Clinically Conserved Genomic Subtypes of Gastric Adenocarcinoma

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions

The Multifunctional Building of Passive Standard

Import 26/02/2015Tato diplomová práce je zaměřena na vyprojektování multifunkčního domu, ve kterém bude zajištěno strojní větrání a zajištěno vytápění pomocí alternativního zdroje tepla. Multifunkční dům podsklepený a má čtyři nadzemní podlaží s pochozí terasou. Objekt je navržen ze sortimentu firmy Porotherm. Funkčně je navržen tak, že v prvním podzemním podlaží se nachází technické zázemí a kóje bytů, první nadzemní podlaží tvoří dvě nezávislé prodejní plochy. Ve druhém patře jsou umístěny kancelářské prostory. Druhou horní polovinu objektu , třetí a čtvrté nadzemní podlaží, tvoří bytové jednotky. Základním kamenem pro nutnou výměnu vzduchu v objektu jsou tři vzduchotechnické systémy, které se starají o dodávku a výměnu vzduchu ve třech celcích. První celkem je jednotka pro prodejní plochy v prvním nadzemním podlaží a kancelářské prostory ve druhém nadzemním podlaží. Druhá jednotka má na starosti byty ve třetím a čtvrtém podlaží a poslední, třetí, jednotka zajišťuje přívod čerstvého vzduchu do společných prostor a odvod odpadního vzduchu do exteriéru. Všechny jednotky jsou vybaveny rekuperátorem. V objektu je také řešeno vytápění pomocí alternativních zdrojů. Jako alternativní zdroje energie jsou použity tepelné čerpadlo vzduch – voda a solární kolektory. Tepelné čerpadlo se stará o pokrytí tepelných ztrát prostupem, větráním a přípravou teplé vody. Solární kolektory umístěné na terase pomáhají s ohřevem teplé vody v objektu.This Master thesis is focused on the projection Multifunctional building, which will ensure mechanical ventilation and heating ensured by using alternative heat sources. Multifunctional building basement and has four floors with walkable terrace. The building is designed from company Porotherm. Functionally, it is designed so that on the first floor there is a technical background and cubicle apartments, first floor consists of two independent sales area. On the second floor there are office spaces. The second half of the upper house, the third and fourth floors, consists of residential units. The cornerstone for the necessary air exchange in the building are three air handling systems that are responsible for the delivery and exchange of air in three units. The first is the total unit sales area on the first floor and office space on the second floor. The second unit is in charge of flats in the third and fourth floors and the last third unit provides fresh air to the common area and the exhaust to the exterior. All units are equipped with a recuperator. There is also heating solutions using alternative sources. As alternative energy sources are used heat pump air - water and solar collectors. The heat pump takes care of the cover heat losses through transmission, ventilation and hot water. Solar collectors located on the terrace help with hot water in the building.Prezenční229 - Katedra prostředí staveb a TZBvýborn

Hematogenous Metastasis of Ovarian Cancer: Rethinking Mode of Spread

SummaryOvarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis

Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer

Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review

Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer

Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review

Effects of different methionine sources on growth performance, meat yield and blood characteristics in broiler chickens

Three graded levels of MHA (methionine hydroxyl analogue) added into the broilers’ diets were based on the assumption that the relative bioavailability of MHA sources to DL-methionine (DLM) on a molar basis was 100%, 90% or 80% to meet the requirement of total sulphur amino acids. DLM was used as the reference control group. Live body weight at 21 and 35 days was retarded (p < 0.05) in chicks fed a diet containing 100% equivalent MHA-FA (methionine hydroxyl analogue free acid) across dietary treatments. Chicks fed the diet containing MHA-Ca vs. MHA-FA grew faster at 35 days (p < 0.05). Chicks consumed least (p < 0.05) when 100% equivalent MHA-FA was added during 1–21 days. FCR was enhanced in MHA-Ca (methionine hydroxyl analogue calcium salt) vs. MHA-FA at all days measured. MHA effect on mortality, being higher (p < 0.05) in chicks on MHA-FA vs. MHA-Ca, was noted. Serum concentration of total cholesterol was lowest (p < 0.05) in chicks fed on DLM-added diet, but highest (p < 0.05) in those fed 100% equivalent MHA-Ca. Serum concentration of immunoglobulin A was low (p < 0.05) in chicks fed on 100% or 80% equivalent MHA-Ca compared with the rest of treatments. Collectively, MHA-Ca performed better than MHA-FA as to performance traits

Prognosis and Sensitivity of Adjuvant Chemotherapy in Mucinous Colorectal Adenocarcinoma without Distant Metastasis

In colorectal cancer, whereas mucinous adenocarcinoma (MAC) has several poor clinical prognostic factors compared to adenocarcinoma (AC), the prognosis of MAC remains controversial. We evaluated the prognosis of MAC without distant metastasis and the effects of adjuvant chemotherapy using health insurance registry data managed by South Korea. Patients with colorectal cancer between January 2014 and December 2016 were included (AC, 22,050 [96.8%]; MAC, 729 [3.2%]). We observed no difference in overall survival (OS) between AC and MAC in stages I and II. However, MAC showed a worse OS than AC in stage III disease, especially in patients administered chemotherapy (p < 0.001). These findings persisted after propensity score matching of clinical characteristics between AC and MAC. In addition, transcriptome analysis of The Cancer Genome Atlas (TCGA) data showed increased chemoresistance-associated pathways in MAC compared to AC. In consensus molecular subtypes (CMS) classification, unlike in AC, CMSs 1, 3, and 4 comprised most of MAC and the proportions of CMSs 3 and 4 increased with stage progression. These results suggest clues to overcome resistance to chemotherapy and develop targeted treatments in MAC