic salivary gland mucoepidermoid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2999.

Background: Recurrent/metastatic head and neck squamous cell carcinoma (SCCHN) and salivary gland malignancies are difficult to treat with limited standard of care options at the present time. Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. Our in vivo studies demonstrated that our novel GSK-3 inhibitors significantly potentiated the effects of conventional chemotherapy in patient-derived xenograft models of glioblastoma and breast cancer leading to regression of tumors. In order to develop a rationale to test our novel GSK-3 inhibitors in head and neck (H&N) malignancies, we evaluated the expression pattern of GSK-3beta in human H&N benign tissue and malignant tumors. Methods: We used immunohistochemical staining of H&N tumor tissue Microarray (TMA), 48 total cases (20 benign tissues, 28 malignant), to study the expression pattern of GSK-3beta. GSK-3beta nuclear accumulation was defined as positive staining of more than 50% of cancer cell nuclei throughout the tumor regardless of cytoplasmic staining. Results: Of the 20 malignant H&N samples (15 SCCHN, 1 nasopharyngeal and 5 other histology), 13 (65%) were found to have aberrant nuclear accumulation of GSK-3beta. Amongst SCCHN, 73% (11 of 15 samples) had aberrant nuclear accumulation of GSK-3beta. In contrast, none (0%) of the 11 benign non-salivary H&N tissue showed detectable expression of GSK-3beta. Of interest, 60% of salivary adenoid cystic carcinoma specimens and 44% of benign salivary gland tissue showed GSK-3beta expression. Conclusions: Our results demonstrate for the first time, that there is aberrant nuclear expression of GSK-3beta in SCCHN. This finding supports further exploring of our novel GSK-3beta inhibitor as a potential therapeutic target for recurrent/metastatic SCCHN and also, as a potential prognostic and predictive biomarker for risk of recurrent disease and chemo- or radio-resistance. Its role in salivary gland malignancies requires further studying. Citation Format: Maria Matsangou, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, Francis J. Giles. Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1127. doi:10.1158/1538-7445.AM2017-1127

A31 ハマダラカ成虫の唾液腺におけるキサンツレン酸含量とマラリア伝播効率(一般講演,演題要旨,第58回日本衛生動物学会大会)