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1.
Sci Rep ; 14(1): 15421, 2024 07 04.
Article in English | MEDLINE | ID: mdl-38965297

ABSTRACT

Aedes aegypti and Aedes albopictus are the main vectors of arboviruses such as Dengue, Chikungunya and Zika, causing a major impact on global economic and public health. The main way to prevent these diseases is vector control, which is carried out through physical and biological methods, in addition to environmental management. Although chemical insecticides are the most effective strategy, they present some problems such as vector resistance and ecotoxicity. Recent research highlights the potential of the imidazolium salt "1-methyl-3-octadecylimidazolium chloride" (C18MImCl) as an innovative and environmentally friendly solution against Ae. aegypti. Despite its promising larvicidal activity, the mode of action of C18MImCl in mosquito cells and tissues remains unknown. This study aimed to investigate its impacts on Ae. aegypti larvae and three cell lines of Ae. aegypti and Ae. albopictus, comparing the cellular effects with those on human cells. Cell viability assays and histopathological analyses of treated larvae were conducted. Results revealed the imidazolium salt's high selectivity (> 254) for mosquito cells over human cells. After salt ingestion, the mechanism of larval death involves toxic effects on midgut cells. This research marks the first description of an imidazolium salt's action on mosquito cells and midgut tissues, showcasing its potential for the development of a selective and sustainable strategy for vector control.


Subject(s)
Aedes , Imidazoles , Insecticides , Larva , Aedes/drug effects , Animals , Larva/drug effects , Imidazoles/toxicity , Imidazoles/pharmacology , Insecticides/toxicity , Insecticides/pharmacology , Humans , Mosquito Vectors/drug effects , Cell Line , Cell Survival/drug effects , Mosquito Control/methods
2.
Eur J Pharmacol ; 977: 176723, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38851560

ABSTRACT

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.


Subject(s)
Phosphotransferases (Alcohol Group Acceptor) , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Phosphotransferases (Alcohol Group Acceptor)/genetics , Cell Line, Tumor , Signal Transduction/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Autophagy/drug effects , Cell Survival/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Apoptosis/drug effects
3.
Complement Ther Clin Pract ; 56: 101864, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38830273

ABSTRACT

BACKGROUND: Yoga practice can increase blood flow in the genital area, increase muscular strength, and improve body perception, which is related to sexual function. This study aimed to summarize the available evidence about the effects of yoga on sexual function in adults. METHODS: Systematic searches of five databases were conducted from inception to April 28, with the last update on September 28, 2023. Randomized clinical trials (RCTs) that compared yoga with nonintervention control groups on sexual function in adults. Risk of bias and certainty of evidence were assessed by the Cochrane risk of bias tool 2, and the GRADE approach, respectively. Summary effect size measures were calculated using a random-effects model estimation and are reported as standardized mean differences and 95% confidence intervals. Reporting followed the PRISMA guidelines. RESULTS: Ten RCTs that comprised 730 adults (range mean age, 26.64-68.2 years; 680 [93.2 %] women) were included. For the primary outcome, yoga intervention was associated with a significant small improvement in sexual function (-0.31; -0.47 to -0.15, p = 0.0002), with some concerns about risk of bias in nine RCTs (90%) and low-certainty evidence. Subgroup analyses revealed that yoga interventions performed by women (-0.36; -0.52 to -0.21, p < 0.00001), healthy individuals (-0.38; -0.59 to -0.16, p = 0.0006), or middle-aged individuals (-0.44; -0.63 to -0.25, p < 00001) significantly improved sexual function compared with control groups. CONCLUSION: Yoga was associated with a small improvement in sexual function compared with nonintervention control groups in adults. However, high-quality, larger RCTs are required to draw more definitive conclusions.


Subject(s)
Randomized Controlled Trials as Topic , Yoga , Humans , Female , Adult , Male , Sexual Dysfunction, Physiological/therapy , Middle Aged , Sexual Behavior , Aged
4.
Front Physiol ; 15: 1371839, 2024.
Article in English | MEDLINE | ID: mdl-38694209

ABSTRACT

Scientific evidence regarding the effect of different ladder-based resistance training (LRT) protocols on the morphology of the neuromuscular system is scarce. Therefore, the present study aimed to compare the morphological response induced by different LRT protocols in the ultrastructure of the tibial nerve and morphology of the motor endplate and muscle fibers of the soleus and plantaris muscles of young adult Wistar rats. Rats were divided into groups: sedentary control (control, n = 9), a predetermined number of climbs and progressive submaximal intensity (fixed, n = 9), high-intensity and high-volume pyramidal system with a predetermined number of climbs (Pyramid, n = 9) and lrt with a high-intensity pyramidal system to exhaustion (failure, n = 9). myelinated fibers and myelin sheath thickness were statistically larger in pyramid, fixed, and failure. myelinated axons were statistically larger in pyramid than in control. schwann cell nuclei were statistically larger in pyramid, fixed, and failure. microtubules and neurofilaments were greater in pyramid than in control. morphological analysis of the postsynaptic component of the plantar and soleus muscles did not indicate any significant difference. for plantaris, the type i myofibers were statistically larger in the pyramid and fixed compared to control. the pyramid, fixed, and failure groups for type ii myofibers had larger csa than control. for soleus, the type i myofibers were statistically larger in the pyramid than in control. pyramid and fixed had larger csa for type ii myofibers than control and failure. the pyramid and fixed groups showed greater mass progression delta than the failure. We concluded that the LRT protocols with greater volume and progression of accumulated mass elicit more significant changes in the ultrastructure of the tibial nerve and muscle hypertrophy without endplate changes.

6.
Ann Hematol ; 103(6): 2033-2039, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38180535

ABSTRACT

Acute lymphoblastic leukemia (ALL) is highly associated with central nervous system (CNS) infiltration and can be associated with higher risk of relapse. Conventional cytology (CC) is the traditional method for diagnosing CNS infiltration, although the use of immunophenotyping by flow cytometry (FC) has gained prominence in recent years due to its higher sensitivity. Also, some authors have proposed that CSF contamination by a traumatic lumbar puncture (TLP) could have a clinical impact. This retrospective study accessed the impact of CNS infiltration by CC or FC on overall survival, event-free survival, and relapse rate. In a cohort of 105 newly diagnosed ALL patients, CNS1, CNS2, and CNS3 status were found in 84%, 14%, and 2%, respectively. We found that extramedullary disease at the diagnosis, higher leukocyte counts, and higher blast percentage were associated with a positive CC. Sensitivity and specificity of CC were 53% and 98%, respectively. Three-year overall survival was 42.5%. Conversely, TLP was not associated with a positive CC nor had an impact on relapse rates. In multivariate analysis, a positive CC was associated with an increased relapse rate (HR 2.074, p = 0.037), while its detection by FC did not associate with this endpoint. Survival rates seem to be increasing over the last years by the adoption of a stratified CNS prophylaxis risk strategy. CSF contamination does not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates.


Subject(s)
Leukemic Infiltration , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/cerebrospinal fluid , Female , Male , Adult , Middle Aged , Retrospective Studies , Leukemic Infiltration/cerebrospinal fluid , Adolescent , Aged , Young Adult , Prognosis , Survival Rate , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/cerebrospinal fluid , Flow Cytometry , Immunophenotyping , Disease-Free Survival
7.
Brain Topogr ; 2023 Dec 07.
Article in English | MEDLINE | ID: mdl-38060074

ABSTRACT

PURPOSE: Identify the presence of a dysfunctional electroencephalographic (EEG) pattern in individuals with sickle cell disease (SCD) and hip osteonecrosis, and assess its potential associations with depression, anxiety, pain severity, and serum levels of brain-derived neurotrophic factor (BDNF). METHODS: In this cross-sectional investigation, 24 SCD patients with hip osteonecrosis and chronic pain were matched by age and sex with 19 healthy controls. Resting-state EEG data were recorded using 32 electrodes for both groups. Power spectral density (PSD) and peak alpha frequency (PAF) were computed for each electrode across Delta, Theta, Alpha, and Beta frequency bands. Current Source Density (CSD) measures were performed utilizing the built-in Statistical nonparametric Mapping Method of the LORETA-KEY software. RESULTS: Our findings demonstrated that SCD individuals exhibited higher PSD in delta and theta frequency bands when compared to healthy controls. Moreover, SCD individuals displayed increased CSD in delta and theta frequencies, coupled with decreased CSD in the alpha frequency within brain regions linked to pain processing, motor function, emotion, and attention. In comparison to the control group, depression symptoms, and pain intensity during hip abduction were positively correlated with PSD and CSD in the delta frequency within the parietal region. Depression symptoms also exhibited a positive association with PSD and CSD in the theta frequency within the same region, while serum BDNF levels showed a negative correlation with CSD in the alpha frequency within the left insula. CONCLUSION: This study indicates that individuals with SCD experiencing hip osteonecrosis and chronic pain manifest a dysfunctional EEG pattern characterized by the persistence of low-frequency PSD during a resting state. This dysfunctional EEG pattern may be linked to clinical and biochemical outcomes, including depression symptoms, pain severity during movement, and serum BDNF levels.

8.
Cancers (Basel) ; 15(24)2023 Dec 10.
Article in English | MEDLINE | ID: mdl-38136329

ABSTRACT

Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure. However, determining the most suitable protocol for less-resourced settings can be challenging. In these situations, we must consider the potential for treatment toxicity and limited access to newer agents and alloSCT facilities. Currently, it is advisable to use less intensive induction regimens for Ph+ ALL. These regimens can achieve high rates of complete remission while causing fewer induction deaths. For consolidation therapy, chemotherapy should remain relatively intensive, with careful monitoring of the BCR-ABL1 molecular transcript and minimal residual disease. AlloSCT may be considered, especially for patients who do not achieve complete molecular remission or have high-risk genetic abnormalities, such as IKZF1-plus. If there is a loss of molecular response, it is essential to screen patients for ABL mutations and, ideally, change the TKI therapy. The T315I mutation is the most common mechanism for disease resistance, being targetable to ponatinib. Blinatumomab, a bispecific antibody, has shown significant synergy with TKIs in treating this disease. It serves as an excellent salvage therapy, aside from achieving outstanding results when incorporated into the frontline.

9.
J Mycol Med ; 33(4): 101434, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37683564

ABSTRACT

INTRODUCTION: Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole is not widely available. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction. METHODS: This is a retrospective cohort encompassing newly diagnosed AML adult patients. All subjects received intensive chemotherapy and were divided into three groups: patients who did not receive any AP and patients who received fluconazole (150-400 mg/day) or anidulafungin (100 mg/day). RESULTS: During AML induction, 82 patients did not receive AP, 108 and 14 patients received anidulafungin and fluconazole, respectively. IFI incidence was 27%, classified as possible, probable, and proven in 65, 2 and 33%, respectively. Multivariable analysis showed that lower neutrophil counts are associated with IFI (OR = 2.8), whereas age, genetic classification, and lymphocyte counts were not. To examine the impact of anidulafungin in comparison with 'no AP', a propensity score matching analysis was performed. Use of anidulafungin was not related to less IFI during induction, while neutrophil counts remained significant. Patients under prophylactic anidulafungin received less amphotericin B (p < 0.001) but not voriconazole (p = 0.49). DISCUSSION: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the incidence of mold infections did not decrease with AP, suggesting that in a setting with a high incidence of IFI, broad spectrum AP might be more suitable.


Subject(s)
Antifungal Agents , Leukemia, Myeloid, Acute , Adult , Humans , Antifungal Agents/therapeutic use , Fluconazole/therapeutic use , Anidulafungin , Retrospective Studies , Propensity Score , Remission Induction , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/drug therapy
10.
Int J Stem Cells ; 16(4): 425-437, 2023 Nov 30.
Article in English | MEDLINE | ID: mdl-37643763

ABSTRACT

Obesity, which continues to increase worldwide, was shown to irreversibly impair the differentiation potential and angiogenic properties of adipose tissue mesenchymal stromal cells (ADSCs). Because these cells are intended for regenerative medicine, especially for the treatment of inflammatory conditions, and the effects of obesity on the immunomodulatory properties of ADSCs are not yet clear, here we investigated how ADSCs isolated from former obese subjects (Ex-Ob) would influence macrophage differentiation and polarization, since these cells are the main instructors of inflammatory responses. Analysis of the subcutaneous adipose tissue (SAT) of overweight (OW) and Ex-Ob subjects showed the maintenance of approximately twice as many macrophages in Ex-Ob SAT, contained within the CD68+/FXIII-A- inflammatory pool. Despite it, in vitro, coculture experiments revealed that Ex-Ob ADSCs instructed monocyte differentiation into a M2-like profile, and under inflammatory conditions induced by LPS treatment, inhibited HLA-DR upregulation by resting M0 macrophages, originated a similar percentage of TNF-α+ cells, and inhibited IL-10 secretion, similar to OW-ADSCs and BMSCs, which were used for comparison, as these are the main alternative cell types available for therapeutic purposes. Our results showed that Ex-Ob ADSCs mirrored OW-ADSCs in macrophage education, favoring the M2 immunophenotype and a mixed (M1/M2) secretory response. These results have translational potential, since they provide evidence that ADSCs from both Ex-Ob and OW subjects can be used in regenerative medicine in eligible therapies. Further in vivo studies will be fundamental to validate these observations.

11.
Trends Parasitol ; 39(9): 774-785, 2023 09.
Article in English | MEDLINE | ID: mdl-37442747

ABSTRACT

Human leishmaniosis caused by Leishmania infantum is an important health problem worldwide. One of the main aspects arousing interest is the epidemiological scenario surrounding Le. infantum infection in the New World (NW) and Old World (OW). This parasite was introduced to the Americas during European colonization leading to different epidemiology outcomes, even more enigmatic in the face of global changes. Thus, this review aims to highlight the differences and similarities between Le. infantum epidemiology between Brazil (NW) and Spain (OW), as both countries are leading the total number of leishmaniosis cases in their respective continents. Grounded on a systemic view, this article also draws attention to possible common innovative strategies to rethink ways of controlling infections caused by Le. infantum.


Subject(s)
Leishmania infantum , Leishmaniasis, Visceral , Leishmaniasis , Parasites , Animals , Humans , Leishmaniasis, Visceral/epidemiology , Leishmaniasis, Visceral/prevention & control , Leishmaniasis, Visceral/parasitology , Spain/epidemiology , Brazil/epidemiology
12.
3D Print Addit Manuf ; 10(3): 420-427, 2023 Jun 01.
Article in English | MEDLINE | ID: mdl-37346194

ABSTRACT

This article evaluates an active thermography algorithm to detect subsurface defects in materials made by additive manufacturing (AM). It is based on the techniques of thermographic signal reconstruction (TSR), thermal contrast, and the physical principles of heat transfer. The subsurface defects have different infill, depth, and size. The results obtained from this algorithm are compared with state-of-the-art TSR technique and show the high performance of the proposed algorithm even for subsurface defects done by 3D AM. The resulting images are better shown using the absolute difference in the place of variance. The proposed algorithm has higher contrast, better sensitivity to the defect depths, and lower noise than the TSR. The resultant image is quite clean and gives no doubt where the subsurface defects are.

13.
An Acad Bras Cienc ; 95(2): e20201039, 2023.
Article in English | MEDLINE | ID: mdl-37133298

ABSTRACT

Geoprocessing techniques are generally applied in natural disaster risk management due to their ability to integrate and visualize different sets of geographic data. The objective of this study was to evaluate the capacity of classification and regression tree (CART) to assess fire risk. MCD45A1 product of the burnt area, relative to a 16-year period (2000-2015) was used to obtain a fire occurrence map, from center points of the raster, using a kernel density approach. The resulting map was then used as a response variable for CART analysis with fire influence variables used as predictors. A total of 12 predictors were determined from several databases, including environmental, physical, and socioeconomic aspects. Rules generated by the regression process allowed to of define different risk levels, expressed in 35 management units, and used to produce a fire prediction map. Results of the regression process (r = 0.94 and r² = 0.88) demonstrate the capability of the CART algorithm in highlighting hierarchical relationships among predictors, while the model's easy interpretability provides a solid basis for decision making. This methodology can be expanded in other environmental risk analysis studies and applied to any area of the globe on a regional scale.


Subject(s)
Machine Learning , Wildfires , Algorithms , Brazil
14.
J Prim Care Community Health ; 14: 21501319231159814, 2023.
Article in English | MEDLINE | ID: mdl-36941757

ABSTRACT

OBJECTIVES: Vaccine hesitancy among essential workers remains a significant public health challenge. We examined psychological constructs of perceived susceptibility, threat, and self-efficacy and their associations with COVID-19 vaccine hesitancy among a racially and ethnically diverse essential workforce population. METHODS: We performed a cross-sectional survey of essential workers from September-December 2020 at a large Los Angeles safety-net medical center as part of a program offering free COVID-19 serology testing. Program participants completed a standardized survey at the time of phlebotomy. Hierarchical logistic regression was utilized to determine factors independently associated with vaccine hesitancy. RESULTS: Among 1327 persons who had serology testing, 1235 (93%) completed the survey. Of these, 958 (78%) were healthcare workers. Based on expressed intent, 22% were vaccine-hesitant 78% were vaccine acceptors. In our multivariate model, vaccine hesitancy was associated with female gender [aOR = 2.09; 95% CI (1.44-3.05)], African American race [aOR = 4.32; (2.16-8.62)], LatinX ethnicity [aOR = 2.47; 95% CI (1.51-4.05)] and history of not/sometimes receiving influenza vaccination [aOR = 4.39; 95% CI (2.98-6.48)]. Compared to nurses, vaccine hesitancy was lower among physicians [aOR = 0.09; 95% CI (0.04-0.23)], non-nursing/non-physician healthcare workers [aOR = 0.55; 95% CI (0.33-0.92)], and non-healthcare care workers [aOR = 0.53; 95% CI (0.36-0.78)]. CONCLUSIONS: Among a racially/ethnically diverse group of safety net medical center essential workers, COVID-19 vaccine hesitancy was associated with racial/ethnic minority groups, employment type, and prior influenza vaccination hesitancy. Interestingly, we found no association with the Health Belief Model construct measures of perceived susceptibility, threat, and self-efficacy. Psychological constructs not assessed may be drivers of vaccine hesitancy in our population.


Subject(s)
COVID-19 , Influenza, Human , Female , Humans , COVID-19 Vaccines , Cross-Sectional Studies , Ethnicity , COVID-19/prevention & control , Minority Groups , Vaccination
15.
Viruses ; 15(3)2023 02 23.
Article in English | MEDLINE | ID: mdl-36992323

ABSTRACT

Between 2016 and 2018, Brazil experienced the largest sylvatic epidemic of yellow fever virus (YFV). Despite to the magnitude and rapid spread of the epidemic, little is known about YFV dispersion. The study evaluated whether the squirrel monkey is a good model for yellow fever (YF) studies. Methods: Ten animals were infected with 1 × 106 PFU/mL of YFV, with one negative control. Blood samples were collected daily during the first 7 days and at 10, 20 and 30 days post infection (dpi) for detection of viral load and cytokines by RT-qPCR; measurements of AST, ALT, urea and creatinine were taken; IgM/IgG antibodies were detected by ELISA, and hemagglutination inhibition and neutralization tests were performed. The animals exhibited fever, flushed appearance, vomiting and petechiae, and one animal died. Viremia was detected between 1 and 10 dpi, and IgM/IgG antibodies appeared between 4 and 30 dpi. The levels of AST, ALT and urea increased. The immune responses were characterized by expression of S100 and CD11b cells; endothelial markers (VCAM-1, ICAM-1 and VLA-4), cell death and stress (Lysozyme and iNOS); and pro-inflammatory cytokines (IL-8, TNF-α, and IFN-γ) and anti-inflammatory cytokines (IL-10 and TGF-ß). The squirrel monkeys showed changes similar to those described in humans with YF, and are a good experimental model for the study of YF.


Subject(s)
Yellow Fever , Humans , Animals , Yellow Fever/epidemiology , Saimiri , Yellow fever virus , Cytokines , Immunoglobulin M , Immunoglobulin G
16.
Article in English | MEDLINE | ID: mdl-38233304

ABSTRACT

INTRODUCTION: High-dose methotrexate (HDMTX) is an essential part of chemotherapy regimens for hematologic neoplasms. The incidence of acute kidney injury (AKI) after HDMTX in unmonitored outpatient infusion had not been reported in adults yet. In this study, we evaluated toxicity data after outpatient administration of HDMTX without drug monitoring. METHODS: Patients 16 years old or over with acute lymphoblastic leukemia and non-Hodgkin lymphoma who received at least one outpatient infusion of HDMTX without drug level monitoring were included. This is a retrospective, nested case-control study, in which the cases comprised patients who developed AKI after HDMTX. RESULTS: Overall, 302 patients were included, encompassing 840 infusions. Hospitalization occurred in 8.6 %. A total of 25 patients presented AKI after HDMTX administration, corresponding to 3 % of the methotrexate (MTX) infusions and 8.3 % of the patients. HIV-associated Burkitt lymphoma was more common in patients who presented AKI (18 vs. 6.8 %, p = 0.03). Baseline factors related to AKI after HDMTX were age > 44 y, body surface area ≥ 1.76 m2, body mass index (BMI) ≥ 23.8 kg/m2, glomerular filtration rate, and thrombocytopenia (< 150×109/L). Multivariable analysis for adjusting such factors found that BMI was independently related to AKI after HDMTX (OR 3.8). Death after AKI occurred in 56 %. CONCLUSION: Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fared worse than expected, with more hospitalizations and death. A higher BMI was associated with the MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.

17.
Blood Cancer J ; 12(11): 151, 2022 Nov 09.
Article in English | MEDLINE | ID: mdl-36347832

ABSTRACT

The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.


Subject(s)
Leukemia, Myeloid, Acute , Tandem Mass Spectrometry , Humans , Chromatography, Liquid , Autophagy , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Apoptosis , Homeostasis
18.
Front Med (Lausanne) ; 9: 679053, 2022.
Article in English | MEDLINE | ID: mdl-36203767

ABSTRACT

Chronic joint pain (CJP) is among the significant musculoskeletal comorbidities in sickle cell disease (SCD) individuals. However, many healthcare professionals have difficulties in understanding and evaluating it. In addition, most musculoskeletal evaluation procedures do not consider central nervous system (CNS) plasticity associated with CJP, which is frequently maladaptive. This review study highlights the potential mechanisms of CNS maladaptive plasticity related to CJP in SCD and proposes reliable instruments and methods for musculoskeletal assessment adapted to those patients. A review was carried out in the PubMed and SciELO databases, searching for information that could help in the understanding of the mechanisms of CNS maladaptive plasticity related to pain in SCD and that presented assessment instruments/methods that could be used in the clinical setting by healthcare professionals who manage chronic pain in SCD individuals. Some maladaptive CNS plasticity mechanisms seem important in CJP, including the impairment of pain endogenous control systems, central sensitization, motor cortex reorganization, motor control modification, and arthrogenic muscle inhibition. Understanding the link between maladaptive CNS plasticity and CJP mechanisms and its assessment through accurate instruments and methods may help healthcare professionals to increase the quality of treatment offered to SCD patients.

20.
J Pharm Biomed Anal ; 221: 115025, 2022 Nov 30.
Article in English | MEDLINE | ID: mdl-36099724

ABSTRACT

The limitations of silica-based sorbents boosted the development of new extraction phases. In this study, boron nitride nanotubes functionalized with octadecyl groups were used for the first time as sorbent for extraction of losartan and valsartan, the most used angiotensin receptor blockers in the clinical practice, from human plasma. The nanotubes were synthesized using the chemical vapor deposition technique, purified by acid treatment, functionalized with octadecylamine in a microwave reactor, and characterized by different techniques. The functionalized nanotubes were packed in solid phase extraction cartridges. Extraction conditions were optimized by means of a 23 factorial design with center points. The separation was performed on a biphenyl core-shell (100 × 4.6 mm; 2.6 µm) column, using 0.1 % (v/v) triethylamine solution and methanol (pH 3.2) as mobile phase, at 0.7 mL/min, in gradient elution. The injection volume was 10 µL and fluorescence detection was performed at excitation and emission wavelengths of 250 and 375 nm, respectively. The developed method was validated according to Brazilian Health Regulatory Agency (ANVISA), United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) guidelines and presented selectivity, precision, accuracy, and linearity in the concentration ranges of 50-1200 ng/mL for losartan and 20-1700 ng/mL for valsartan. Recoveries higher than 80 % were obtained. The method was fit for the quantification of losartan in plasma samples from patients under antihypertensive therapy, being useful in therapeutic drug monitoring, pharmacokinetics and bioequivalence studies.


Subject(s)
Angiotensin Receptor Antagonists , Nanotubes , Antihypertensive Agents , Boron Compounds , Chromatography, High Pressure Liquid/methods , Humans , Losartan , Methanol , Silicon Dioxide , United States , Valsartan
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