MedComm - Future medicine最新文献

Although immunoassays are an indispensable tool for scientific research, antibody specificity has been recognized as a major challenge to the rigor and reproducibility of research findings. A 2016 proposal published by the International Working Group for Antibody Validation identified five pillars of antibody validation.¹ Among these is genetic validation, in which “The expression of the target protein is eliminated or significantly reduced by genome editing or RNA interference.”

Y chromosome-encoded genes present unique opportunities and challenges to validate antibodies on this genetic principle. Fortunately, readily available female-derived cells and tissues can serve as a target-negative source material, which is far more convenient than typical sources of genetic validation, which require knockout or knockdown approaches to a target gene. However, an additional challenge for the specificity of these antibodies is that many Y chromosome proteins have “gametologs,” or highly homologous genes encoded on the X chromosome. As gametologs can share over 90% amino acid identity, these protein targets present unique specificity challenges. However, this obstacle has not impeded commercial antibody suppliers who market hundreds of antibodies with purported specificity for Y chromosome-encoded genes.

We performed an analysis of the extent to which Y chromosome gene-targeted commercial antibodies recognize female-derived materials using data provided in their marketing materials (a detailed methodology is provided in the Supporting Information). Table 1 lists 65 antibodies purporting to target a Y chromosome-encoded gene with company-supplied marketing demonstrating immunoreactivity in female-derived tissues. Product page URLs are provided in Supporting Information: Table S1. For one example, an antibody targeting sex-determining region chromosome Y marketed by MyBioSource (catalog # MBS8513980) presents validation data in HeLa cells, which is a cervical cancer cell line with no Y chromosomes.²

Among these antibodies, frequently used female-derived cell lines were HeLa, 30/65 (46%), HEK293T, female human embryonic kidney cells used in 14 (22%), and MCF-7 breast cancer cells used in 7 (11%). One antibody, a rabbit polyclonal raised against the “N terminus” of DEAD-box helicase 3 Y-linked (DDX3Y) (LS Biosciences, catalog # LS-C355991) presented positive immunohistochemistry in human breast cancer tissue. While not definitively a Y-chromosome absent tissue, we included this as a likely female-positive tissue, based on the prevalence of breast cancer in females compared to males being roughly 99-to-1 in the United States.³ Among 65 antibodies, we noted just two that had disclaimers warning that the antibody may cross-react with homologous X chromosome-encoded proteins.

This survey provides evidence of widespread off-target antigen recognition in commercial ant

Metabolic dysregulation is a hallmark of cancer, underpinning diverse aggressive behaviors such as uncontrolled proliferation, immune evasion, and metastasis. Despite the potential of tumor metabolites as biomarkers, their utility has been hampered by metabolic heterogeneity. Exploring cancer metabolism aims to discern shared metabolic pathways and have a better understanding the metabolic heterogeneity of tumors. This approach offers a holistic view of cancer metabolism, facilitating the identification of multicancer-relevant metabolic targets and the development of more broadly effective therapeutics. In this review, we present a comprehensive overview of the current landscape of cancer metabolism and its prospective applications in cancer diagnosis and prognosis. We delineate common metabolic aberrations observed across a spectrum of cancer types and elucidate the unique metabolic signatures characterizing the six leading causes of cancer-related mortality. Furthermore, we survey the utilization of untargeted metabolomics and single-cell technologies in cancer screening, diagnosis, and prognosis, while also spotlighting available data resources for pan-cancer metabolomics analyses. Throughout this discussion, we tackle prevailing research challenges and propose strategies aimed at enhancing cancer management. Our objective is to furnish valuable insights that can inform and guide future research endeavors in the dynamic realm of cancer metabolism.

Given the numerous crucial roles of RNA molecules in disease initiation and progression, RNAs have emerged as promising therapeutic targets for many diseases. Tong et al. report their discovery¹ of small-molecule bioactive degraders that selectively bind to disease-associated RNAs and recruit ribonuclease (RNase) enzymes to facilitate the degradation of RNAs. They have demonstrated the therapeutic potential of RNA degraders in the animal models of different cancers. The findings pave the way to target the development of novel RNA-targeted small-molecule drugs.

Despite considerable advances in drug discovery, there are only hundreds of proteins that have been targeted by approved drugs, compared to the estimated 20,000 human genes. To widen the scope of druggable targets, sustained research efforts have been devoted to modulating the challenging “undruggable” targets in novel ways. Targeting cellular RNA represents one such emerging strategy with the potential to expand the scope that can be drugged. There are multiple different classes of RNA molecules, contributing to various and essential biological functions. Messenger RNA (mRNA) and ribosomal RNA are involved in gene expression and protein synthesis. Noncoding RNAs are critical for the regulation of transcription and translation, such as long noncoding RNA, microRNA (miRNA), and antisense RNAs. Recent evidence has illustrated the important roles of RNA in various diseases, including neurodegenerative diseases, cancer, genetic disorders, and viral infections.²

A range of natural RNA-processing mechanisms have been leveraged to develop RNA-based therapeutics. They provide potential ways to specifically inhibit the expression of disease-related genes and prevent the translation of corresponding proteins. The most well-known RNA-based therapeutics include small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs).³ The siRNAs are double-stranded RNA molecules with 20–25 nucleotides. The ASOs are short synthetic single-stranded DNA or RNA. Both siRNAs and ASOs are gene silencers designed to target RNA molecules in a sequence-specific manner. However, one of the challenges that hindered their clinical application is their limited in vivo stability and cellular permeability due to their large molecular weight. Drug delivery systems are required to deliver the therapeutics intracellularly and systemically.⁴

Small molecules usually follow Lipinski's rule of five and face no such impediments. Compared to oligonucleotides, small-molecule drugs targeting RNAs have the advantage of nonimmunogenic and lower molecular weight. This makes them more effective in cell penetration and overcomes the delivery challenges of RNA-based therapeutics. Orally delivered small molecules also significantly increase patient comfort and compliance. Traditionally, small molecules have been primarily

Inflammation is characterized by activation of the immune and nonimmune cells that act by removing the stress stimuli such as pathogens, toxins and so on. It can be categorized in two types namely, acute and chronic inflammation that depends on the extent of the injury caused due to inflammation. Basically, acute inflammatory responses regulate various cellular and molecular events and the interaction of different types of immune cells, that helps to minimize the injury. These events may lead to recovery of tissue homeostasis during acute inflammation. However, during chronic inflammation as in neurodegenerative diseases, a variety of key players orchestrate the process to amplify the magnitude of inflammation.¹

Mitogen-activated protein kinases (MAPKs) are one of the widely studied kinase family that composed of three well known subfamily: p38 MAPKs, extracellular signal-regulated protein kinases (ERKs) and c-Jun N-terminal kinases (JNKs). The p38MAPKs are encoded by p38α, p38β, p38γ, and p38δ genes. It has been shown that the p38MAPK pathway is critically involved in the regulation of inflammation via activation of TLR4 receptor. MAPK-activated protein kinase 2 (MK2) is one of the key substrates downstream to p38α/p38β, which on phosphorylation regulate the production and signaling of pro-inflammatory cytokines.^{2, 3}

The inhibition of MK2 by tool compound, PF-3644022 has shown reduction of inflammatory biomarkers in various in vitro and in vivo models.⁴ So, the present study is designed to investigate and compare the anti-inflammatory effects of quercetin⁵ with MK2 inhibitor, PF-3644022 in LPS induced SH-SY5Y cell line in vitro and rat whole blood ex vivo.

The computational docking study (binding affinity) data was obtained through the Auto Dock Vina software and the interaction among the protein-ligand inhibition was studied through Biovia (discovery studio) and Ligplot+ software (Figure 1A-D). The structure-based binding site identification study method was performed to compare the binding affinities among PF-3644022 and quercetin against MK2 protein. The binding affinity of PF-3644022 with MK2 was found to be −8.4 Kcal/mol. The interaction between PF-3644022 and MK2 is divided into two types. At first, it formed one hydrophilic bond having bond length 3.17 Å against Arg 149 (A chain) of MK2 protein. Second, the hydrophobic bonds were formed with Glu 165, Ser 169, Asn 200, Lys 168, Ile 202, Tyr 194, Ile 166, and pro 199 in MK2 protein. The binding affinity of quercetin was found to be −8.1 Kcal/mol. The interaction between quercetin and MK2 showed that there were four hydrophilic bonds with showing different bond length against MK2 protein amino acid sequence like Asp 207 (2.70 Å), Glu 139(2.70 Å), Leu 141(2.80 Å), and Glu 145(2.91 Å). This binding also showed hydrophobic interaction against MK2 protein amino acid such as Gly 73

In November 2022, a large number of Omicron infections suddenly appeared in Beijing, but the epidemiological and clinical characteristics of the epidemic cases were unknown. We collected the data on COVID-19 cases in Fangcang Hospital in Beijing from November 20, 2022, to December 8, 2022, and analyzed the epidemiological and clinical characteristics. Of the enrolled study, 85.9% were asymptomatic and 14.1% were mild. Epidemiological data showed that the transmission speed of the Omicron variant was fast and the transmission range was wide, large-scale infections occurred in both rural and urban areas, and all age groups were susceptible to the Omicron variant. In addition, antipyretics and cough drugs were the two most used drugs, because 51.3% and 22.7% of patients had fever and cough, respectively, and 10.3% of patients took hypnotics. Furthermore, the proportion of patients with chronic diseases was low (13.9%), while the vaccination rate (71.2%) was relatively high. Based on the results, we found that most mild and asymptomatic cases did not need treatment, indicating that home isolation is correct and feasible. Although SARS-CoV-2 variants have characteristics such as high infectivity and immune-escape ability, the public should not be too afraid of COVID-19 infection; appropriate measures such as wearing masks and maintaining social distancing are sufficient to prevent reinfection.

Recently, researchers from Cancer Research UK and The Francis Crick Institute published a paper entitled “Lung adenocarcinoma promotion by air pollutants” in Nature.¹ The study focused on the impact of air pollutants, specifically PM2.5, on lung adenocarcinoma development. By analyzing human data and conducting subsequent animal experiments, the researchers found that air pollutants PM2.5 leads to an influx of macrophages into the lung and triggers the release of interleukin-1β. This, in turn, induces a progenitor-like cell state within estimated glomerular filtration rate (EGFR) mutant lung alveolar type II epithelial cells, fueling tumorigenesis, and potentially exacerbating pre-existing cancerous mutations in normal tissues.

While the association between smoking and lung cancer risk is well-established, attention has increasingly turned towards understanding the carcinogenic factors in never-smokers. As the eighth leading cause of cancer-related deaths in the United Kingdom, lung cancer in never-smokers (LCINS) is often an adenocarcinoma carrying the EGFR mutation.² In an effort to identify significant factors influencing the development of lung cancer LCINS, the researchers analyzed environmental and epidemiological data from 32,957 cases of EGFR-driven lung cancer in the United Kingdom, Canada, South Korea, Taiwan, and China. The findings revealed a correlation between increased levels of PM2.5 and a higher incidence of lung cancer among the study participants. Later analysis of 407,509 individuals from the UK Biobank support these results, demonstrating significant increase in the projected incidence of lung cancer among those exposed to high levels of PM2.5. The researchers also conducted a 3-year follow-up study involving 228 Canadian lung cancer patients. The incidence of lung cancer was found to be significantly higher (73%) in those exposed to high levels of PM2.5 compared to those exposed to low levels (40%). Notably, this association was not observed in the Canadian cohort over a 20-year period, suggesting that 3 years of exposure to high levels of pollution may be sufficient to produce cancer.

Hill et al. further employed genetically engineered mice carrying EGFR mutations (EGFR^L858R) associated with human cancer to functionally investigate whether PM2.5 exposure promoted the development of lung adenocarcinoma. The study revealed that mice were exposed to similar air pollution particles, resulting in a higher likelihood of developing lung tumors compared to control mice not exposed to pollution particles. The same experiments were performed on genetically engineered mice with Kras mutations, a common mutation in various lung tumors, yielding similar results. Through spatial analysis of clonal dynamics, the researchers discovered that PM2.5 promotes early tumorigenesis through two mechanisms: increasing the number of EGFR-mutated cells capable of forming tumors