Targeting Oncogenic KRAS in Non-Small-Cell Lung Cancer

Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance.

A review on the potential of filamentous fungi for microbial self-healing of concrete

Concrete is the most used construction material worldwide due to its abundant availability and inherent ease of manufacturing and application. However, the material bears several drawbacks such as the high susceptibility for crack formation, leading to reinforcement corrosion and structural degradation. Extensive research has therefore been performed on the use of microorganisms for biologically mediated self-healing of concrete by means of CaCO3 precipitation. Recently, filamentous fungi have been recognized as high-potential microorganisms for this application as their hyphae grow in an interwoven three-dimensional network which serves as nucleation site for CaCO3 precipitation to heal the crack. This potential is corroborated by the current state of the art on fungi-mediated self-healing concrete, which is not yet extensive but valuable to direct further research. In this review, we aim to broaden the perspectives on the use of fungi for concrete self-healing applications by first summarizing the major progress made in the field of microbial self-healing of concrete and then discussing pioneering work that has been done with fungi. Starting from insights and hypotheses on the types and principles of biomineralization that occur during microbial self-healing, novel potentially promising candidate species are proposed based on their abilities to promote CaCO3 formation or to survive in extreme conditions that are relevant for concrete. Additionally, an overview will be provided on the challenges, knowledge gaps and future perspectives in the field of fungi-mediated self-healing concrete.

Neuroarchitecture Assessment: An Overview and Bibliometric Analysis

Research on the relationship between architecture and neuroscience has increased in number and significance since the 1990s. Although a growing number of studies revolve around this field of research, there are very limited studies that have reviewed and assessed the field and there is a gap in the literature to address the overall analysis of neuroarchitecture literature and its evolution. Additionally, neuroarchitecture literature is now challenging to manage because of its multidisciplinary scope and wide range spread within different themes and journals. The primary aim of this study is to present a bibliometric analysis of three decades of research on neuroarchitecture. This provides an overall picture of the field and its research landscape. Two hundred and ninety-five publications were included in the final database of the study after screening processes. Next, a science mapping tool, VOSviewer, was utilized to detect major topics as well as influential authors, countries, publications, and prominent journals using different network analysis techniques such as term co-citation, term co-occurrence, and bibliographic coupling. Next, a similar co-occurrence analysis was conducted to identify the major themes and the evolution of the intellectual basis of the field. SciMAT was also used to detect how the intellectual base of the knowledge in the field has evolved over time. It also assisted to identify the major themes that have contributed to this evolution. The results show that this field has initially been mainly focused on few themes but has later become more diversified to acknowledge the multi-faceted characteristics of neuroarchitecture; over time, the intellectual base of the field of neuroarchitecture started to grow, particularly from 2016. Major progress in the development of theoretical and methodological approaches has been achieved and there has been a paradigm shift toward major keywords in neuroarchitecture such as EEG, fMRI, and virtual reality.

The recruitment mechanisms and potential therapeutic targets of podocytes from parietal epithelial cells

Podocytes are differentiated postmitotic cells which cannot be replaced after podocyte injury. The mechanism of podocyte repopulation after injury has aroused wide concern. Parietal epithelial cells (PECs) are heterogeneous and only a specific subpopulation of PECs has the capacity to replace podocytes. Major progress has been achieved in recent years regarding the role and function of a subset of PECs which could transdifferentiate toward podocytes. Additionally, several factors, such as Notch, Wnt/ß-catenin, Wilms’ tumor-1, miR-193a and growth arrest-specific protein 1, have been shown to be involved in these processes. Finally, PECs serve as a potential therapeutic target in the conditions of podocyte loss. In this review, we discuss the latest observations and concepts about the recruitment of podocytes from PECs in glomerular diseases as well as newly identified mechanisms and the most recent treatments for this process.

Client-server Identification Protocols with Quantum PUF

Recently, major progress has been made towards the realisation of quantum internet to enable a broad range of classically intractable applications. These applications such as delegated quantum computation require running a secure identification protocol between a low-resource and a high-resource party to provide secure communication. In this work, we propose two identification protocols based on the emerging hardware-secure solutions, the quantum Physical Unclonable Functions (qPUFs). The first protocol allows a low-resource party to prove its identity to a high-resource party and in the second protocol, it is vice versa. Unlike existing identification protocols based on Quantum Read-out PUFs that rely on the security against a specific family of attacks, our protocols provide provable exponential security against any Quantum Polynomial-Time adversary with resource-efficient parties. We provide a comprehensive comparison between the two proposed protocols in terms of resources such as quantum memory and computing ability required in both parties as well as the communication overhead between them.

Resveratrol reverses the cadmium-promoted migration, invasion, and epithelial–mesenchymal transition procession by regulating the expression of ZEB1

Resveratrol has been reported as an ideal medicine in the treatment of colorectal cancer. Meanwhile, cadmium could affect the occurrence and development of tumors in various ways. Epithelial–mesenchymal transition is a major progress regulated with colorectal cancer (CRC). We aimed to determine the effect and mechanism of resveratrol on the Cd-promoted EMT in CRC cells. First, we investigated the migration and invasion of CRC cells with or without the treatment of different concentrations of Cd in vitro by the transwell assay. Second, Western blot and RT-qPCR assay were used to detect the expressions of EMT-related markers (ZEB1, vimentin, E-cadherin, and N-cadherin) in Cd-exposed CRC cells. Subsequently, after treating with different concentrations of resveratrol, the migration and invasion of Cd-exposed CRC cells were detected again, as well as the expressions of EMT-related markers. Moreover, m6A-related RNAs in Cd-exposed CRC cells after treating with resveratrol were immunoprecipitated and validated by Me-RIP and RT-qPCR. These indicated that Cd promoted the migration and invasion of CRC cells. In addition, Cd up-regulated the expressions of N-cadherin, vimentin, and ZEB1, while it down-regulated that of E-cadherin in CRC cells. Resveratrol could reverse the Cd-promoted migration, invasion, and EMT procession by regulating the expression of ZEB1.

Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.

The exploration of N6-deoxyadenosine methylation in mammalian genomes

N6-methyladenine (N6-mA, m6dA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response. Here, we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes, predominantly mammals.

A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.

Effects of Combination Therapy of Methotrexate with Sulfasalazine and Hydroxychloroquine: Comparative Clinical Trial

Aims: To study the role of two combination therapies in the treatment of rheumatoid arthritis. Study Design: This an open-label, randomized 180-days clinical trial. Place and Duration of Study: This study was conducted in the Department of Pharmacology and Therapeutics, BMSI and Medical unit ward 6. Methodology: Eighty-nine patients were enrolled (69 women, 20 men; age range 28-62 years). A and B were the groups assigned to the patients. MTX 7.5-20 mg/ week orally and SSZ 10-20 mg / day orally as maximally tolerated were prescribed to the 55 patients of group A. MTX 7.5-20 mg/ week orally and HCQ 200 mg twice daily were prescribed to the 54 patients of group B.. Results: When we compared group A with group B, group A showed major progress in mean swollen joint count (1.9 ± 0.97) as compared to group B (2.7 ± 1.78). Group B showed major progress in mean physician’s global assessment (2.7 ± 0.92) as compared to group A (3.8 ± 1.22). For that reason, our study showed that patients receiving both the combinations responded equally in terms of efficacy but the combination of MTX and HCQ is better tolerated than the combination of MTX and SSZ. Conclusion: Both combinations of MTX & SSZ and MTX & HCQ were equally effective but the combination of MTX & HCQ was superior in terms of tolerability than the combination of MTX and SSZ.