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18 pages, 9126 KiB  
Article
Investigation of the Antimicrobial Resistance of Important Pathogens Isolated from Poultry from 2015 to 2023 in the United States
by Asher T. Wang, Liya Tang, Andrew Gao, Ethan Zhang, Grace Huang, Justin Shen, Qian Jia and Zuyi Huang
Pathogens 2024, 13(11), 919; https://doi.org/10.3390/pathogens13110919 - 22 Oct 2024
Abstract
Foodborne pathogens cause around 47.8 million illnesses in the U.S. annually, with antimicrobial misuse in food production, particularly in poultry processing, contributing significantly to this public health challenge. Misuse of antimicrobials can contribute to antimicrobial resistance (AMR) and make the treatment of pathogens [...] Read more.
Foodborne pathogens cause around 47.8 million illnesses in the U.S. annually, with antimicrobial misuse in food production, particularly in poultry processing, contributing significantly to this public health challenge. Misuse of antimicrobials can contribute to antimicrobial resistance (AMR) and make the treatment of pathogens increasingly difficult. This emphasizes the need to investigate antimicrobial resistance in U.S. poultry. This study analyzes data from the NCBI Pathogen Isolates Browser (2015–2023) to explore the relationships between antimicrobial-resistant pathogens, AMR genes, and antimicrobials detected with resistance in pathogens isolated from chicken and turkey. Using principal component analysis and hierarchical clustering, we mapped and profiled regional and temporal patterns of antimicrobial resistance. Salmonella enterica was the most prevalent antimicrobial-resistant pathogen across both chicken and turkey, with notable outbreaks, particularly in the Northeast. Antimicrobial-resistant Campylobacter jejuni was more prevalent in chicken, particularly in California and Georgia, while Escherichia coli and Shigella were more prominent in turkey, with concentrated antimicrobial resistance in Texas for pathogen samples isolated from chicken. Resistance to tetracycline and streptomycin was widespread, with distinct regional clusters: antimicrobial resistance was concentrated in states like Minnesota for pathogens isolated from chicken, while AMR found in pathogens isolated from turkey was more evenly distributed across the Midwest. Key AMR genes, such as tet(A), mdsA, and mdsB, also followed similar patterns, peaking in 2019 and significantly declining by 2022. The observed decline in AMR cases may be linked to improved biosecurity measures and disruptions in detection due to the COVID-19 pandemic. This comprehensive study of antimicrobial resistance in U.S. poultry provides valuable insights into resistance trends, which provide useful information to inform targeted interventions and policies to mitigate AMR threats in the poultry production industry. For consumers, these findings emphasize the importance of proper food handling and cooking practices to reduce the risk of exposure to resistant pathogens. Regulatory authorities should focus on enforcing stricter antimicrobial usage policies and enhancing surveillance systems to sustain the reduction in AMR cases. Full article
(This article belongs to the Special Issue Foodborne Pathogens: The Antimicrobial Resistance from Farm to Fork)
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16 pages, 997 KiB  
Article
Quinolone and Tetracycline-Resistant Biofilm-Forming Escherichia coli Isolates from Slovak Broiler Chicken Farms and Chicken Meat
by Nikola Dančová, Gabriela Gregová, Tatiana Szabóová, Ivana Regecová, Ján Király, Vanda Hajdučková and Patrícia Hudecová
Appl. Sci. 2024, 14(20), 9514; https://doi.org/10.3390/app14209514 - 18 Oct 2024
Viewed by 440
Abstract
Escherichia coli isolates from intensive poultry production are associated with antimicrobial resistance and worldwide health problems. The aim of the study was to detect and evaluate the phenotypic and genotypic antimicrobial resistance, biofilm formation, phylogenetic typing, and virulence factors in E. coli isolates [...] Read more.
Escherichia coli isolates from intensive poultry production are associated with antimicrobial resistance and worldwide health problems. The aim of the study was to detect and evaluate the phenotypic and genotypic antimicrobial resistance, biofilm formation, phylogenetic typing, and virulence factors in E. coli isolates from the rectal swabs of chickens from two farms and swabs of chicken meat purchased from Slovakian food markets. Interpretative readings of minimal inhibitory concentration (MIC) revealed dominant resistance to ampicillin (>50%) in both groups. We also detected higher resistance to ciprofloxacin (45%), tetracycline, ampicillin + sulbactam, and trimethoprim + sulfonamide (each >30%). Here, 28.57% of the strains studied were multidrug-resistant (MDR). The formation of weak biofilms was confirmed in 8.8% of E. coli, while one of the strains obtained from chicken cloacal swabs was classified as a strong biofilm producer. The most frequently confirmed phylogenetic groups in E. coli were B1 and A1 in all groups. PCR detection revealed the presence of genes encoding tetracycline resistance (tetAB) and plasmid-mediated quinolone resistance (qnrABS), and Int1 (52.9%), Tn3 (76.5%), kpsMT II (8.8%), fimA (97.1%), cvaC (38.2%), and iutA (76.5%) genes in the strains studied. Our results demonstrate that chickens and chicken meat were the source of antibiotic-resistant, biofilm-forming, and virulent E. coli, representing a potential risk from the point of view of the One Health concept. Full article
(This article belongs to the Section Applied Microbiology)
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16 pages, 30847 KiB  
Article
Notch3 and Its Clinical Importance in Ovarian Cancer
by Bimal Prasad Jit, Alisha Behera, Sahar Qazi, Khushi Mittal, Subhadip Kundu, Babul Bansal, MD Ray and Ashok Sharma
Drugs Drug Candidates 2024, 3(4), 707-722; https://doi.org/10.3390/ddc3040040 - 16 Oct 2024
Viewed by 283
Abstract
Background: Ovarian cancer (OC) is the most prevalent gynecological malignancy in women, often diagnosed at an advanced stage due to the absence of specific clinical biomarkers. Notch signaling, particularly Notch3, is frequently activated in OC and contributes to its oncogenic role. Despite its [...] Read more.
Background: Ovarian cancer (OC) is the most prevalent gynecological malignancy in women, often diagnosed at an advanced stage due to the absence of specific clinical biomarkers. Notch signaling, particularly Notch3, is frequently activated in OC and contributes to its oncogenic role. Despite its known association with poor clinical outcomes, the biomarker potential of Notch3 remains inadequately explored. Methods: We investigated the biomarker potential of Notch3 in OC using multiple databases, including ONCOMINE, GEPIA, Human Protein Atlas, UALCAN, Kaplan–Meier Plotter, and LinkedOmics. We analyzed Notch3 expression levels, survival correlations, and clinicopathological parameters. Results: Notch3 expression was significantly upregulated in OC, as well as other cancers. Correlation analysis demonstrated that high Notch3 mRNA levels were associated with poor overall survival (OS) (p < 0.05) and relapse-free survival (p < 0.05) in OC patients. Human Protein Atlas data showed elevated Notch3 protein levels in OC tissues compared to healthy controls. Clinicopathological analysis indicated significant associations between Notch3 expression and patient age (p < 0.5), TP53 mutation status (p < 0.5), and cancer stage (p < 0.1). Additionally, genes such as WIZ, TET1, and CHD4 were found to be co-expressed with Notch3 in OC. Notch3 expression also correlated with immune cell infiltration in OC. Conclusions: Our bioinformatics analysis highlights Notch3 as a potential biomarker for poor prognosis in OC. However, further in vitro and in vivo studies, along with validation using larger tissue samples, are necessary to confirm its biomarker utility. Full article
(This article belongs to the Section Preclinical Research)
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21 pages, 6105 KiB  
Article
Guanethidine Restores Tetracycline Sensitivity in Multidrug-Resistant Escherichia coli Carrying tetA Gene
by Xiaoou Zhao, Mengna Zhang, Zhendu Zhang, Lei Wang, Yu Wang, Lizai Liu, Duojia Wang, Xin Zhang, Luobing Zhao, Yunhui Zhao, Xiangshu Jin, Xiaoxiao Liu and Hongxia Ma
Antibiotics 2024, 13(10), 973; https://doi.org/10.3390/antibiotics13100973 - 15 Oct 2024
Viewed by 544
Abstract
The worrying issue of antibiotic resistance in pathogenic bacteria is aggravated by the scarcity of novel therapeutic agents. Antibiotic adjuvants offer a promising solution due to their cost-effectiveness and high efficacy in addressing this issue, such as the β-lactamase inhibitor sulbactam (a β-lactam [...] Read more.
The worrying issue of antibiotic resistance in pathogenic bacteria is aggravated by the scarcity of novel therapeutic agents. Antibiotic adjuvants offer a promising solution due to their cost-effectiveness and high efficacy in addressing this issue, such as the β-lactamase inhibitor sulbactam (a β-lactam adjuvant) and the dihydrofolate reductase inhibitor trimethoprim (a sulfonamide adjuvant). This study aimed to discover potential adjuvants for tetracyclines from a list of previously approved drugs to restore susceptibility to Escherichia coli carrying the tetA gene. We have screened guanethidine, a compound from the Chinese pharmacopoeia, which effectively potentiates the activity of tetracyclines by reversing resistance in tetA-positive Escherichia coli, enhancing its antibacterial potency, and retarding the development of resistance. Guanethidine functions via the inhibition of the TetA efflux pump, thereby increasing the intracellular concentration of tetracyclines. Our findings suggest that guanethidine holds promise as an antibiotic adjuvant. Full article
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11 pages, 869 KiB  
Article
Immune Checkpoint Inhibitor Therapy and Associations with Clonal Hematopoiesis
by Abhay Singh, Nuria Mencia Trinchant, Rahul Mishra, Kirti Arora, Smit Mehta, Teodora Kuzmanovic, Maedeh Zokaei Nikoo, Inderpreet Singh, Amanda C. Przespolewski, Mahesh Swaminathan, Marc S. Ernstoff, Grace K. Dy, Lunbiao Yan, Eti Sinha, Shruti Sharma, Duane C. Hassane, Elizabeth A. Griffiths, Eunice Wang, Monica L. Guzman and Swapna Thota
Int. J. Mol. Sci. 2024, 25(20), 11049; https://doi.org/10.3390/ijms252011049 - 15 Oct 2024
Viewed by 337
Abstract
Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary [...] Read more.
Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary leukemias. The advent of immune checkpoint blockade (ICB) has dramatically changed our understanding of cancer biology and has altered the standards of care for patients. However, the impact of ICB on hematopoietic myeloid clonal expansion remains to be determined. We studied if exposure to ICB therapy affects hematopoietic clonal architecture and if their evolution contributed to altered hematopoiesis. Blood samples from patients with melanoma and NSCLC (n = 142) demonstrated a high prevalence of CH. Serial samples (or post ICB exposure samples; n = 25) were evaluated in melanoma and NSCLC patients. Error-corrected sequencing of a targeted panel of genes recurrently mutated in CH was performed on peripheral blood genomic DNA. In serial sample analysis, we observed that mutations in DNMT3A and TET2 increased in size with longer ICB exposures in the melanoma cohort. We also noted that patients with larger size DNMT3A mutations with further post ICB clone size expansion had longer durations of ICB exposure. All serial samples in this cohort showed a statistically significant change in VAF from baseline. In the serial sample analysis of NSCLC patients, we observed similar epigenetic expansion, although not statistically significant. Our study generates a hypothesis for two important questions: (a) Can DNMT3A or TET2 CH serve as predictors of a response to ICB therapy and serve as a novel biomarker of response to ICB therapy? (b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes). Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)
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15 pages, 1685 KiB  
Article
Prevalence, Virulence Genes, Drug Resistance and Genetic Evolution of Trueperella pyogenes in Small Ruminants in Western China
by Yuchen Wei, Bin Wang, Ke Wu, Chenxiao Wang, Xindong Bai, Juan Wang and Zengqi Yang
Animals 2024, 14(20), 2964; https://doi.org/10.3390/ani14202964 - 14 Oct 2024
Viewed by 325
Abstract
Trueperella pyogenes is a significant opportunistic pathogen that causes substantial economic losses in animal agriculture due to its ability to infect various animal tissues and organs. Limited research has been conducted on the prevalence and biological characteristics of T. pyogenes isolated from sheep [...] Read more.
Trueperella pyogenes is a significant opportunistic pathogen that causes substantial economic losses in animal agriculture due to its ability to infect various animal tissues and organs. Limited research has been conducted on the prevalence and biological characteristics of T. pyogenes isolated from sheep and goats. This study aimed to isolate T. pyogenes from clinical samples of sheep and goats in western China, examining genetic evolutionary relationships, antibiotic resistance, and virulence genes. Between 2021 and 2023, standard bacteriological methods were used to isolate and identify T. pyogenes from 316 samples (209 from goats and 107 from sheep) collected from 39 farms. Susceptibility to 14 antibiotics was tested using broth microdilution per CLSI guidelines, and PCR detected eight virulence genes. Whole-genome sequencing analyzed genetic relationships and gene carriage status in 39 isolates. The results indicated that 86 strains of T. pyogenes were isolated from 316 samples, yielding an isolation rate of 27.2% (goats n = 47, 22.5%; sheep n = 39, 36.4%). The virulence genes plo, cbpA, nanH, nanP, fimA, fimC, and fimE were present in 100%, 66.7%, 64.1%, 71.8%, 69.2%, 59.0%, and 82.1% of isolates, respectively, with none carrying the fimG gene. The dominant virulence genotype was plo/nanH/nanP/fimA/fimC/fimE. The isolates exhibited resistance to erythromycin (44.2%, 38/86), gentamicin (38.4%, 33/86), sulfamethoxazole/trimethoprim (37.2%, 32/86), tetracycline (32.6%, 28/86), and streptomycin (32.6%, 28/86), and low resistance to chloramphenicol (14.0%, 12/86), ciprofloxacin (7.0%, 6/86), penicillin (5.8%, 5/86), and clindamycin (4.7%, 4/86). All isolates were susceptible to cefotaxime, vancomycin, and linezolid. Among the 86 isolates, 37 (43.0%) displayed multidrug resistance (MDR) characteristics. The whole genome sequencing of 39 isolates identified eight types of resistance genes, including ant(2″)-Ia, ant(3″)-Ia, cmlA1, cmx, erm(X), lnu(A), sul1, and tet(W). Except for tet(W), erm(X), and sul1, the other resistance genes were reported for the first time in T. pyogenes isolated in China. The drug susceptibility test results and resistance gene detection for the isolated strains were consistent for tetracycline, erythromycin, gentamicin, and sulfisoxazole. Similar allelic profiles and genetic evolutionary relationships were found among isolates from different farms. This study highlights the antibiotic resistance status and virulence gene-carrying rate of Trueperella pyogenes, providing a basis for clinical medication. Full article
(This article belongs to the Section Veterinary Clinical Studies)
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12 pages, 1596 KiB  
Perspective
Lactobacillus Eats Amyloid Plaque and Post-Biotically Attenuates Senescence Due to Repeat Expansion Disorder and Alzheimer’s Disease
by Suresh C. Tyagi
Antioxidants 2024, 13(10), 1225; https://doi.org/10.3390/antiox13101225 - 12 Oct 2024
Viewed by 600
Abstract
Patients with Alzheimer’s disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive [...] Read more.
Patients with Alzheimer’s disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive clinical outcomes. The chronic high-fat diet (HFD), or gut dysbiosis, is one of the major contributors of ADRD in part by disrupted transport, epigenetic DNMT1 and the folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active part of epigenetic memory during genes turning off and on by the gene writer (DNMT1) and eraser (TET2/FTO) and the transsulfuration pathway by mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H2S. The repeat CAG expansion and m6A disorder causes senescence and AD. We aim to target the paradigm-shift pathway of the gut–brain microbiome axis that selectively inhibits amyloid deposits and increases mitochondrial transsulfuration and H2S. We have observed an increase in DNMT1 and decreased FTO levels in the cortex of the brain of AD mice. Interestingly, we also observed that probiotic lactobacillus-producing post-biotic folate and lactone/ketone effectively prevented FOCM-associated gut dysbiosis and amyloid deposits. The s-adenosine-methionine (SAM) transporter (SLC25A) was increased by hyperhomocysteinemia (HHcy). Thus, we hypothesize that chronic gut dysbiosis induces SLC25A, the gene writer, and HHcy, and decreases the gene eraser, leading to a decrease in SLC7A and mitochondrial transsulfuration H2S production and bioenergetics. Lactobacillus engulfs lipids/cholesterol and a tri-directional post-biotic, folic acid (an antioxidant and inhibitor of beta amyloid deposits; reduces Hcy levels), and the lactate ketone body (fuel for mitochondria) producer increases SLC7A and H2S (an antioxidant, potent vasodilator and neurotransmitter gas) production and inhibits amyloid deposits. Therefore, it is important to discuss whether lactobacillus downregulates SLC25A and DNMT1 and upregulates TET2/FTO, inhibiting β-amyloid deposits by lowering homocysteine. It is also important to discuss whether lactobacillus upregulates SLC7A and inhibits β-amyloid deposits by increasing the mitochondrial transsulfuration of H2S production. Full article
(This article belongs to the Special Issue Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease)
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14 pages, 2854 KiB  
Article
Serotype Distribution and Antimicrobial Resistance of Salmonella Isolates from Poultry Sources in China
by Chu Wang, Xianwen Wang, Juyuan Hao, He Kong, Liyuan Zhao, Mingzhen Li, Ming Zou and Gang Liu
Antibiotics 2024, 13(10), 959; https://doi.org/10.3390/antibiotics13100959 - 11 Oct 2024
Viewed by 491
Abstract
Background: Salmonella is an important zoonotic pathogen, of which poultry products are important reservoirs. This study analyzed the prevalence, antimicrobial resistance, and characterization of Salmonella from broiler and laying hen sources in China. Methods: A total of 138 (12.27%) strains of Salmonella were [...] Read more.
Background: Salmonella is an important zoonotic pathogen, of which poultry products are important reservoirs. This study analyzed the prevalence, antimicrobial resistance, and characterization of Salmonella from broiler and laying hen sources in China. Methods: A total of 138 (12.27%) strains of Salmonella were isolated from 1125 samples from broiler slaughterhouses (20.66%, 44/213), broiler farms (18.21%, 55/302), and laying hen farms (6.39%, 39/610). Multiplex PCR was used to identify the serotypes. Antibiotic susceptibility testing to a set of 21 antibiotics was performed and all strains were screened by PCR for 24 selected antimicrobial resistance genes (ARGs). In addition, 24 strains of Salmonella were screened out by whole-genome sequencing together with 65 released Salmonella genomes to evaluate phylogenetic characteristics, multilocus sequence typing (MLST), and plasmid carriage percentages. Results: A total of 11 different serotypes were identified, with the dominance of S. Enteritidis (43/138, 31.16%), S. Newport (30/138, 21.74%), and S. Indiana (19/138, 13.77%). The results showed that S. Enteritidis (34.34%, 34/99) and S. Newport (51.28%, 20/39) were the dominant serotypes of isolates from broilers and laying hens, respectively. The 138 isolates showed the highest resistance to sulfisoxazole (SXZ, 100%), nalidixic acid (NAL, 54.35%), tetracycline (TET, 47.83%), streptomycin (STR, 39.86%), ampicillin (AMP, 39.13%), and chloramphenicol (CHL, 30.43%), while all the strains were sensitive to both tigacycline (TIG) and colistin (COL). A total of 45.65% (63/138) of the isolates were multidrug-resistant (MDR) strains, and most of them (61/63, 96.83%) were from broiler sources. The results of PCR assays revealed that 63.77% of the isolates were carrying the quinolone resistance gene qnrD, followed by gyrB (58.70%) and the trimethoprim resistance gene dfrA12 (52.17%). Moreover, a total of thirty-four ARGs, eighty-nine virulence genes, and eight plasmid replicons were detected in the twenty-four screened Salmonella strains, among which S. Indiana was detected to carry the most ARGs and the fewest plasmid replicons and virulence genes compared to the other serotypes. Conclusions: This study revealed a high percentage of multidrug-resistant Salmonella from poultry sources, stressing the importance of continuous monitoring of Salmonella serotypes and antimicrobial resistance in the poultry chain, and emergency strategies should be implemented to address this problem. Full article
(This article belongs to the Special Issue Antimicrobial Resistance and Infections in Animals)
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14 pages, 1644 KiB  
Article
Characteristics and Prognosis of “Acute Promyelocytic Leukemia-like” Nucleophosmin-1-Mutated Acute Myeloid Leukemia in a Retrospective Patient Cohort
by Vasiliki Papadopoulou, Giulia Schiavini, Gregoire Stalder, Valentin Basset, Jacqueline Schoumans, Mitja Nabergoj and Muriel Schaller
Biomedicines 2024, 12(10), 2282; https://doi.org/10.3390/biomedicines12102282 - 9 Oct 2024
Viewed by 402
Abstract
Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases [...] Read more.
Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases also exhibit HLA-DR negativity, classifying them as “double-negative”, and mimicking, therefore, the CD34 HLA-DR immunophenotype of acute promyelocytic leukemia (APL). Objectives: This study focuses on the “acute promyelocytic leukemia-like” (“APL-like”) subset of NPM1-mutated AML, which can be challenging to distinguish from APL at presentation, prior to confirming RARa translocations. We aim to investigate the hematologic and immunophenotypic parameters that may aid to its distinction from APL. Additionally, we explore differences in genetic profile and prognosis between “APL-like” and “non-APL-like” NPM1-mutated AML cases. Methods: We conducted a retrospective evaluation of 77 NPM1-mutated AML cases and 28 APL cases. Results: Morphological characteristics, hematologic parameters (such as DD/WBC and PT/WBC), and specific immunophenotypic markers (including SSC, CD64, and CD4) can assist in the early distinction of “APL-like” NPM1-mutated AML from APL. Regarding differences in genetic profiles and outcomes between “APL-like” and non-“APL-like” NPM1-mutated AML cases, we observed a significantly higher incidence of IDH1/2 /TET2 mutations, along with a significantly lower incidence of DNMT3A mutations in the “APL-like” subset compared to the non-“APL-like” subset. The frequency of Ras-pathway and FLT3 mutations did not differ between these last two groups, nor did their prognoses. Conclusions: Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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14 pages, 2676 KiB  
Article
Concurrence of Inactivation Enzyme-Encoding Genes tet(X), blaEBR, and estT in Empedobacter Species from Chickens and Surrounding Environments
by Chong Chen, Yilin Lv, Taotao Wu, Jing Liu, Yanan Guo and Jinlin Huang
Foods 2024, 13(19), 3201; https://doi.org/10.3390/foods13193201 - 9 Oct 2024
Viewed by 517
Abstract
The emergence of inactivation enzyme-encoding genes tet(X), blaEBR, and estT challenges the effectiveness of tetracyclines, β-lactams, and macrolides. This study aims to explore the concurrence and polymorphism of their variants in Empedobacter sp. strains from food-producing animals and surrounding environments. [...] Read more.
The emergence of inactivation enzyme-encoding genes tet(X), blaEBR, and estT challenges the effectiveness of tetracyclines, β-lactams, and macrolides. This study aims to explore the concurrence and polymorphism of their variants in Empedobacter sp. strains from food-producing animals and surrounding environments. A total of eight tet(X) variants, seven blaEBR variants, and seven estT variants were detected in tet(X)-positive Empedobacter sp. strains (6.7%) from chickens, sewage, and soil, including 31 Empedobacter stercoris and 6 novel species of Taxon 1. All of them were resistant to tigecycline, tetracycline, colistin, and ciprofloxacin, and 16.2% were resistant to meropenem, florfenicol, and cefotaxime. The MIC90 of tylosin, tilmicosin, and tildipirosin was 128 mg/L, 16 mg/L, and 8 mg/L, respectively. Cloning expression confirmed that tet(X6) and the novel variants tet(X23), tet(X24), tet(X25), tet(X26), and tet(X26.2) conferred high-level tigecycline resistance, while all of the others exhibited relatively low-level activities or were inactivated. The bacterial relationship was diverse, but the genetic environments of tet(X) and blaEBR were more conserved than estT. An ISCR2-mediated tet(X6) transposition structure, homologous to those of Acinetobacter sp., Proteus sp., and Providencia sp., was also identified in Taxon 1. Therefore, the tet(X)-positive Empedobacter sp. strains may be ignored and pose a serious threat to food safety and public health. Full article
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17 pages, 3157 KiB  
Article
Epigenetic Reprogramming and Inheritance of the Cellular Differentiation Status Following Transient Expression of a Nonfunctional Dominant-Negative Retinoblastoma Mutant in Murine Mesenchymal Stem Cells
by Mikhail Baryshev, Irina Maksimova and Ilona Sasoveca
Int. J. Mol. Sci. 2024, 25(19), 10678; https://doi.org/10.3390/ijms251910678 - 3 Oct 2024
Viewed by 530
Abstract
The retinoblastoma gene product (Rb1), a master regulator of the cell cycle, plays a prominent role in cell differentiation. Previously, by analyzing the differentiation of cells transiently overexpressing the ΔS/N DN Rb1 mutant, we demonstrated that these cells fail to differentiate into mature [...] Read more.
The retinoblastoma gene product (Rb1), a master regulator of the cell cycle, plays a prominent role in cell differentiation. Previously, by analyzing the differentiation of cells transiently overexpressing the ΔS/N DN Rb1 mutant, we demonstrated that these cells fail to differentiate into mature adipocytes and that they constitutively silence Pparγ2 through CpG methylation. Here, we demonstrate that the consequences of the transient expression of ΔS/N DN Rb1 are accompanied by the retention of Cebpa promoter methylation near the TSS under adipogenic differentiation, thereby preventing its expression. The CGIs of the promoters of the Rb1, Ezh2, Mll4, Utx, and Tet2 genes, which are essential for adipogenic differentiation, have an unmethylated status regardless of the cell differentiation state. Moreover, Dnmt3a, a de novo DNA methyltransferase, is overexpressed in undifferentiated ΔS/N cells compared with wild-type cells and, in addition to Dnmt1, Dnmt3a is significantly upregulated by adipogenic stimuli in both wild-type and ΔS/N cells. Notably, the chromatin modifier Ezh2, which is also involved in epigenetic reprogramming, is highly induced in ΔS/N cells. Overall, we demonstrate that two major genes, Pparγ2 and Cebpa, which are responsible for terminal adipocyte differentiation, are selectively epigenetically reprogrammed to constitutively silent states. We hypothesize that the activation of Dnmt3a, Rb1, and Ezh2 observed in ΔS/N cells may be a consequence of a stress response caused by the accumulation and malfunctioning of Rb1-interacting complexes for the epigenetic reprogramming of Pparγ2/Cebpa and prevention of adipogenesis in an inappropriate cellular context. The failure of ΔS/N cells to differentiate and express Pparγ2 and Cebpa in culture following the expression of the DN Rb1 mutant may indicate the creation of epigenetic memory for new reprogrammed epigenetic states of genes. Full article
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20 pages, 908 KiB  
Review
Histone Deacetylase Inhibitors for Peripheral T-Cell Lymphomas
by Ruxandra Irimia and Pier Paolo Piccaluga
Cancers 2024, 16(19), 3359; https://doi.org/10.3390/cancers16193359 - 30 Sep 2024
Viewed by 456
Abstract
Histone deacetylase inhibitors (HDACis) are being recognized as a potentially effective treatment approach for peripheral T-cell lymphomas (PTCLs), a heterogeneous group of aggressive malignancies with an unfavorable prognosis. Recent evidence has shown that HDACis are effective in treating PTCL, especially in cases where [...] Read more.
Histone deacetylase inhibitors (HDACis) are being recognized as a potentially effective treatment approach for peripheral T-cell lymphomas (PTCLs), a heterogeneous group of aggressive malignancies with an unfavorable prognosis. Recent evidence has shown that HDACis are effective in treating PTCL, especially in cases where the disease has relapsed or is resistant to conventional treatments. Several clinical trials have demonstrated that HDACis, such as romidepsin and belinostat, can elicit long-lasting positive outcomes in individuals with PTCLs, either when used alone or in conjunction with conventional chemotherapy. They exert their anti-tumor effects by regulating gene expression through the inhibition of histone deacetylases, which leads to cell cycle arrest, induction of programmed cell death, and,the transformation of cancerous T cells, as demonstrated by gene expression profile studies. Importantly, besides clinical trials, real-world evidence indicated that the utilization of HDACis presents a significant and beneficial treatment choice for PTCLs. However, although HDACis showed potential effectiveness, they could not cure most patients. Therefore, new combinations with conventional drugs as well as new targeted agents are under investigation. Full article
(This article belongs to the Special Issue Novel Targeted Therapies for T-cell Malignancies)
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19 pages, 1474 KiB  
Article
Molecular Characterization of MDR and XDR Clinical Strains from a Tertiary Care Center in North India by Whole Genome Sequence Analysis
by Uzma Tayyaba, Shariq Wadood Khan, Asfia Sultan, Fatima Khan, Anees Akhtar, Geetha Nagaraj, Shariq Ahmed and Bhaswati Bhattacharya
J. Oman Med. Assoc. 2024, 1(1), 29-47; https://doi.org/10.3390/joma1010005 - 24 Sep 2024
Viewed by 391
Abstract
Whole genome sequencing (WGS) has the potential to greatly enhance AMR (Anti-microbial Resistance) surveillance. To characterize the prevalent pathogens and dissemination of various AMR-genes, 73 clinical isolates were obtained from blood and respiratory tract specimens, were characterized phenotypically by VITEK-2 (bioMerieux), and 23 [...] Read more.
Whole genome sequencing (WGS) has the potential to greatly enhance AMR (Anti-microbial Resistance) surveillance. To characterize the prevalent pathogens and dissemination of various AMR-genes, 73 clinical isolates were obtained from blood and respiratory tract specimens, were characterized phenotypically by VITEK-2 (bioMerieux), and 23 selected isolates were genotypically characterized by WGS (Illumina). AST revealed high levels of resistance with 50.7% XDR, 32.9% MDR, and 16.4% non-MDR phenotype. A total of 11 K. pneumoniae revealed six sequence types, six K-locus, and four O-locus types, with ST437, KL36, and O4 being predominant types, respectively. They carried ESBL genes CTX-M-15 (90.9%), TEM-1D (72.7%), SHV-11 (54.5%), SHV-1, SHV-28, OXA-1, FONA-5, and SFO-1; NDM-5 (72.7%) and 63.6%OXA48-like carbapenamases; 90.9%OMP mutation; dfrA12, sul-1, ermB, mphA, qnrB1, gyrA831, and pmrB1 for other groups. Virulence gene found were Yerisiniabactin (90.9%), aerobactin, RmpADC, and rmpA2. Predominant plasmid replicons were Col(pHAD28), IncFII, IncFIB(pQil), and Col440. A total of seven XDR A. baumannii showed single MLST type(2) and single O-locus type(OCL-1); with multiple AMR-genes: blaADC-73, blaOXA-66, blaOXA-23, blaNDM-1, gyrA, mphE, msrE, and tetB. Both S. aureus tested were found to be ST22, SCCmec IVa(2B), and spa type t309; multiple AMR-genes: blaZ, mecA, dfrC, ermC, and aacA-aphD. Non-MDR Enterococcus faecalis sequenced was ST 946, with multiple virulence genes. This study documents for the first-time prevalent virulence genes and MLST types, along with resistance genes circulating in our center. Full article
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12 pages, 2159 KiB  
Article
Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study
by Fei Fei, Amar Jariwala, Sheeja Pullarkat, Eric Loo, Yan Liu, Parastou Tizro, Haris Ali, Salman Otoukesh, Idoroenyi Amanam, Andrew Artz, Feras Ally, Milhan Telatar, Ryotaro Nakamura, Guido Marcucci and Michelle Afkhami
Int. J. Mol. Sci. 2024, 25(18), 10214; https://doi.org/10.3390/ijms251810214 - 23 Sep 2024
Viewed by 664
Abstract
The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = [...] Read more.
The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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10 pages, 1617 KiB  
Article
Prevalence and Characteristics of Plasmid-Mediated Fosfomycin Resistance Gene fosA3 among Salmonella Enteritidis Isolates from Retail Chickens and Children with Gastroenteritis in China
by Liyuan Liu, Shanrong Yi, Xuebin Xu, Liya Zheng, Hong Liu and Xiujuan Zhou
Pathogens 2024, 13(9), 816; https://doi.org/10.3390/pathogens13090816 - 21 Sep 2024
Viewed by 669
Abstract
A total of 265 Salmonella Enteritidis isolates collected from retail markets and children’s hospitals in Shanghai were used to investigate the prevalence and molecular epidemiology of plasmid-mediated fosfomycin resistance genes. Nine of the isolates—7 from the 146 (4.79%) retail chicken-related samples and 2 [...] Read more.
A total of 265 Salmonella Enteritidis isolates collected from retail markets and children’s hospitals in Shanghai were used to investigate the prevalence and molecular epidemiology of plasmid-mediated fosfomycin resistance genes. Nine of the isolates—7 from the 146 (4.79%) retail chicken-related samples and 2 from the 119 (1.68%) samples from clinical children—were fosfomycin-resistant (FosR). The fosA3 gene was detected in all of the nine FosR isolates, which were located on Inc F-type (8/9, 88.9%) and unknown-type (1/9, 11.1%) transferable plasmids. In total, five plasmid types, namely Inc HI2 (1/9, 11.1%), Inc I1 (3/9, 33.3%), Inc X (8/9, 88.9%), Inc FIIs (9/9, 100%), and Inc FIB (9/9, 100%), were detected in these FosR isolates, which possessed five S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) profiles. The extended-spectrum β-lactamase determinant blaCTX-M-14 subtype was identified in one FosR S. Enteritidis isolate, which was located in a transferable unknown-type plasmid co-carrying fosA3 and tetR genes. Sequence homology analysis showed that this plasmid possessed high sequence similarity to previously reported blaCTX-M-14- and fosA3-positive plasmids from E. coli strains, implying that plasmids carrying the fosA3 gene might be disseminated among Enterobacterales. These findings highlight further challenges in the prevention and treatment of Enterobacteriaceae infections caused by plasmids containing fosA3. Full article
(This article belongs to the Special Issue Detection and Epidemiology of Drug-Resistant Bacteria)
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