Venetoclax for pediatric patients with newly diagnosed acute myeloid leukemia.

This retrospective study at the University of Texas MD Anderson Cancer Center evaluated frontline venetoclax combination therapy in 11 pediatric/adolescent patients with acute myeloid leukemia (AML). Despite the small sample size and retrospective nature, the treatment demonstrated safety and potential efficacy, with most patients achieving early complete remission. Adverse events were consistent with other AML therapies, and no discontinuations due to toxicity occurred. While acknowledging study limitations, including selection bias and diverse concurrent therapies, this research underscores the promising role of venetoclax in pediatric AML. Further investigation is crucial to validate its long-term efficacy in this population.

Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience.

Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations.

Characteristics and outcomes of children, adolescent, and young adult patients with myelodysplastic neoplasms: A single-center retrospective analysis.

Myelodysplastic syndrome, or myelodysplastic neoplasms, are a rare finding in pediatric, adolescent, and young adult (AYA) patients. More literature is needed to highlight trends of survival or treatment resistance in subpopulations to improve treatment. Here we report a single center retrospective analysis of pediatric and AYA patients from 2000 to 2022 including molecular and cytogenetic data. Using the IPSS-R and IPSS-M, which have been reported exclusively in adults, and excluding patients with bone marrow failure syndromes, we analyzed 119 pediatric and AYA patients with myelodysplastic neoplasms. Therapy-related myelodysplastic neoplasms were present in 36 % of patients, and 31 % of patients developed acute myeloid leukemia. The 5-year overall survival (OS) rate for the entire cohort was 45 %. Contrary to young adults and older adults, mutations were not common in pediatrics. Those who underwent stem cell transplant (SCT)(at any time) had significantly longer median OS. Although SCT at any time improved OS in the de novo myelodysplastic neoplasm group, the choice of the initial treatment with intensive chemotherapy, hypomethylating agents, or SCT did not significantly alter OS. Median OS was shorter in the pediatric group (<18 years old) and longer for those with isolated deletion of 5q or TET2 mutation, but these were not significant findings. Median OS was significantly shorter in those with monosomy 7 or 7q deletion and those with therapy-related myelodysplastic neoplasms. These findings build on previously reported findings and encourage the use of SCT along with molecular and cytogenetic analysis.

Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community.

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

A birth-death model to understand bacterial antimicrobial heteroresistance from time-kill curves.

Antimicrobial heteroresistance refers to the presence of different subpopulations with heterogeneous antimicrobial responses within the same bacterial isolate, so they show reduced susceptibility compared with the main population. Though it is widely accepted that heteroresistance can play a crucial role in the outcome of antimicrobial treatments, predictive Antimicrobial Resistance (AMR) models accounting for bacterial heteroresistance are still scarce and need to be refined as the techniques to measure heteroresistance become standardised and consistent conclusions are drawn from data. In this work, we propose a multivariate Birth-Death (BD) model of bacterial heteroresistance and analyse its properties in detail. Stochasticity in the population dynamics is considered since heteroresistance is often characterised by low initial frequencies of the less susceptible subpopulations, those mediating AMR transmission and potentially leading to treatment failure. We also discuss the utility of the heteroresistance model for practical applications and calibration under realistic conditions, demonstrating that it is possible to infer the model parameters and heteroresistance distribution from time-kill data, i.e., by measuring total cell counts alone and without performing any heteroresistance test.

Are Mycoplasma pneumoniae coinfections frequent in COVID-19 patients? A systematic review.

Understanding the proportion of SARS-CoV-2 patients with Mycoplasmapneumoniae coinfection is crucial for treating patients suffering from coronavirus disease (COVID-19), help to ensure responsible use of antibiotics and minimize the negative consequences of overuse. In addition, this knowledge could have an impact on empirical antibiotic management guidelines for patients with COVID-19. This systematic review aimed to identify the prevalence of M. pneumoniae in patients with coronavirus disease 2019 (COVID-19). A bibliographic search of studies published in Spanish or English was conducted using the PubMed search engine. Fourteen articles from different continents (America, Asia and Europe) were included, involving a total of 5855 patients in these studies. The mean age of COVID-19 patients with M. pneumoniae was 48 years old (range 1-107), most of whom were male. The detection of laboratory-confirmed M. pneumoniae infection varied between 0 and 33.3%. Most of patients referred fever, cough, and dyspnea, and received empirical antibiotic treatment. Bacterial coinfection was not associated with increased ICU admission and mortality. The prevalence of coinfection showed extremely dissimilar figures according to the population studied and diagnostic criteria. However, it is important to develop Latin American studies, given the heterogeneity observed in the studies conducted in different countries. Standardized definitions should be developed in order to be able to assess the impact of coinfections in patients with a diagnosis of COVID-19.

PBMC therapy reduces cell death and tissue fibrosis after acute kidney injury by modulating the pattern of monocyte/macrophage survival in tissue.

In this study, we investigated if the therapeutic potential of peripheral blood mononuclear cell (PBMC) therapy in a murine model of ischemic AKI is related with the survival pattern of monocyte/macrophages in tissue. CD-1 mice were subjected to bilateral renal ischemia followed by reperfusion to induce AKI. M2-polarized PBMCs isolated from CD-1 mice were administered intravenously at different time points post-injury. Our results demonstrate that early administration of PBMC therapy attenuates renal tissue damage, reduces tissue cell death and prevents fibrosis development. Reduction of tissue pyroptosis was observed by reduction on NLRP3 inflammasome activation and decreasing IL-1beta and Caspase-1 expression in the kidney. Furthermore, the therapy was shown to mitigate ferroptosis by inducing GPX4 overexpression. Early administration of PBMCs increased the survival pattern of renal tissue-macrophages, promoting a "pro-survival phenotype" resulting in decreased pyroptotic marker NLRP3, IL-1beta and Caspase 1 and increased anti-ferroptotic gene GPX4. Conversely, delayed administration of PBMC therapy exhibits diminished efficacy in preventing cell death and fibrosis in tissue and provoked a decrease in the pro-survival phenotype of both monocyte /macrophages in tissue. Our findings highlight the therapeutic potential of PBMC therapy in mitigating AKI and preventing CKD progression by modulating tissue-resident macrophage survival and reducing their cell death pathways. The fact that the effectiveness of the therapy depends on the time of administration after the injury underscores the importance of early intervention in AKI management.

Synergistic Bactericidal Effects of Quaternary Ammonium Compounds with Essential Oil Constituents.

Antimicrobial tolerance is a significant concern in the food industry, as it poses risks to food safety and public health. To overcome this challenge, synergistic combinations of antimicrobials have emerged as a potential solution. In this study, the combinations of two essential oil constituents (EOCs), namely carvacrol (CAR) and eugenol (EUG), with the quaternary ammonium compounds (QACs) benzalkonium chloride (BAC) and didecyldimethylammonium chloride (DDAC) were evaluated for their antimicrobial effects against Escherichia coli and Bacillus cereus, two common foodborne bacteria. The checkerboard assay was employed to determine the fractional inhibitory concentration index (FICI) and the fractional bactericidal concentration index (FBCI), indicating the presence of bactericidal, but not bacteriostatic, synergy in all QAC-EOC combinations. Bactericidal synergism was clearly supported by Bliss independence analysis. The bactericidal activity of the promising synergistic combinations was further validated by time-kill curves, achieving a >4-log10 reduction of initial bacterial load, which is significant compared to typical industry standards. The combinations containing DDAC showed the highest efficiency, resulting in the eradication of bacterial population in less than 2-4 h. These findings emphasize the importance of considering both bacteriostatic and bactericidal effects when evaluating antimicrobial combinations and the potential of EOC-QAC combinations for sanitization and disinfection in the food industry.

Effects of Dietary Inclusion of a Proprietary Combination of Quillaja saponaria and Yucca schidigera on Intestinal Permeability and Immune Response in Broiler Chickens during a Coccidia Challenge.

This study assessed the impact of Magni-Phi Ultra (MPU) inclusion on intestinal integrity and immunity in broiler chickens challenged with coccidia during peak and recovery phases. A total of 128 male Ross 708 broiler chicks were randomly allotted to one of four treatment groups (four chicks/cage). Treatments included an uninfected control (UUC); a coccidial challenge (CC) infected control (IUC); a CC fed salinomycin at 66 ppm (SAL); and a CC fed Magni-Phi Ultra at 0.11 g/kg of diet (MPU). At 16 days post-hatch, all birds in the CC groups were orally gavaged with a 3× dose of a live coccidia vaccine. At 5 dpi, the birds fed MPU and SAL showed decreased plasma FITC-d, oocyte shedding, and lesion scores and higher BWG compared to the IUC birds (p < 0.05). Jejunum IL-17, IL-10, and IFN-ϒ mRNA expression was higher in the IUC compared to the UUC (p < 0.05) group at 5 dpi. At 12 dpi, the birds fed MPU or SAL had lower plasma FITC-d and jejunum IFN-ϒ and IL-10 mRNA expression compared to the IUC birds (p < 0.05). This study indicates that MPU supports intestinal integrity and mucosal immune responses during the peak and recovery phases of infection, which may lead to improved health and performance.

Removal of Mo(VI), Pb(II), and Cu(II) from wastewater using electrospun cellulose acetate/chitosan biopolymer fibers.

Environmentally friendly polymers such as cellulose acetate (CA) and chitosan (CS) were used to obtain electrospun fibers for Cu2+, Pb2+, and Mo6+ capture. The solvents dichloromethane (DCM) and dimethylformamide (DMF) allowed the development of a surface area of 148 m2 g-1 for CA fibers and 113 m2 g-1 for cellulose acetate/chitosan (CA/CS) fibers. The fibers were characterized by IR-DRIFT, SEM, TEM, CO2 sorption isotherms at 273 K, Hg porosimetry, TGA, stress-strain tests, and XPS. The CA/CS fibers had a higher adsorption capacity than CA fibers without affecting their physicochemical properties. The capture capacity reached 102 mg g-1 for Cu2+, 49.3 mg g-1 for Pb2+, and 13.1 mg g-1 for Mo6+. Furthermore, optimal pH, adsorption times qt, and C0 were studied for the evaluation of kinetic models and adsorption isotherms. Finally, a proposal for adsorbate-adsorbent interactions is presented as a possible capture mechanism where, in the case of Mo6+, a computational study is presented. The results demonstrate the potential to evaluate the fibers in tailings wastewater from copper mining.

Combination low-intensity chemotherapy plus inotuzumab ozogamicin, blinatumomab and rituximab for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

Not available.

Delabeling of allergy to beta-lactam antibiotics in hospitalized patients: a prospective study evaluating cost savings.

BACKGROUND: Patients with a penicillin allergy label are at risk of an associated increase in adverse antibiotic events and hospitalization costs. AIM: We aimed to study the economic savings derived from the correct diagnosis and delabeling inpatients with suspected beta-lactam allergy, considering the acquisition cost of antimicrobials prescribed during a patient's hospital stay. METHOD: We prospectively evaluated patients admitted to the University Hospital of Salamanca who had been labeled as allergic to beta-lactams and performed a delabeling study. Subsequently, cost differences between antibiotics administered before and after the allergy study and those derived from those patients who received alternative antibiotics during admission and those who switched to beta-lactams after the allergy study were calculated. RESULTS: One hundred seventy-seven inpatients labeled as allergic to beta-lactams underwent a delabeling study; 34 (19.2%) were confirmed to have allergy to beta-lactams. Of the total number of patients, 136 (76.8%) received antibiotics during their hospitalization, involving a mean (SD) cost of €203.07 (318.42) and a median (IQR) cost of €88.97 (48.86-233.56). After delabeling in 85 (62.5%) patients, the antibiotic treatment was changed to beta-lactams. In this group of patients, the mean cost (SD) decreased from €188.91 (351.09) before the change to 91.31 (136.07) afterward, and the median cost (IQR) decreased from €72.92 (45.82-211.99) to €19.24 (11.66-168). The reduction was significant compared to the median cost of patients whose treatment was not changed to beta-lactams (p<0.001). CONCLUSION: Delabeling hospitalized patients represents a cost-saving measure for treating patients labeled as allergic to beta-lactams.

Preparation of a ruthenium complex covalently bonded to multilayer graphene and its evaluation as a photocatalyst.

Multilayer graphene (MLG), obtained by mild sonication of graphite in NMP, was functionalised via 1,3-dipolar cycloaddition with azomethine ylides generated by thermal 1,2-prototropy from various imino esters. The microwave-assisted functionalisation took place in five hours at 100 °C. The resulting MLG, containing substituted proline-based amine functional groups, was characterized using XPS and showed a nitrogen loading three times that obtained for the same transformation performed for five days using convection-assisted heating. The preparation of the imino ester containing a bipyridine unit at the arylidene position allowed for the preparation of the corresponding functionalised MLG, which incorporated the ruthenium atom to achieve a heterogeneous MLG-Ru complex. This supported complex was tested, as a proof of concept, as a photocatalyst of the aerobic oxidative hydroxylation of 4-methoxyphenylboronic acid.

Biological Markers of High-Risk Childhood Acute Lymphoblastic Leukemia.

Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.

e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response.

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.