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International Microbiology : the... Jun 2024Microbes play an essential role in soil fertility by replenishing the nutrients; they encounter various biotic and abiotic stresses disrupting their cellular...
Microbes play an essential role in soil fertility by replenishing the nutrients; they encounter various biotic and abiotic stresses disrupting their cellular homeostasis, which expedites activating a conserved signaling pathway for transient over-expression of heat shock proteins (HSPs). In the present study, a versatile soil bacterium Bacillus subtilis strain PSK.A2 was isolated and characterized. Further, the isolated bacterium was exposed with several stresses, viz., heat, salt, acid, alkaline, and antibiotics. Stress-attributed cellular morphological modifications such as swelling, shrinkage, and clump formation were observed under the scanning electron microscope. The comparative protein expression pattern was studied by SDS-PAGE, relative protein stabilization was assessed by protein aggregation assay, and relative survival was mapped by single spot dilution and colony-counting method under control, stressed, lethal, and stressed lethal conditions of the isolate. The findings demonstrated that bacterial stress tolerance was maintained via the activation of various HSPs of molecular weight ranging from 17 to 115 kD to respective stimuli. The treatment of subinhibitory dose of antibiotics not interfering protein synthesis (amoxicillin and ciprofloxacin) resulted in the expression of eight HSPs of molecular weight ranging from 18 to 71 kD. The pre-treatment of short stress dosage showed endured overall tolerance of bacterium to lethal conditions, as evidenced by moderately enhanced total soluble intracellular protein content, better protein stabilization, comparatively over-expressed HSPs, and relatively enhanced cell survival. These findings hold an opportunity for developing novel approaches towards enhancing microbial resilience in a variety of conditions, including industrial bioprocessing, environmental remediation, and infectious disease management.
PubMed: 38898189
DOI: 10.1007/s10123-024-00549-z -
Breast (Edinburgh, Scotland) May 2024This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in...
This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in 2021, virtual, and ABC 7 in 2023, in Lisbon, Portugal), organized by the ABC Global Alliance. It provides the main recommendations on how to best manage patients with advanced breast cancer (inoperable locally advanced or metastatic), of all breast cancer subtypes, as well as palliative and supportive care. These guidelines are based on available evidence or on expert opinion when a higher level of evidence is lacking. Each guideline is accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage of consensus reached at the consensus conferences. Updated diagnostic and treatment algorithms are also provided. The guidelines represent the best management options for patients living with ABC globally, assuming accessibility to all available therapies. Their adaptation (i.e. resource-stratified guidelines) is often needed in settings where access to care is limited.
PubMed: 38896983
DOI: 10.1016/j.breast.2024.103756 -
British Journal of Haematology Jun 2024Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques...
Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM.
PubMed: 38894496
DOI: 10.1111/bjh.19589 -
Cancers May 2024The objective of this retrospective study is to assess the effectiveness and safety of two beta-emitting prostate-specific membrane antigen (PSMA) radioligands, [Lu]Lu...
The objective of this retrospective study is to assess the effectiveness and safety of two beta-emitting prostate-specific membrane antigen (PSMA) radioligands, [Lu]Lu and [161Tb]Tb, in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 148 cycles of beta-emitting PSMA radioligand therapy were given to 53 patients at a specialized cancer care center in Amman, Jordan. This treatment was offered following the exhaustion of all prior treatment modalities. Approximately half of the cases (n = 26) demonstrated an initial partial response to PSMA radioligand therapy. Moreover, roughly one-fourth of the patients (n = 13) exhibited a sustained satisfactory biochemical response, which qualified them to receive a total of six PSMA radioligand therapy cycles and maintain continued follow-up for additional treatment cycles. This was reflected by an adequate prostate-specific antigen (PSA) decline and a concomitant partial response evident on [Ga]Ga-PSMA positron emission tomography/computed tomography imaging. A minority of patients (n= 18; 34%) experienced side effects. Generally, these were low-grade and self-limiting toxicities. This study endorses previous research evidence about PSMA radioligand therapy's safety and efficacy. It also provides the first clinical insight from patients of Arab ethnicity. This should facilitate and promote further evidence, both regionally and internationally.
PubMed: 38893095
DOI: 10.3390/cancers16111974 -
Journal of Clinical Medicine May 2024Augmented reality (AR) and 3D printing (3DP) are novel technologies in the orthopedic field. Over the past decade, enthusiasm for these new digital applications has...
Augmented reality (AR) and 3D printing (3DP) are novel technologies in the orthopedic field. Over the past decade, enthusiasm for these new digital applications has driven new perspectives in improving diagnostic accuracy and sensitivity in the field of traumatology. Currently, however, it is still difficult to quantify their value and impact in the medical-scientific field, especially in the improvement of diagnostics in complex fractures. Acetabular fractures have always been a challenge in orthopedics, due to their volumetric complexity and low diagnostic reliability. : The goal of this study was to determine whether these methods could improve the learning aspect and diagnostic accuracy of complex acetabular fractures compared to gold-standard CT (computed tomography). : Orthopedic residents of our department were selected and divided into Junior (JUN) and Senior (SEN) groups. Associated fractures of acetabulum were included in the study, and details of these were provided as CT scans, 3DP models, and AR models displayed on a tablet screen. In a double-blind questionnaire, each resident classified every fracture. Diagnostic accuracy (DA), response time (RT), agreement (R), and confidence (C) were measured. : Twenty residents (JUN = 10, SEN = 10) classified five fractures. Overall DA was 26% (CT), 18% (3DP), and 29% (AR). AR-DA was superior to 3DP-DA ( = 0.048). DA means (JUN vs. SEN, respectively): CT-DA was 20% vs. 32% ( < 0.05), 3DP-DA was 12% vs. 24% ( = 0.08), and AR-DA was 28% vs. 30% ( = 0.80). Overall RT was 61.2 s (±24.6) for CT, 35.8 s (±20.1) for 3DP, and 46.7 s (±20.8) for AR. R was fairly poor between methods and groups. Overall, 3DPs had superior C (65%). : AR had the same overall DA as CT, independent of experience, 3DP had minor differences in DA and R, but it was the fastest method and the one in which there was the most confidence. Intra- and inter-observer R between methods remained very poor in residents.
PubMed: 38892770
DOI: 10.3390/jcm13113059 -
International Journal of Molecular... May 2024Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential...
Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential therapeutic interventions for depression. While the behavioral and neurobiological effects of CVS have been extensively studied, its impact on myocardial function remains largely unexplored. To induce the CVS model, rats were exposed to various stressors over 40 days. Behavioral assessments confirmed depressive-like behavior. Biochemical analyses revealed alterations in myocardial metabolism, including changes in NAD+ and NADP+, and NADPH concentrations. Free amino acid analysis indicated disturbances in myocardial amino acid metabolism. Evaluation of oxidative DNA damage demonstrated an increased number of abasic sites in the DNA of rats exposed to CVS. Molecular analysis showed significant changes in gene expression associated with glucose metabolism, oxidative stress, and cardiac remodeling pathways. Histological staining revealed minor morphological changes in the myocardium of CVS-exposed rats, including increased acidophilicity of cells, collagen deposition surrounding blood vessels, and glycogen accumulation. This study provides novel insights into the impact of chronic stress on myocardial function and metabolism, highlighting potential mechanisms linking depression and cardiovascular diseases. Understanding these mechanisms may aid in the development of targeted therapeutic strategies to mitigate the adverse cardiovascular effects of depression.
Topics: Animals; Rats; Myocardium; Male; Stress, Psychological; Oxidative Stress; Depression; Disease Models, Animal; DNA Damage; Adaptation, Physiological; NAD; Glucose
PubMed: 38892086
DOI: 10.3390/ijms25115899 -
International Journal of Molecular... May 2024Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid... (Meta-Analysis)
Meta-Analysis Review
The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.
Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.
Topics: Humans; Inflammatory Bowel Diseases; Psoriasis; Polymorphism, Single Nucleotide; Biological Products; Arthritis, Rheumatoid; Arthritis, Psoriatic; NLR Family, Pyrin Domain-Containing 3 Protein; Myeloid Differentiation Factor 88
PubMed: 38891983
DOI: 10.3390/ijms25115793 -
Plants (Basel, Switzerland) Jun 2024Pepper is a high-economic-value agricultural crop that faces diverse disease challenges such as blight and anthracnose. These diseases not only reduce the yield of...
Pepper is a high-economic-value agricultural crop that faces diverse disease challenges such as blight and anthracnose. These diseases not only reduce the yield of pepper but, in severe cases, can also cause significant economic losses and threaten food security. The timely and accurate identification of pepper diseases is crucial. Image recognition technology plays a key role in this aspect by automating and efficiently identifying pepper diseases, helping agricultural workers to adopt and implement effective control strategies, alleviating the impact of diseases, and being of great importance for improving agricultural production efficiency and promoting sustainable agricultural development. In response to issues such as edge-blurring and the extraction of minute features in pepper disease image recognition, as well as the difficulty in determining the optimal learning rate during the training process of traditional pepper disease identification networks, a new pepper disease recognition model based on the TPSAO-AMWNet is proposed. First, an Adaptive Residual Pyramid Convolution (ARPC) structure combined with a Squeeze-and-Excitation (SE) module is proposed to solve the problem of edge-blurring by utilizing adaptivity and channel attention; secondly, to address the issue of micro-feature extraction, Minor Triplet Disease Focus Attention (MTDFA) is proposed to enhance the capture of local details of pepper leaf disease features while maintaining attention to global features, reducing interference from irrelevant regions; then, a mixed loss function combining Weighted Focal Loss and L2 regularization (WfrLoss) is introduced to refine the learning strategy during dataset processing, enhancing the model's performance and generalization capabilities while preventing overfitting. Subsequently, to tackle the challenge of determining the optimal learning rate, the tent particle snow ablation optimizer (TPSAO) is developed to accurately identify the most effective learning rate. The TPSAO-AMWNet model, trained on our custom datasets, is evaluated against other existing methods. The model attains an average accuracy of 93.52% and an F1 score of 93.15%, demonstrating robust effectiveness and practicality in classifying pepper diseases. These results also offer valuable insights for disease detection in various other crops.
PubMed: 38891389
DOI: 10.3390/plants13111581 -
Blood Cancer Journal Jun 2024Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in...
Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.
Topics: Humans; Male; Female; Aged; Tumor Suppressor Protein p53; Mutation; Middle Aged; Aged, 80 and over; Adult; Prognosis; Treatment Outcome
PubMed: 38890297
DOI: 10.1038/s41408-024-01077-9 -
Cell Death & Disease Jun 2024Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs....
Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.
Topics: Alpha Particles; Humans; Tumor Suppressor Protein p53; Animals; Mice; Radiation-Sensitizing Agents; Mutation; Quinuclidines; Cell Line, Tumor; Mice, Nude; Xenograft Model Antitumor Assays; Apoptosis; Neoplasms
PubMed: 38890278
DOI: 10.1038/s41419-024-06830-3