SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. Importantly, SETD2 loss sensitized KRAS-mutant lung cancer to inhibition of histone chaperones, the FACT complex, or transcriptional elongation both in vitro and in vivo. Overall, our studies not only provide insight into how SETD2 loss shapes the epigenetic and transcriptional landscape to promote tumorigenesis, but they also identify potential therapeutic strategies for SETD2 mutant cancers

Clinical Outcome of Patients with Pelvic and Retroperitoneal Bone and Soft Tissue Sarcoma : A Retrospective Multicenter Study in Japan

This study aimed to retrospectively analyze the clinical outcomes of patients with pelvic and retroperitoneal bone and soft tissue sarcoma (BSTS). Overall, 187 patients with BSTS in the pelvis and retroperitoneal region treated at 19 specialized sarcoma centers in Japan were included. The prognostic factors related to overall survival (OS), local control (LC), and progression-free survival (PFS) were evaluated. The 3-year OS and LC rates in the 187 patients were 71.7% and 79.1%, respectively. The 3-year PFS in 166 patients without any distant metastases at the time of primary tumor diagnosis was 48.6%. Osteosarcoma showed significantly worse OS and PFS than other sarcomas of the pelvis and retroperitoneum. In the univariate analyses, larger primary tumor size, soft tissue tumor, distant metastasis at the time of primary tumor diagnosis, P2 location, chemotherapy, and osteosarcoma were poor prognostic factors correlated with OS. Larger primary tumor size, higher age, soft tissue tumor, chemotherapy, and osteosarcoma were poor prognostic factors correlated with PFS in patients without any metastasis at the initial presentation. Larger primary tumor size was the only poor prognostic factor correlation with LC. This study has clarified the epidemiology and prognosis of patients with pelvic and retroperitoneal BSTS in Japan

Adjunctive application of solid-state culture products and its freeze-dried powder from Aspergillus sojae for semi-hard cheese

BACKGROUND Species belonging to the genusAspergillushave been used in traditional Japanese fermented foods.Aspergillus sojaeis a species responsible for strong proteolytic activity. Freeze-drying treatments followed by physical disruption enables the pulverization of the mycelia ofA. sojaeRIB 1045 grown in whey protein-base solid media. Intracellular proteases were extracted using this protocol to compare extracellular protease activity in terms of the reaction's pH dependence in the presence or absence of inhibitors. RESULT With different sensitivities to inhibitors, intracellular and extracellular proteases showed the strongest activity under acidic conditions, which were considered suitable for cheese application. The raw culture product (CP) and its freeze-dried product (FDP) were mixed with cheese curds, prepared according to Gouda-type cheese-making methods, and were allowed to ripen for 3 months. Chemical analysis of the products showed 13.3% water-soluble nitrogen (WSN) in the control, which had received noncultured media, whereas 20.0% and 21.1% WSN was found in the CP and FDP experimental cheeses, respectively. Although these adjuncts significantly increased WSN, an insignificant difference was found between CP and FDP. Free fatty acids in all experimental cheeses were similar, showing that CP and FDP caused no rancid defects. CONCLUSION The introduction of freeze-drying treatments accompanied by cell disruption resulted in a negligible effect in terms of WSN. However, the application ofA. sojaecan be beneficial when it comes to increasing the level of WSN compared withA. oryzae, as shown in our previous study. (c) 2020 Society of Chemical Industr

A study of lipolysis induced by adjuncts from edible Aspergillus sp. solid culture products on ripened semi-hard cheese

BACKGROUND Aspergillus sp. has been used in traditional Japanese fermented foods. Protease-containing culture products of A. oryzae have been applied as the adjunct enzyme source to enrich the flavor in ripened cheese. Although proteolysis was stimulated, the increase of free fatty acids (FFA) was recognized in some products. Since an excess amount of FFA accumulation can cause rancidity in cheese products, the assessment of lipase activity was considered to be essential for the cheese adjunct preparation. RESULTS Although an equal lipase activity from the adjunct materials of A. kawachii NBRC 4308, A. luchuensis RIB 2604 and A. oryzae AHU 7139 was applied to semi-hard cheese, the FFA level was significantly higher in A. oryzae cheese than in the others. Furthermore, the profiles of volatile components were different in experimental cheeses. An in vitro study with experimental curds demonstrated that the high FFA might not depend on the lipase retainability on curds. On the contrary, the pronounced activation of the lipases occurred in A. oryzae after incubation with the curds. Moreover, incubation of the insoluble lipase that had been attached to the cells with skim milk curd extracts allowed the release of lipases from the cells into the medium with remarkable activation. CONCLUSION A. oryzae AHU 7139 possessed a complex lipolytic system comprising extracellular and cell-binding lipases that were attributed to the increase in FFA in A. oryzae cheese

Application of red pigment producing edible fungi for development of a novel type of functional cheese

To develop a novel type of functional cheese, nine strains of edible fungi, Monascus sp. were cultured on whey protein-based solid medium and screened in terms of secondary metabolite production including red pigments, lovastatin, and citrinin. The amount of these metabolites in culture products depended not only on the strain, but also on the pH and temperature environment. The strain of M. ruber NBRC 32318 was selected because it produced red pigments and lovastatin with negligible amount of citrinin. After incubation at 25°C for 10 days with initial pH condition of 4.0, the culture products were mixed with cheese curds, followed by ripening for 3 months at 11.5°C. Higher level of water-soluble nitrogen was recognized in the culture products containing cheese compared to control cheese. Practical applications For cheese making, diverse microorganisms have been used. However, there have been limited trials on the development of dairy products using red pigment producing Monascus species used for fermented rice in the Eastern Asia for more than 1,000 years. Using whey protein base solid substrate, we selected suitable Monascus strain and defined the culture condition that provided nephrotoxin citrinin-free and functional metabolite of lovastatin-containing culture products, which were mixed with fresh cheese curds for ripening. In the resulting red mold cheese, proteolysis was accelerated with no bitter flavor and rancid. Although further assessments concerning health benefits by animal studies and cheese quality by sensory evaluation are necessary to be commercialized as a novel type of functional cheese, this study provides fundamental information regarding screening of suitable strains with its appropriate culture condition on whey protein solid substrate, focusing on biotechnological, and chemical respects to ensure food safety

Eribulin Provides a Remarkable Effect in Trabectedin-Resistant Myxoid Liposarcoma

Adriamycin-based chemotherapy is commonly used for malignant soft tissue sarcoma including myxoid liposarcoma. However, in the case of unavailability or failure of the adriamycin-based regimen, trabectedin or eribulin can produce a good antitumor effect for myxoid liposarcoma. We relate the experience of a 64-year-old female with myxoid liposarcoma, who noticed a nodule on her left thigh and visited our institute. At initial presentation, the tumor was 18.7 cm in diameter, and the magnetic resonance imaging (MRI) showed a malignant lipomatous tumor with a myxoid component. We recommended that she undergo treatment; however, she refused. Three years later, the tumor had grown larger, so she finally decided to undergo treatment. A needle biopsy revealed a myxoid liposarcoma. The tumor massively involved the neurovascular structures; we thus determined that hip disarticulation was inevitable. Two years later, metastases in the right thigh, left lung, right ileum, and abdominal space were pointed out and chemotherapy was initiated. Adriamycin was unusable due to cardiac dysfunction, so trabectedin was administered; however, the tumors progressed. Eribulin was subsequently started and has been considerably effective for more than 2 years without severe adverse effects. In conclusion, we experienced a case showing the remarkable and long-lasting effect of eribulin against trabectedin-resistant myxoid liposarcoma

Lactococcus lactis subsp. cremoris Produces Zinc Protoporphyrin IX Both Aerobically and Anaerobically and Improves the Bright Red Color of Fermented Meat Products

This study assessed the color improvement via zinc protoporphyrin IX (ZnPP) formation in nitrite-free, dry-cured sausages processed using five varieties of ZnPP-forming lactic acid bacteria (LAB). The ZnPP contents and color intensity of the sausages and other technological properties were analyzed during the processing of sausages. LAB count and acidity significantly increased in the LAB-inoculated sausages compared to the control group. The bright red color was observed both inside and outside the sausages inoculated with Lactococcus lactis subsp. cremoris and Leuconostoc lactis. However, a brown color was observed on the surface of the sausage inoculated with Lactobacillus spp. The redness of Lactococcus lactis subsp. cremoris-inoculated sausages was close to that of the nitrite-added group. Moreover, the external bright red color was improved by Lactococcus lactis subsp. cremoris due to the aerobic formation of ZnPP. Therefore, Lactococcus lactis subsp. cremoris can be used to improve the color of fermented meat products