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Frontiers in Bioscience (Landmark... May 2024Lung cancer is the primary cause of cancer-related deaths, with one of the highest incidence and mortality rates of all malignant tumors. Dysregulated expression of...
BACKGROUND
Lung cancer is the primary cause of cancer-related deaths, with one of the highest incidence and mortality rates of all malignant tumors. Dysregulated expression of DEPDC1B has been reported to occur in various tumor types. However, the functional implications of this alteration in lung adenocarcinoma (LUAD) and the underlying molecular mechanism remains unclear. In this study, we investigated the role and clinical significance of DEPDC1B in LUAD.
METHODS
The expression of DEPDC1B in LUAD and its relationship with prognosis were systematically evaluated in several publically available datasets. The effects of DEPDC1B knockdown on the proliferation and motility of LUAD cells were assessed using the JULI Stage Real-time Cell History Recorder, while the effect of knockdown on the cell cycle was studied by flow cytometry. Furthermore, RNA-Sequencing (RNA-Seq) analysis was conducted to identify the downstream target genes and pathways regulated by DEPDC1B. Correlations between the expression of DEPDC1B and immune cell infiltration, immunotherapy resistance, and chemoresistance were also examined. Additionally, molecular biological methods were used to explore the regulatory mechanism of B-Myb on DEPDC1B expression.
RESULTS
DEPDC1B was found to be upregulated in LUAD patients and this was associated with poor clinical outcomes. Knockdown of inhibited cell growth, migration and motility, as well as cell cycle progression. Knockdown also resulted in the down-regulation of several downstream genes, including , , and , as well as the inactivation of multiple critical pathways, such as the ERK and PI3K-AKT pathways. Analysis of the tumor immuno-environment in LUAD revealed that high DEPDC1B expression was associated with an abundance of activated CD4+ memory T cells, M0 macrophages, M1 macrophages, and CD8+ T cells. Moreover, these tumors responded poorly to immunotherapy. Analysis of chemo-drug sensitivity showed that LUADs with high DEPDC1B expression were more responsive to frontline chemotherapeutic drugs such as Vinorelbine, Cisplatin, and Etoposide. Additionally, mechanistic investigations revealed that DEPDC1B is a direct target gene of B-Myb, and that its knockdown attenuated the proliferation and motility effects of B-Myb.
CONCLUSIONS
In summary, our findings indicate that DEPDC1B is a critical regulator during the malignant progression of LUAD. DEPDC1B could therefore be a promising prognostic marker and therapeutic target in LUAD diagnosis and treatment.
Topics: Humans; Adenocarcinoma of Lung; GTPase-Activating Proteins; Lung Neoplasms; Cell Proliferation; Cell Movement; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Disease Progression; Cell Cycle Proteins; Prognosis; Drug Resistance, Neoplasm; Male; Gene Knockdown Techniques; Signal Transduction; Neoplasm Proteins; Trans-Activators
PubMed: 38940035
DOI: 10.31083/j.fbl2906204 -
Journal of Extracellular Biology Feb 2024Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell...
Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RNA levels were continually detected in colorectal tissue arrays. Additionally, protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, -induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that /AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.
PubMed: 38939899
DOI: 10.1002/jex2.141 -
Biomaterials Research 2024The management of infected wounds poses a significant challenge due to the growing issue of antibiotic resistance, underscoring the urgent necessity to innovate and...
The management of infected wounds poses a significant challenge due to the growing issue of antibiotic resistance, underscoring the urgent necessity to innovate and implement alternative therapeutic strategies. These strategies should be capable of eliminating bacterial infections in infected wounds while circumventing the induction of multi-drug resistance. In the current study, we developed an easily prepared and injectable fibrin gel (FG) loaded with nanoparticles (NPs) that exhibit antibacterial and immunomodulatory properties to facilitate the healing of infected wounds. Initially, a novel type of NP was generated through the electrostatic interaction between the photothermal agent, mPEG-modified polydopamine (MPDA), and the nitric oxide (NO) donor, S-nitrosocysteamine (SNO). This interaction resulted in the formation of NPs referred to as SNO-loaded MPDA (SMPDA). Subsequently, the SMPDA was encapsulated into the FG using a double-barreled syringe, thereby producing the SMPDA-loaded FG (SMPDA/G). Experimental results revealed that SMPDA/G could effectively eliminate bacterial infections and alter the immune microenvironment. This efficacy is attributed to the synergistic combination of NO therapy and photothermal therapy, along with the role of SMPDA in facilitating M2 macrophage polarization within the gel. Accordingly, these findings suggest that the SMPDA/G holds substantial promise for clinical application in infected wound healing.
PubMed: 38938648
DOI: 10.34133/bmr.0019 -
Lung Cancer (Auckland, N.Z.) 2024The year 2024 is the 20 anniversary of the discovery of activating epidermal growth factor receptor () mutations in non-small cell lung cancer (NSCLC). Since then,...
Top 20 NSCLC Clinical and Translational Science Papers That Shaped the 20 Years Since the Discovery of Activating Mutations in NSCLC. An Editor-in-Chief Expert Panel Consensus Survey.
The year 2024 is the 20 anniversary of the discovery of activating epidermal growth factor receptor () mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20 anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25 anniversay of the discovery mutations (i.e. top 25 papers on the 25 years since the discovery of activating mutations).
PubMed: 38938224
DOI: 10.2147/LCTT.S463429 -
Cell Biochemistry and Function Jul 2024Multidrug resistance (MDR) during clinical chemotherapy for cancer has been considered a major obstacle to treatment efficacy. The involvement of adenosine...
Multidrug resistance (MDR) during clinical chemotherapy for cancer has been considered a major obstacle to treatment efficacy. The involvement of adenosine triphosphate-binding cassette (ABC) transporters in the MDR mechanism significantly reduces the efficacy of chemotherapeutics. This study investigates the potential of morin, a dietary bioflavonoid, to overcome colchicine resistance in KBChR-8-5 MDR cells. The P-gp inhibitory activity by morin was measured by calcein-AM drug efflux assay. Western blot analysis was employed to evaluate P-gp messenger RNA and protein expressions following morin treatment. Flow cytometry analysis and acridine orange/ethidium bromide fluorescence staining were utilised to investigate the induction of apoptosis and cell cycle arrest upon treatment with morin and paclitaxel in combination. Additionally, polymerase chain reaction (PCR) array analysis was conducted to study the gene expression profiles related to MDR, apoptosis and cell cycle arrest during treatment with morin, paclitaxel or their combination. Morin exhibited a strong binding interaction with human P-gp. This was corroborated by drug efflux assays, which showed a reduction in P-gp efflux function with increasing morin concentration. Furthermore, morin and paclitaxel combination potentiated the induction of apoptosis and G2/M phase cell cycle arrest. Morin treatment significantly downregulated the gene expression of ABCB1 and P-gp membrane expressions in MDR cells. Additionally, PCR array gene expression analysis revealed that the combination treatment with morin and paclitaxel upregulated proapoptotic and cell cycle arrest genes while downregulating ABCB1 gene and antiapoptotic genes. Thus, morin effectively reversed paclitaxel resistance in KBChR-8-5 drug-resistant cancer cells and concluded that morin resensitized the paclitaxel resistance in KBChR8-5 drug-resistant cancer cells.
Topics: Humans; Flavonoids; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Apoptosis; Paclitaxel; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Cycle Checkpoints; ATP Binding Cassette Transporter, Subfamily B; Antineoplastic Agents; Flavones
PubMed: 38938150
DOI: 10.1002/cbf.4083 -
Animal Bioscience Jun 2024This research aimed to analyze the prevalence, molecular characteristics, toxinotyping, alpha toxin production potential, and antibiotic resistance pattern of...
OBJECTIVE
This research aimed to analyze the prevalence, molecular characteristics, toxinotyping, alpha toxin production potential, and antibiotic resistance pattern of Clostridium perfringens (C. perfringens) isolates in meat samples collected from various sources.
METHODS
Sixty meat samples were screened for alpha toxin using Enzyme-Linked Immunosorbent Assay (ELISA), revealing a positivity rate of 13.3%, predominantly in raw poultry meat. Subsequent culturing on Perfringens agar identified nine samples harboring characteristic C. perfringens colonies, primarily isolated from raw poultry meat. Molecular confirmation through 16S rRNA gene amplification and sequencing authenticated twelve isolates as C. perfringens, with nine strains exhibiting genetic resemblance to locally isolated strains. Toxinotyping assays targeting alpha toxin-specific genes confirmed all nine isolates as type A C. perfringens, with no detection of beta or epsilon toxin genes. Hemolytic assays demonstrated varying alpha toxin production potentials among isolates, with accession number OQ721004.1 displaying the highest production capacity. Moreover, antibiotic resistance profiling revealed multi-drug resistance patterns among the isolates.
RESULTS
The study identified distinct clusters within C. perfringens strains, indicating variations. Phylogenetic analysis delineated genetic relatedness among strains, elucidating potential evolutionary paths and divergences.
CONCLUSION
The findings underscore the need for robust surveillance and control measures to mitigate the risk of C. perfringens contamination in meat products, particularly in raw poultry meat. Enhanced monitoring and prudent antimicrobial stewardship practices are warranted in both veterinary and clinical settings to address the observed antibiotic resistance profiles and prevent foodborne outbreaks.
PubMed: 38938034
DOI: 10.5713/ab.24.0210 -
Assessing the quality of life in patients with drug-resistant tuberculosis: a cross-sectional study.BMC Pulmonary Medicine Jun 2024This study investigated the current status of the quality of life (QOL) of drug-resistant tuberculosis (DR-TB) patients in Nanjing, China, and analyzed the influencing...
BACKGROUND
This study investigated the current status of the quality of life (QOL) of drug-resistant tuberculosis (DR-TB) patients in Nanjing, China, and analyzed the influencing factors.
METHODS
The survey was conducted among patients with DR-TB who were hospitalized in the tuberculosis department of the Second Hospital of Nanjing (Nanjing Public Health Medical Center) from July 2022 to May 2023. The Chinese version of the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire was used to investigate the QOL levels of patients with DR-TB, and a multiple linear regression model was used to analyze the QOL influencing factors.
RESULTS
A total of 135 patients participated in the study; 69.6% were male, the average age was 46.30 ± 17.98 years, 13.33% had an education level of elementary school or below, and 75.56% were married. The QOL scores were 51.35 ± 17.24, 47.04 ± 20.28, 43.89 ± 17.96, and 35.00 ± 11.57 in the physiological, psychological, social, and environmental domains, respectively. The differences between the four domain scores and the Chinese normative results were statistically significant (P < 0.05). The results of multiple linear regression analysis showed that the factors related to the physiological domain included residence, family per-capita monthly income, payment method, adverse drug reactions (ADRs), and comorbidities; psychological domain correlates included educational level, family per-capita monthly income, course of the disease, and caregivers; social domain correlates included age and comorbidities; and factors related to the environmental domain included age, education level, and comorbidities.
CONCLUSIONS
In Nanjing, China, patients with younger age, higher education level, living in urban areas, high family per-capita monthly income, no adverse drug reactions, no comorbidities, and having caregivers have better quality of life. Future interventions to improve the quality of life of patients with drug-resistant tuberculosis could be tailored to a specific factor.
Topics: Humans; Quality of Life; Male; Female; Tuberculosis, Multidrug-Resistant; Middle Aged; Cross-Sectional Studies; Adult; China; Surveys and Questionnaires; Linear Models; Aged
PubMed: 38937809
DOI: 10.1186/s12890-024-03119-1 -
BMC Infectious Diseases Jun 2024Tuberculosis (TB), one of the leading causes of death worldwide, has a higher incidence among indigenous people. Albeit uncommon, autoimmune hemolytic anemia (AIHA) has...
BACKGROUND
Tuberculosis (TB), one of the leading causes of death worldwide, has a higher incidence among indigenous people. Albeit uncommon, autoimmune hemolytic anemia (AIHA) has been deemed a risk condition to develop mycobacterial infection, as a result of the immunosuppressive treatments. TB, in turn, can be a predisposing factor for secondary infections.
CASE PRESENTATION
Here we present a case of a 28-year-old indigenous woman from Colombia, previously diagnosed with AIHA and pulmonary TB. Despite various treatments, therapies and medical interventions, the patient died after severe medullary aplasia of multiple causes, including secondary myelotoxicity by immunosuppressive therapy and secondary disseminated infections, underlining infection by Staphylococcus aureus, Klebsiella pneumoniae and Candida glabrata, which were identified as drug-resistant microorganisms. Together, this led to significant clinical complications. Invasive aspergillosis was diagnosed at autopsy.
CONCLUSIONS
This report presents a rarely finding of AIHA followed by TB, and highlights the great challenges of dealing with co-infections, particularly by drug resistant pathogens. It also aims to spur governments and public health authorities to focus attention in the prevention, screening and management of TB, especially among vulnerable communities, such as indigenous people.
Topics: Humans; Female; Adult; Coinfection; Fatal Outcome; Anemia, Hemolytic, Autoimmune; Colombia; Klebsiella pneumoniae; Staphylococcus aureus; Candida glabrata; Tuberculosis, Pulmonary; Staphylococcal Infections; Indigenous Peoples; Candidiasis
PubMed: 38937714
DOI: 10.1186/s12879-024-09557-w -
Integrated surveillance systems for antibiotic resistance in a One Health context: a scoping review.BMC Public Health Jun 2024Antibiotic resistance (ABR) has emerged as a major threat to health. Properly informed decisions to mitigate this threat require surveillance systems that integrate... (Review)
Review
BACKGROUND
Antibiotic resistance (ABR) has emerged as a major threat to health. Properly informed decisions to mitigate this threat require surveillance systems that integrate information on resistant bacteria and antibiotic use in humans, animals, and the environment, in line with the One Health concept. Despite a strong call for the implementation of such integrated surveillance systems, we still lack a comprehensive overview of existing organizational models for integrated surveillance of ABR. To address this gap, we conducted a scoping review to characterize existing integrated surveillance systems for ABR.
METHODS
The literature review was conducted using the PRISMA guidelines. The selected integrated surveillance systems were assessed according to 39 variables related to their organization and functioning, the socio-economic and political characteristics of their implementation context, and the levels of integration reached, together with their related outcomes. We conducted two distinct, complementary analyses on the data extracted: a descriptive analysis to summarize the characteristics of the integrated surveillance systems, and a multiple-correspondence analysis (MCA) followed by a hierarchical cluster analysis (HCA) to identify potential typology for surveillance systems.
RESULTS
The literature search identified a total of 1330 records. After the screening phase, 59 references were kept from which 14 integrated surveillance systems were identified. They all operate in high-income countries and vary in terms of integration, both at informational and structural levels. The different systems combine information from a wide range of populations and commodities -in the human, animal and environmental domains, collection points, drug-bacterium pairs, and rely on various diagnostic and surveillance strategies. A variable level of collaboration was found for the governance and/or operation of the surveillance activities. The outcomes of integration are poorly described and evidenced. The 14 surveillance systems can be grouped into four distinct clusters, characterized by integration level in the two dimensions. The level of resources and regulatory framework in place appeared to play a major role in the establishment and organization of integrated surveillance.
CONCLUSIONS
This study suggests that operationalization of integrated surveillance for ABR is still not well established at a global scale, especially in low and middle-income countries and that the surveillance scope is not broad enough to obtain a comprehensive understanding of the complex dynamics of ABR to appropriately inform mitigation measures. Further studies are needed to better characterize the various integration models for surveillance with regard to their implementation context and evaluate the outcome of these models.
Topics: Humans; One Health; Drug Resistance, Microbial; Anti-Bacterial Agents; Population Surveillance
PubMed: 38937706
DOI: 10.1186/s12889-024-19158-6 -
BMC Microbiology Jun 2024Bacterial antimicrobial resistance poses a severe threat to humanity, necessitating the urgent development of new antibiotics. Recent advances in genome sequencing offer...
BACKGROUND
Bacterial antimicrobial resistance poses a severe threat to humanity, necessitating the urgent development of new antibiotics. Recent advances in genome sequencing offer new avenues for antibiotic discovery. Paenibacillus genomes encompass a considerable array of antibiotic biosynthetic gene clusters (BGCs), rendering these species as good candidates for genome-driven novel antibiotic exploration. Nevertheless, BGCs within Paenibacillus genomes have not been extensively studied.
RESULTS
We conducted an analysis of 554 Paenibacillus genome sequences, sourced from the National Center for Biotechnology Information database, with a focused investigation involving 89 of these genomes via antiSMASH. Our analysis unearthed a total of 848 BGCs, of which 716 (84.4%) were classified as unknown. From the initial pool of 554 Paenibacillus strains, we selected 26 available in culture collections for an in-depth evaluation. Genomic scrutiny of these selected strains unveiled 255 BGCs, encoding non-ribosomal peptide synthetases, polyketide synthases, and bacteriocins, with 221 (86.7%) classified as unknown. Among these strains, 20 exhibited antimicrobial activity against the gram-positive bacterium Micrococcus luteus, yet only six strains displayed activity against the gram-negative bacterium Escherichia coli. We proceeded to focus on Paenibacillus brasilensis, which featured five new BGCs for further investigation. To facilitate detailed characterization, we constructed a mutant in which a single BGC encoding a novel antibiotic was activated while simultaneously inactivating multiple BGCs using a cytosine base editor (CBE). The novel antibiotic was found to be localized to the cell wall and demonstrated activity against both gram-positive bacteria and fungi. The chemical structure of the new antibiotic was elucidated on the basis of ESIMS, 1D and 2D NMR spectroscopic data. The novel compound, with a molecular weight of 926, was named bracidin.
CONCLUSIONS
This study outcome highlights the potential of Paenibacillus species as valuable sources for novel antibiotics. In addition, CBE-mediated dereplication of antibiotics proved to be a rapid and efficient method for characterizing novel antibiotics from Paenibacillus species, suggesting that it will greatly accelerate the genome-based development of new antibiotics.
Topics: Paenibacillus; Anti-Bacterial Agents; Multigene Family; Genome, Bacterial; Peptide Synthases; Polyketide Synthases; Bacteriocins; Biosynthetic Pathways; Bacterial Proteins; Drug Discovery
PubMed: 38937695
DOI: 10.1186/s12866-024-03375-5