EClinicalMedicine. 2024 Dec 6;79:102979. doi: 10.1016/j.eclinm.2024.102979. eCollection 2025 Jan.

ABSTRACT

[This corrects the article DOI: 10.1016/j.eclinm.2024.102679.].

PMID:39720605 | PMC:PMC11665706 | DOI:10.1016/j.eclinm.2024.102979

Heliyon. 2024 Dec 3;10(24):e40890. doi: 10.1016/j.heliyon.2024.e40890. eCollection 2024 Dec 30.

ABSTRACT

Recent studies have revealed that intratumoral microbiota is implicated in pancreatic cancer (PC), yet the spectra of intratumoral microbiota and their relationship with PC in Chinese patients remained to be clarified. In this study, tumor and paired paracancerous tissue from 53 patients were profiled by bacterial 16S rRNA gene sequencing. Both α- and β-diversity displayed significant differences between tumors and adjacent tissues, with higher diversity in tumors. Three bacteria phyla (Proteobacteria, Firmicutes, and Actinobacteria) were prevalent in both cancers and adjacent normal tissues. A high prevalence of Pseudomonas has been identified in the PC tumor microenvironment and was associated with prolonged overall survival. Furthermore, the results of in vitro experiments suggested that Pseudomonas fluorescens (P. fluorescens) could inhibit the proliferation and induce apoptosis of pancreatic cancer cells. These findings revealed distinctive microbial features of the PC tumors and normal tissues in Chinese populations and exhibited the antitumor potential of P. fluorescens in PC.

PMID:39720030 | PMC:PMC11665473 | DOI:10.1016/j.heliyon.2024.e40890

J Pain Res. 2024 Dec 17;17:4187-4196. doi: 10.2147/JPR.S488416. eCollection 2024.

ABSTRACT

BACKGROUND: Cancer patients frequently suffer from pain, often managed with opioids. However, undertreated pain remains a significant concern. Opioid effectiveness varies due to genetic differences in how individuals metabolize some of these medications. While prior research suggests promise in tailoring opioid prescriptions based on CYP2D6 genetic makeup, its application in cancer pain management remains limited. This study investigates the potential benefits of preemptive CYP2D6 genotyping for cancer patients initiating opioid therapy, focusing on codeine, tramadol, and hydrocodone, whose efficacy is demonstrably impacted by CYP2D6 variations.

METHODS: This is a randomized, prospective study to evaluate the effects of preemptive pharmacogenomic (PGx) testing on opioid dosing decisions/selections and composite pain score in oncology patients. Patients with metastatic solid tumors for whom near-future opioid therapy is anticipated will be randomized to PGx and control arms, stratified by the presence or absence of bony metastases and history of opioid use. In the PGx arm, patients will be preemptively tested using a panel of pharmacogenomic genetic variants, and providers will receive opioid dosing guidance via an electronic medical record-embedded clinical decision support tool. In the control arm, pain prescribing will occur per standard of care without genotype information.

PLANNED OUTCOME: The primary study outcome will be composite pain intensity during the first 45 days after an index opioid prescription for codeine, tramadol, or hydrocodone. Safety will be assessed by comparing opioid-related adverse event rates between the two study arms. Secondary outcomes will include rates of hospitalization/emergency room visits, cumulative morphine equivalents received, and type of first opioid prescribed.

PMID:39717756 | PMC:PMC11664000 | DOI:10.2147/JPR.S488416

Cureus. 2024 Nov 23;16(11):e74288. doi: 10.7759/cureus.74288. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Hypertension management typically relies on standardized treatment regimens, which may not account for individual genetic variations that affect drug metabolism and response.

OBJECTIVE: The objective of this study was to evaluate the effectiveness of personalized antihypertensive therapy, guided by pharmacogenetic testing, in terms of blood pressure (BP) control and medication tolerability.

MATERIALS AND METHODS: A retrospective cohort study was conducted at Jinnah Postgraduate Medical Centre, Karachi, from January 2023 to December 2023. The study included 330 hypertensive patients who received either conventional care (n = 165) or personalized therapy directed by pharmacogenetic testing (n = 165). Data on patient demographics, genetic test results, antihypertensive drug prescriptions, and blood pressure readings at baseline, three months, and six months were extracted from electronic health records. Reports of adverse effects were used to assess medication tolerability. Independent t-tests were employed for statistical analysis (SPSS version 25 (IBM Corp., Armonk, NY)) to evaluate changes in blood pressure and adverse effects between the two groups, with a significance level set at p < 0.05.

RESULTS: Among the 330 hypertensive patients, the Personalized Therapy group (n = 165) showed a significant reduction in systolic blood pressure by 17.8 mmHg (±6.4) and diastolic blood pressure by 11.3 mmHg (±5.7) over six months, compared to reductions of 8.7 mmHg (±6.7) and 5.7 mmHg (±4.8), respectively, in the Standard Therapy group (n = 165) (p < 0.001). Additionally, the Personalized Therapy group experienced fewer adverse effects, with 15 patients reporting dizziness and five reporting gastrointestinal issues, compared to 30 patients with dizziness and 10 with gastrointestinal issues in the Standard Therapy group.

CONCLUSION: Personalized antihypertensive therapy based on pharmacogenetic testing significantly improves blood pressure control and medication tolerability compared to standard treatment, supporting its broader implementation in hypertension management.

PMID:39717305 | PMC:PMC11664490 | DOI:10.7759/cureus.74288

Curr Rev Clin Exp Pharmacol. 2024 Dec 23. doi: 10.2174/0127724328335492241206075509. Online ahead of print.

ABSTRACT

Previous genetic studies on the genetic makeup of Arab populations highlight the diversity resulting from the distribution of specific genetic markers among various Arab descendant populations. Different genetic variants classified as clinically significant have been identified, impacting the response to administered drugs. Absorption, distribution, and excretion of drugs throughout the human body are managed through the actions of drug transporters and receptor proteins, which are expressed on the cellular membrane. Drug metabolism involves activating or inactivating various compounds, transforming them into therapeutically active or toxic metabolites. With the rapid advancement of pharmacogenetic testing techniques and increased genetic studies involving Arab populations, insights into genetic polymorphisms have emerged, leading to a better understanding of the diverse phenotypes of drug response associated with genotype variation. Variations in transporters and receptor genes have significantly contributed to generating variant phenotypes that affect individuals' responses to treatments and substrates. This necessitates administering individualized drug doses based on the patient's haplotype, which can be determined through advanced genetic diagnosis. This review summarizes the findings of recent pharmacogenetic studies in the Arab world, emphasizing the benefits of pharmacogenetic research and applications to enhance therapeutic aspects of healthcare and treatment among patients in Arab countries.

PMID:39716793 | DOI:10.2174/0127724328335492241206075509

Exp Eye Res. 2024 Dec 21:110219. doi: 10.1016/j.exer.2024.110219. Online ahead of print.

ABSTRACT

Organelles such as mitochondria, lysosomes, peroxisomes, and the endoplasmic reticulum form highly dynamic cellular networks and exchange information through sites of physical contact. While each organelle performs unique functions, this inter-organelle crosstalk helps maintain cell homeostasis. Age-related macular degeneration (AMD) is a devastating blinding disease strongly associated with mitochondrial dysfunction, oxidative stress, and decreased clearance of cellular debris in the retinal pigment epithelium (RPE). However, how these occur, and how they relate to organelle function both with the RPE and potentially the photoreceptors are fundamental, unresolved questions in AMD biology. Here, we report the discussions of the "Mitochondria, Lysosomes, and other Organelle Interactions" task group of the 2024 Ryan Initiative for Macular Research (RIMR). Our group focused on understanding the interplay between cellular organelles in maintaining homeostasis in the RPE and photoreceptors, how this could be derailed to promote AMD, and identifying where these pathways could potentially be targeted therapeutically.

PMID:39716681 | DOI:10.1016/j.exer.2024.110219

bioRxiv [Preprint]. 2024 Dec 13:2024.12.09.627436. doi: 10.1101/2024.12.09.627436.

ABSTRACT

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model, this combination therapy significantly improved memory function and reduced AD-related pathologies compared to vehicle and single-drug treatments. Single-nuclei transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.

PMID:39713353 | PMC:PMC11661161 | DOI:10.1101/2024.12.09.627436

PLoS One. 2024 Dec 23;19(12):e0313764. doi: 10.1371/journal.pone.0313764. eCollection 2024.

ABSTRACT

OBJECTIVE: Meropenem degradation poses a challenge to continuous infusion (CI) implementation. However, data about the impact of degradation on the probability of target attainment (PTA) of meropenem has been limited. This study evaluated the stability of meropenem brands and the consequence of in-bottle degradation on PTA in different environmental scenarios.

METHOD: Seven meropenem generic brands prepared at concentrations of 1 g/48mL and 2 g/48mL in saline were examined at 25, 30, and 37°C over 8 h. A linear mixed-effects model was used to estimate degradation rate constant and potential covariates. In-bottle stability data was subsequently integrated as input for a deterministic and stochastic simulation using a published population pharmacokinetic model of critical illness. The impact of the degradation on target attainment at 98%fT>MIC was assessed.

RESULTS: Time, temperature, and infusion concentration were factors affecting the stability of the meropenem solution for all products. The differences in the degradation of seven generics were subtle, so their simulated plasma concentrations were equal. Meropenem CI with 8 h renewal infusion achieved a higher PTA than the extended 3 h infusion, even at the highest degradation condition. The impact of meropenem degradation on PTA was minimal vis-à-vis the meropenem dose, patient's renal function, and microbial susceptibility. Meropenem degradation reduced PTA by an observable magnitude in patients with augmented renal clearance and difficult-to-treat pathogens. Dose escalation up to 1.5-2g every 8 h could restore this reduction to the target 90% PTA.

CONCLUSION: Meropenem CI with 8 h of renewal infusion, considering stability even in tropical areas, was feasible to maximize the efficacy to difficult-to-treat pathogens.

PMID:39715157 | DOI:10.1371/journal.pone.0313764

Wiad Lek. 2024;77(11):2340-2347. doi: 10.36740/WLek/197123.

ABSTRACT

OBJECTIVE: Aim: To systematize and comprehensively analyze scientific sources and research on integrating personalized medicine into the national healthcare system.

PATIENTS AND METHODS: Materials and Methods: A comprehensive literature review was conducted using PubMed, Google Scholar, and Scopus, focusing on data from the past 10 years (2014-2024). Articles in both English and Ukrainian were analyzed. Personalized approaches from the authors' own research were also included. The following methods were used: a systematic approach and bibliosemantic analysis.

CONCLUSION: Conclusions: However, for the implementation of personalized medicine in Ukraine, it is necessary to have awareness of the medical community about the possibilities of using molecular genetic profiling, competence to conduct risk assessment with the participation of several specialists, with the involvement of the patient in decision-making on treatment and diagnostic measures. The main tools for the widespread implementation of personalized medicine in Ukraine are qualified specialists, a wide network of molecular genetic diagnostics and pharmacogenetics laboratories, the development of competencies among healthcare providers and the development of personalized pharmacy. The expected result is the widespread implementation of diagnostic and treatment programs using personalized protocols based on the state of the individual patient's body at a specific time.

PMID:39715138 | DOI:10.36740/WLek/197123

Adv Lab Med. 2024 Nov 7;5(4):425-431. doi: 10.1515/almed-2024-0146. eCollection 2024 Dec.

ABSTRACT

OBJECTIVES: Genetic variants with associated pharmacokinetic and pharmacodynamic effects have an impact on the development of adverse drug reactions and survival of patients with colorectal cancer.

METHODS: A selection of genetic variants was performed according to the established chemotherapy and the pharmacogenetic databases. Genotyping was performed using MassArray technology (Agena Bioscience). Variant-toxicity and survival-genotype correlations were assessed using logistic regression (SPSS v.28.0.1.1).

RESULTS: Genotyping of 25 SNPs was performed in 96 patients. In relation to the DPYD gene, 3.5 % had the rs75017182 mutation; 4.7 % the rs1801158 mutation and 7.1 % the rs1801160 mutation. Genotypic frequencies in the UGT1A1 gene were 39.4 % (*1/*1); 37.9 % (*1/*28); 19.7 % (*28/*28); and 3 % (*1/*36). The genotypes CT of the rs1801160 variant, AT of the rs67376798 variant (DPYD) and *1/*36 (UGT1A1) were associated with low survival (p-value: 0.006, <0.001, and 0.052, respectively). The most frequent adverse reactions were gastrointestinal disorders, followed by neurotoxicity. The CC genotype (rs1801160, DPYD) was associated with a lower risk for developing severe gastrointestinal events, whereas CC (rs1801158, DPYD) was associated with a lower risk of developing severe general hematologic toxicity.

CONCLUSIONS: The population frequencies obtained in our study for rs1801160 and rs75017182 (DPYD); and for *1/*28, *28/*, and *1/*36 (UGT1A1) were inconsistent with the frequencies reported for the Spanish population in the literature. The genotypes CT of rs1801160, AT of rs67376798 (DPYD), and 1/*36 (UGT1A1) were associated with lower survival rates.

PMID:39713544 | PMC:PMC11661530 | DOI:10.1515/almed-2024-0146

bioRxiv [Preprint]. 2024 Dec 11:2024.12.10.627527. doi: 10.1101/2024.12.10.627527.

ABSTRACT

Pharmacogenomics is central to precision medicine, informing medication safety and efficacy. Pharmacogenomic diplotyping of complex genes requires full-length DNA sequences and detection of structural rearrangements. We introduce StarPhase, a tool that leverages PacBio HiFi sequence data to diplotype 21 CPIC Level A pharmacogenes and provides detailed haplotypes and supporting visualizations for HLA-A, HLA-B, and CYP2D6. StarPhase diplotypes have high concordance with benchmarks where 99.5% are either exact matches or minor discrepancies. Manual inspection of the 0.5% mismatches indicates they were correctly called by StarPhase. With StarPhase, we update or correct 26.2% of GeT-RM pharmacogenomic diplotypes. Population distributions from StarPhase mostly reflect those of the All of Us cohort, while also highlighting gaps in existing pharmacogenomic databases that long-read sequencing can fill. With a single HiFi whole genome sequencing assay, StarPhase enables robust PGx diplotyping even as additional pharmacogenes and haplotypes are discovered.

PMID:39713404 | PMC:PMC11661245 | DOI:10.1101/2024.12.10.627527

Pan Afr Med J. 2024 Sep 19;49:19. doi: 10.11604/pamj.2024.49.19.41189. eCollection 2024.

ABSTRACT

Since its inception in 2003, the African Society of Human Genetics (AfSHG) has been central to the promotion of genetics research on the continent, and facilitated the networking of African researchers within Africa and abroad, thereby significantly contributing to the career development of African geneticists. The continuation of these accomplishments was stimulated by the 12th international conference of AfSHG held jointly with the 1st Congress of the Malian Society of Human Genetics (MSHG) in Bamako, Mali from September 18th to 21st 2019. The main theme of the conference was "Human Genetics and Genomics as a Unifying Factor for Harmony and Progress in Africa". The goals of the meeting were to promote the work conducted mainly by African researchers and to contribute to scientific knowledge through genetic research. Despite challenges due to security issues in Mali, this conference attracted many scientists, including key experts in genetics and associated fields, making the conference successful scientifically and geographically. Overall, 172 delegates from 24 countries attended. Sessions on various topics relevant to Africa were held. These included the genetics of infectious diseases, cancer, and rare diseases as well as bioinformatics, pharmacogenomics, population genetics, and ethical, legal, and social issues, particularly with respect to genetic research in African populations. The need for genetic data sharing to improve research and health and the focus of actionable research for African populations was stressed throughout the meeting.

PMID:39711838 | PMC:PMC11662216 | DOI:10.11604/pamj.2024.49.19.41189

HLA. 2024 Dec;104(6):e15799. doi: 10.1111/tan.15799.

ABSTRACT

HLA-G, an important immune-checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Since specific single-nucleotide polymorphisms (SNP) in the HLA-G 3'untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA-G expression, we analysed the contribution of these genetic variants as host factors in SARS-CoV-2 infection during acute and post-acute phases. HLA-G gene polymorphisms in the 3'UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID-19) cohort during acute SARS-CoV-2 infection (N = 505) and in the post-acute phase (N = 253). The HLA-G 3'UTR haplotype known as UTR-3 (p = 0.002) and the variant rs17875408 (also known as +3422) T variant (p = 0.004) are independent prognostic risk factors for fatal COVID-19. The +3422T variant (p = 0.006) predicted also the early loss of neutralising SARS-CoV-2 antibodies. In addition, the HLA-G 3'UTR haplotype UTR-7 (p = 0.023) emerged as an independent prognostic factor for increased susceptibility to Long-COVID symptoms after SARS-CoV-2 infection. Our study highlights that due to the variability of the 3'UTR genetic background, HLA-G has the potential to contribute to the progression of SARS-CoV-2 infection, extending to the development of Long-COVID symptoms, despite the likely alterations in the microenvironment and associated HLA-G-specific regulatory elements over the course of the disease. By spotlighting HLA-G, the importance of the genetic background of IC and their pivotal role in modulating immune responses during and after COVID-19 are emphasised.

PMID:39711218 | DOI:10.1111/tan.15799

Transl Oncol. 2024 Dec 21;52:102228. doi: 10.1016/j.tranon.2024.102228. Online ahead of print.

ABSTRACT

BACKGROUND: Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.

METHODS: Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.

RESULTS: A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA ("shedders"). Higher ECOG PS (p = 0.04), bilateral localization of primary tumor (p = 0.04), and the presence of intrathoracic/extrathoracic disease (p = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (p = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (p = 0.05).

CONCLUSION: Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.

PMID:39709717 | DOI:10.1016/j.tranon.2024.102228

Cell Biosci. 2024 Dec 20;14(1):151. doi: 10.1186/s13578-024-01332-3.

ABSTRACT

The inherent heterogeneity of tumor cells impedes the development of targeted therapies for specific glioblastoma (GBM) subtypes. This study aims to investigate the mesenchymal subtype of GBM to uncover detailed characteristics, potential therapeutic strategies, and improve precision treatment for GBM patients. We integrated single-cell RNA sequencing (scRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and bulk RNA sequencing datasets to identify core gene modules, candidate therapeutic drugs, and key transcription factors specific to mesenchymal subtype GBM tumor cells which we validated in vitro and human samples. Our analysis encompassed a heterogeneous single-cell landscape of 55,845 cells from tumor and adjacent normal tissues, focusing on the mesenchymal subtype's adverse prognosis and its association with hypoxia. We identified a core gene module composed of 38 genes and, through pharmacogenomic analysis, found that Trametinib and Dasatinib exhibit increased effectiveness against mesenchymal subtype GBM cells. Furthermore, by incorporating snATAC-seq data, we delineated a crucial regulatory network and pinpointed the key transcription factor CEBPG. Our research has highlighted the strong link between the mesenchymal-like (MES-like) properties of GBM and hypoxia, providing valuable insights into candidate drugs and pivotal targets for precision treatment of the mesenchymal subtype.

PMID:39707474 | DOI:10.1186/s13578-024-01332-3

Per Med. 2024 Dec 20:1-16. doi: 10.1080/17410541.2024.2442897. Online ahead of print.

ABSTRACT

Personalized treatment optimization considers individual clinical, genetic, and environmental factors influencing drug efficacy and tolerability. As evidence accumulates, these approaches may become increasingly integrated into standard psychiatric care, potentially transforming the treatment landscape for mental health disorders. While personalized treatment optimization shows promise in enhancing therapeutic outcomes and minimizing adverse effects, further research is needed to establish its clinical utility and cost-effectiveness across various psychiatric disorders. This review examines the potential utility of personalized treatment optimization in psychiatry, addressing the challenge of suboptimal effectiveness and variable patient responses to psychiatric medications. It explores how therapeutic drug monitoring, pharmacogenomics, and biomarker testing can be used to individualize and optimize pharmacotherapy for mental disorders such as depression, bipolar disorder, and schizophrenia.

PMID:39706800 | DOI:10.1080/17410541.2024.2442897

Eur J Clin Pharmacol. 2024 Dec 20. doi: 10.1007/s00228-024-03786-3. Online ahead of print.

ABSTRACT

BACKGROUND: Women are underrepresented in drug development trials and there is no sex-tailored drug regimen for most medications. It has been repeatedly shown that women have more adverse drug reactions than men for several medications. These differences could be explained by higher dose-adjusted drug concentrations in women. Thus, we aim to identify sex-related differences and to characterize the clinical and genetic predictors of these differences in drug concentrations, dosing, and adherence for 47 commonly used drugs in a large cohort. The objective of this article is to present an overview of the methods and characteristics of the study population.

METHODS: We performed a cross-sectional study that included 10,082 men and women of European ancestry aged ≥ 18 years from the Montreal Heart Institute Hospital Cohort taking at least one of the 47 medications regularly.

RESULTS: Of the 10,082 participants included, 36% were women. Women had lower weight, height, waist girth, and body mass index than men, but they had higher hip girth (all p < 0.001). Men had a higher level of education and annual income and were more likely to be employed full-time compared to women. Furthermore, men had a higher prevalence of hypertension, type 2 diabetes, dyslipidemia, and myocardial infarction (all p < 0.001) and were more likely receiving lipid-lowering agents, beta-blockers, antidiabetic drugs, and angiotensin-converting enzyme inhibitors. Conversely, proton pump inhibitors were more prevalent in women. Interestingly, nearly half of the women had a history of drug allergy or intolerance, compared with less than one-third of the men (p < 0.001).

CONCLUSION: This study has a high potential in understanding eventual sex differences in drug dosing requirements and will most likely provide useful information to personalize drug regimens in women.

PMID:39704823 | DOI:10.1007/s00228-024-03786-3

Microbiol Spectr. 2024 Dec 20:e0087224. doi: 10.1128/spectrum.00872-24. Online ahead of print.

ABSTRACT

Genetic characterization of multidrug-resistant (MDR) Acinetobacter baumannii remains scarce in Malaysia. This study aimed to characterize antibiotic resistance, genomic location, and genetic relatedness among the A. baumannii isolates obtained from a tertiary hospital in Malaysia. A total of 128 MDR A. baumannii isolates were collected from patients admitted to various wards (intensive care unit [ICU], neonatal intensive care unit, coronary care unit, high dependency ward [HDW], and general wards). The isolates were identified by Vitek 2 and PCR amplification of the 16S rRNA gene followed by sequencing. The isolates were tested against imipenem, ceftazidime, amikacin, gentamicin, ampicillin, and ciprofloxacin using disk diffusion, Epsilometer test, and broth microdilution. The antibiotic resistance genes, blaOXA-23, blaOXA-24, blaADC, blaVIM, and blaIMP, were detected in chromosomal and plasmid DNA using PCR. Insertion sequence ISAba1/blaOXA-23 gene was detected on chromosomal DNA only. Isolates with different antibiotic susceptibility patterns and PCR profiles were subjected to multi-locus sequence typing. MDR A. baumannii was predominantly found in HDW (39.84%), general wards (29.69%), and ICU (28.13%). All isolates conferred resistance to carbapenem and more than 90% resistance to the remaining antibiotics. The antibiotic resistance genes blaOXA-23, blaVIM, and blaADC were detected in both chromosomal and plasmid DNA. The ISAba1/blaOXA-23 gene was detected in 99.22% of the isolates. Four sequence types (STs) were distinguished: ST2 (76.67%), ST164 (10%), ST642 (10%), and ST643 (3.33%). ST164 and ST642 were unique and represent a significant finding in Malaysia's surveillance data. These STs are associated with acquired blaOXA-23, indicating an evolutionary adaptation of A. baumannii within the hospital setting.IMPORTANCEAcinetobacter baumannii is a ubiquitous Gram-negative coccobacillus bacterium that is primarily associated with nosocomial infections that can colonize biotic and abiotic surfaces to enhance cell-to-cell adhesion, ensuring the establishment of infections. To date, the spread of multidrug-resistant A. baumannii (MDRAB) has become rampant and a great concern in the hospital setting, as the available antibiotics are insufficient to treat infections. The antibiotic resistance island resides in a mobile element and rapidly evolved. The antibiotic susceptibility data with its resistance mechanisms would contribute to and facilitate the management and infection control caused by MDRAB.

PMID:39704504 | DOI:10.1128/spectrum.00872-24

Dent Med Probl. 2024 Nov-Dec;61(6):885-892. doi: 10.17219/dmp/183776.

ABSTRACT

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy characterized by the presence of abnormal plasma cells. It is associated with anemia, bone lesions and renal dysfunction. Immunomodulatory drugs (IMiDs) are commonly used in MM treatment. Recent studies indicate that their therapeutic effect is caused by binding to cereblon (CRBN), which in turn causes the degradation of 2 important immune cell regulatory factors, IKZF1 and IKZF3. These are necessary for the anti-myeloma effect of IMiDs. Their expression level has been shown to affect MM survival and response to treatment. Potentially important single-nucleotide polymorphisms (SNPs) in the genes coding for IKZF1 and IKZF3 have been identified, but they have not been analyzed in MM patients before.

OBJECTIVES: The study was designed to establish the relationship between 4 SNPs in the genes coding for IKZF1 (rs61731359, rs4132601 and rs10272724) and IKZF3 (rs907091), and MM survival, response to treatment and other parameters.

MATERIAL AND METHODS: The study involved 222 MM patients, as well as 100 control individuals. The IKZF1 and IKZF3 genotypes were determined by the LightSNiP assay. Genotyping was performed in the real-time polymerase chain reaction (PCR) LightCycler 480 device.

RESULTS: No difference was observed between the patients and the controls for any of the SNPs, but the IKZF1 and IKZF3 variants were associated with various clinical parameters. Allele IKZF1 rs4132601 G was more common in the patients with worse response to first-line therapy (p = 0.040), particularly in the patients treated with thalidomide (p = 0.017). The patients tended to have worse overall survival. IKZF3 rs907091 CC was detected more commonly in the patients in stage I than in those in stages II and III, according to the International Staging System (ISS) criteria (p = 0.015). This genotype was also associated with a higher albumin level (p = 0.033), and was less common in the patients with the albumin level below 3.5 g/dL (p = 0.030).

CONCLUSIONS: Our results suggest that IKZF1 rs4132601 and IKZF3 rs907091 may affect response to treatment and progression in patients with MM.

PMID:39704419 | DOI:10.17219/dmp/183776

Amyloid. 2024 Dec 19:1-3. doi: 10.1080/13506129.2024.2441784. Online ahead of print.

NO ABSTRACT

PMID:39699273 | DOI:10.1080/13506129.2024.2441784