Emerging actionable targets to treat therapy-resistant colorectal cancers

In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a “big killer” mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

Repair Bond Strength of Composite Resin to Aged Resin and Glass-Matrix CAD/CAM Ceramic Materials Using Two Different Repair Systems

This study evaluates the repair bond strength of resin-matrix and glass-matrix CAD/CAM ceramic materials based on two repair systems. Thirty specimens measuring 2.5 mm in thickness were prepared from Crystal Ultra (CU), Vita Enamic (EN), Lava Ultimate (LU), Cerasmart (CS), and Vitablocs Mark II (VM2) materials and aged for 5000 thermal cycles. Specimens were randomly allocated into three groups: control, Monobond-S (MS) primer, and Monobond Etch & Prime (MEP). Composite resin (Tetric N Ceram) (5 mm in diameter and 2 mm thick) was packed and light-cured onto treated specimen surfaces. Subsequently, the specimens’ shear bond strength (SBS) was evaluated, and failure modes was recorded. Statistical analysis was performed using factorial ANOVA and Tukey’s post hoc tests (a = 0.05). The factorial ANOVA revealed significant interactions between the material type and repair system, which was significant (p < 0.01). The highest and lowest SBS were obtained for CU (27.09 ± 1.11) and VM2 (4.30 ± 0.59) in MS and control groups, respectively. In all the groups, CU demonstrated higher SBS, whereas VM2 demonstrated lower SBS. There were no significant differences in SBS between EN and LU, and CS and CU in all the study groups (p > 0.05). The Monobond-S repair system provided non-significantly higher SBS compared to the MEP systems, except for VM2 and LU materials. The new resin-matrix CAD/CAM material demonstrated the highest SBS compared to the other materials for both conventional and MEP repair systems. Both repair systems showed clinically acceptable bond strength and allowed for successful repair of the resin-matrix ceramic materials.

Long-Term Duration of Composite Repair Systems for Pipeline Defects

Composite repair systems of buried pipeline will be affected by moisture and other factors due to anti-corrosion and construction problems. These environmental factors will reduce the service life of the composite system. In this paper, the performance of composite and interface between composite and steel under the action of water were studied. It was found that the formation of micro-cracks on the surface of composite materials and the hydrolysis of epoxy resin were the important reasons for the Performance degradation. Moreover, the aging properties of composite materials and their interfaces under water immersion were analyzed by residual strength theory, and the life prediction equation of composite materials and interfaces were obtained, which can be useful to the field application of composite repair systems.

Hepatitis B virus cccDNA is formed through distinct repair processes of each strand

Hepatitis B virus (HBV) is a highly contagious pathogen that afflicts over a third of the world’s population, resulting in close to a million deaths annually. The formation and persistence of the HBV covalently closed circular DNA (cccDNA) is the root cause of HBV chronicity. However, the detailed molecular mechanism of cccDNA formation from relaxed circular DNA (rcDNA) remains opaque. Here we show that the minus and plus-strand lesions of HBV rcDNA require different sets of human repair factors in biochemical repair systems. We demonstrate that the plus-strand repair resembles DNA lagging strand synthesis, and requires proliferating cell nuclear antigen (PCNA), the replication factor C (RFC) complex, DNA polymerase delta (POLδ), flap endonuclease 1 (FEN-1), and DNA ligase 1 (LIG1). Only FEN-1 and LIG1 are required for the repair of the minus strand. Our findings provide a detailed mechanistic view of how HBV rcDNA is repaired to form cccDNA in biochemical repair systems.

Automated patch assessment for program repair at scale

In this paper, we do automatic correctness assessment for patches generated by program repair systems. We consider the human-written patch as ground truth oracle and randomly generate tests based on it, a technique proposed by Shamshiri et al., called Random testing with Ground Truth (RGT) in this paper. We build a curated dataset of 638 patches for Defects4J generated by 14 state-of-the-art repair systems, we evaluate automated patch assessment on this dataset. The results of this study are novel and significant: First, we improve the state of the art performance of automatic patch assessment with RGT by 190% by improving the oracle; Second, we show that RGT is reliable enough to help scientists to do overfitting analysis when they evaluate program repair systems; Third, we improve the external validity of the program repair knowledge with the largest study ever.