Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

No abstract

No abstract

Vascular smooth muscle (VSM) cell phenotypic expression and autophagic state are dynamic responses to stress. Vascular pathologies, such as hypoxemia and ischemic injury induce a synthetic VSM phenotype and autophagic flux resulting in a loss of vascular integrity and VSM cell death respectfully. Both clinical pilot and experimental stroke studies demonstrate that sphingosine-1-phosphate receptor (S1PR) modulation improves stroke outcome; however, specific mechanisms associated with a beneficial outcome at the level of the cerebrovasculature have not been clearly elucidated. We hypothesized that ozanimod, a selective S1PR type 1 ligand, will attenuate VSM synthetic phenotypic expression and autophagic flux in primary human brain VSM cells following acute hypoxia plus glucose deprivation (HGD; in vitro ischemic-like injury) exposure. Cells were treated with ozanimod and exposed to normoxia or HGD. Crystal violet staining, standard immunoblotting, and immunocytochemical labeling techniques assessed cellular morphology, vacuolization, phenotype, and autophagic state. We observed that HGD temporally decreased VSM cell viability and concomitantly increased vacuolization, both of which ozanimod reversed. HGD induced a simultaneous elevation and reduction in levels of pro- and anti-autophagic proteins respectfully, and ozanimod attenuated this response. Protein levels of VSM phenotypic biomarkers, smoothelin and SM22, were decreased following HGD. Furthermore, we observed an HGD-induced epithelioid and synthetic morphological appearance accompanied by disorganized cytoskeletal filaments which was rescued by ozanimod. Thus, we conclude that ozanimod, a selective S1PR1 ligand, protects against acute HGD-induced phenotypic switching and promotes cell survival, in part, by attenuating HGD-induced autophagic flux thus improving vascular patency in response to acute ischemia-like injury.

Objective:The present objective This work was to determine black coat inheritance and evaluate production performance for crossbreed F4 pigs from Berkshire × Chenghua (BC) comparison compared with Chinese indigenous Chenghua (CH) pigs. Methods:The coat color phenotypes were recorded for more than 16,000 pigs, and the genotypes of MC1R gene were identified by sequencing. The reproductive performance for of 927 crossbreed BC F4 gilts and 320 purebred CH gilts were was recorded. 60 Sixty pigs per of each breed were randomly selected at approximatelyabout 60 days of age to determine growth performance during fattening period, which lasted for 150 days for BC pigs and 240 days for CH pigs, respectively. At the end of the fattening period, 30 pigs of eachper breed were slaughtered to determine carcass-composition and meat quality. Results:The Ccoat color of BC pigs exhibits a "dominant black" hereditary pattern, and all piglets derived from boars or sows genotyped E D1 E D1 homozygous for MC1R gene showed a uniform black coat phenotype. The BC F4 gilts displayed a relatively good reproductive performance, showing a higher litter and tear size, and were heavier at farrowing litter and at weaning litter than the CH gilts, but they reached puberty later than the CH gilts. BC F4 pigs exhibited improved growth and carcass characteristics with a higher average daily live weight gain, lower feed-to-gain ratio, and higher carcass lean meat rate than CH pigs. Similar to those ofLike CH pigs, BC F4 pigs produced superior meat-quality characteristics, showing ideal pH and meat-color values, high intramuscular fat content and water-holding capacity, and acceptable muscle-fibrefiber parameters. C18:1, C16:0, C18:0, and C18:2 were the main fatty acids in M. longissimus lumborum in the two breeds, and a remarkablyvery high polyunsaturated/saturated fatty acid ratio of ~0.39 was observed in the BC F4 pigs. Conclusion:The BC F4 pigs exhibit a uniform black coat pattern and acceptable total production performance.

The homo-valent diruthenium(II,II) carbonates have been underexplored hitherto. This paper reports the synthesis and crystal structure of a diruthenium(II,II) compound, Na4Ru2(CO3)4‧10H2O (1). It has a two-dimensional structure in which the...

The method of strain-based fatigue analysis is applied on the study of fatigue behavior of reinforced concrete (RC) beams strengthened with fiber reinforced polymer (FRP) laminates in this paper. Based on the investigation of fatigue performance of RC beams strengthened with FRP laminates presented in the published literatures, the values of stress concentration factors and the coefficients in Neuber’s rule are suggested. The exponent of fatigue strength in Manson-Coffin formula is discussed so as to having a general stain-life curve which is suitable for the fatigue behavior prediction of RC beam strengthened with FRP laminates. The S-N curves of different stress ratios can be developed and the fatigue lives of the strengthened beams are pointed out.

No abstract