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1.
Cyberpsychol Behav Soc Netw ; 27(7): 467-481, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38757677

RÉSUMÉ

Phubbing, a pervasive social behavior linked to smartphone usage, involves users neglecting their conversation partners to engage with their phones. Despite consistent exploration of its association with the concept of fear of missing out (FOMO), findings in the existing literature exhibit notable inconsistency. To address this gap, this study employs a systematic review and meta-analysis to scrutinize the intricate relationship between phubbing behavior and FOMO. A comprehensive systematic review, spanning up to December 10, 2023, encompassed databases such as PubMed, Scopus, Web of Science, ProQuest, and Google Scholar. The resulting dataset comprised 27 eligible studies, incorporating insights from 20,415 participants across 15 countries. Rigorous evaluation of study quality was executed using the Newcastle Ottawa Scale, while statistical analyses were meticulously conducted using R Studio. Revealing a robust positive association, phubbing behavior was significantly linked to FOMO (effect size[ES] = 0.43, 95% CI: 0.36, 0.49, I2: 97.5%, τ2: 0.05). Correcting for detected publication bias using the Trim and Fill method, an additional 16 studies were included, fortifying the robustness of the findings. Moderation analysis uncovered significant influences of location (p < 0.01), income level (p < 0.01), sampling method (p < 0.01), phubbing scale (p < 0.01), and FOMO scale and type (p < 0.01) on the estimated relationship. Univariate meta-regression highlighted the substantial impact of sample size (R2 = 11.81%, p < 0.01), while multivariate meta-regression illuminated the combined effects of publication year, study quality score, sample size, mean age, and female proportion on the estimated relationship (k = 19, R2 = 52.85%, I2 = 93.78%, p < 0.05). Furthermore, post hoc influential analysis, conducted through the leave-one-out method, offered additional depth to the examination.


Sujet(s)
Peur , Humains , Peur/psychologie , Ordiphone , Comportement social , Femelle
3.
Cell Death Discov ; 10(1): 211, 2024 May 02.
Article de Anglais | MEDLINE | ID: mdl-38697979

RÉSUMÉ

Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here induce FOXM1 overexpression in solid cancers. The therapy-induced FOXM1 overexpression may explain the failure or reduced efficacy of these drugs in cancer patients. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.

4.
Blood Cancer J ; 14(1): 42, 2024 Mar 07.
Article de Anglais | MEDLINE | ID: mdl-38453907

RÉSUMÉ

As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1mut) AML comprising a third of all AML patients. While the leukemia initiating function of the NPM1 mutation is clearly dependent on HOX activity, the favorable treatment responses in these patients with upregulation of HOX cluster genes is a poorly understood paradoxical observation. Recent data confirm FOXM1 as a suppressor of HOX activity and a well-known binding partner of NPM suggesting that FOXM1 inactivation may mediate the effect of cytoplasmic NPM on HOX upregulation. Conversely the residual nuclear fraction of mutant NPM has also been recently shown to have chromatin modifying effects permissive to HOX expression. Recent identification of the menin-MLL interaction as a critical vulnerability of HOX-dependent AML has fueled the development of menin inhibitors that are clinically active in NPM1 and MLL rearranged AML despite inconsistent suppression of the HOX locus. Insights into context-specific regulation of HOX in AML may provide a solid foundation for targeting this common vulnerability across several major AML subtypes.


Sujet(s)
Protéines à homéodomaine , Leucémie aigüe myéloïde , Humains , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Leucémie aigüe myéloïde/anatomopathologie , Protéines nucléaires/génétique , Nucléophosmine , Régulation de l'expression des gènes dans la leucémie , Facteurs de transcription/génétique , Chromatine , Expression des gènes
5.
Am J Clin Pathol ; 161(6): 586-597, 2024 Jun 03.
Article de Anglais | MEDLINE | ID: mdl-38345307

RÉSUMÉ

OBJECTIVES: Because of its low frequency in adult populations and clinical and laboratory overlap with hemophagocytic lymphohistiocytosis and other T-cell lymphomas, T-cell/natural killer (NK) cell systemic, chronic, active Epstein-Barr virus (EBV) (T/NK sCAEBV) infection remains underdiagnosed, preventing critical, prompt therapeutic interventions. METHODS: We report a 5-case series that included 2 adult patients with T/NK sCAEBV and 3 additional adult patients with T/NK lymphomas with concomitant systemic EBV infection to review these entities' overlapping diagnostic and clinical features. RESULTS: Approximately 95% of the world population has been infected with EBV during their lifetime, and infection is usually asymptomatic, with symptomatic cases eventually resolving spontaneously. A small subset of immunocompetent patients develops CAEBV, a life-threatening complication resulting from EBV-infected T-cell or NK cell neoplastic lymphocytes. The sites of end-organ damage in T/NK sCAEBV demonstrate pathologic findings such as reactive lymphoid proliferations, making the diagnosis difficult to establish, with the only curative option being an allogeneic hematopoietic stem cell transplant. CONCLUSIONS: This diagnosis is most prevalent in Asia, with few cases reported in Western countries. Adult age is an independent risk factor for poor outcomes, and most cases are diagnosed in pediatric populations.


Sujet(s)
Infections à virus Epstein-Barr , Humains , Infections à virus Epstein-Barr/complications , Infections à virus Epstein-Barr/diagnostic , Mâle , Femelle , Adulte , Adulte d'âge moyen , Cellules tueuses naturelles/anatomopathologie , Cellules tueuses naturelles/immunologie , Syndromes lymphoprolifératifs/virologie , Syndromes lymphoprolifératifs/diagnostic , Syndromes lymphoprolifératifs/anatomopathologie , Herpèsvirus humain de type 4/isolement et purification , Sujet âgé , Maladie chronique , Lymphome T-NK extraganglionnaire/anatomopathologie , Lymphome T-NK extraganglionnaire/virologie , Lymphome T-NK extraganglionnaire/diagnostic
6.
Leukemia ; 38(4): 865-876, 2024 Apr.
Article de Anglais | MEDLINE | ID: mdl-38388647

RÉSUMÉ

Racial and socioeconomic disparities impact outcomes after chemotherapy and limit access to allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML), yet studies have yielded mixed results on the influence of disparities on post-HCT outcomes. Therefore, we studied 1024 adults with AML who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Collected data included non-biologic and demographic characteristics (including race/ethnicity, marital status, distance traveled, and household size), transplant- and disease-related characteristics, and area-level and individual-level socioeconomic factors (i.e., area deprivation index and occupational status). After multivariable adjustment, no socioeconomic- or non-biologic factors were associated with non-relapse mortality (NRM), overall survival (OS), relapse-free survival (RFS), or relapse except being married (associated with improved NRM: hazard ratio [HR] = 0.7 [0.50-0.97]) and having no insurance (associated with worse OS: HR = 1.49 [1.05-2.12] and RFS: HR = 1.41 [1.00-1.98]). Despite a relatively racially homogenous cohort, Asian race was associated with improved NRM (HR = 0.47 [0.23-0.93]) and American Indian/Alaskan Native race was associated with higher relapse risk (HR = 2.45 [1.08-5.53]). In conclusion, in our retrospective analysis, socioeconomic-, demographic-, and non-biologic factors had limited impact on post-HCT outcomes in AML patients allografted in morphologic remission. Further research is needed to investigate disparities among HCT-eligible patients.


Sujet(s)
Transplantation de cellules souches hématopoïétiques , Leucémie aigüe myéloïde , Adulte , Humains , Études rétrospectives , , Transplantation de cellules souches hématopoïétiques/méthodes , Récidive , Conditionnement pour greffe/méthodes
7.
Naunyn Schmiedebergs Arch Pharmacol ; 397(1): 189-205, 2024 01.
Article de Anglais | MEDLINE | ID: mdl-37401968

RÉSUMÉ

This work is aimed at studying the drug delivery applications of iron oxide (Fe3O4) nanoparticles with strontium (Sr) doping with varying molar ratios prepared by the co-precipitation route. The impact of increased strontium content on the particle size and magnetic properties was investigated. The impending of these nanoparticles for drug loading, drug release, and their respective cytotoxicity was also inspected.First, iron oxide nanoparticles were doped with various amounts of strontium, from 0.25, 0.50, and 0.75, to 1 mol using co-precipitation method. These synthesized nanoparticles were characterized by XRD, SEM, EDX, VSM, and FTIR for evaluating crystal structure, phase purity, morphology, composition, magnetic properties, and functional groups, respectively. Drug loading and drug release properties were determined using UV-vis spectroscopy, whereas MTT assay evaluated cytotoxicity. Colloidal stability was assessed using zeta potential in PBS solution.The findings confirmed the successful doping of iron oxide with strontium via XRD and EDX. SEM results confirmed spherical morphology for all and needle-like structure for 1 mol strontium doped sample. For VSM results, a single domain structure was established. It was also observed that the drug encapsulation efficiency increases with increased strontium content. Cytotoxicity results by MTT assay revealed increased cytotoxicity with increasing nanoparticle concentration, and ibuprofen-loaded nanoparticles showed higher cytotoxicity than un-loaded nanoparticles at the same concentration. Zeta potential results showed colloidal stability of iron oxide nanoparticles increased by the addition of strontium.This study provided predominantly comparison of the cytotoxicity of ibuprofen-loaded and non-loaded nanoparticles on Hep-2 cancer cells at similar concentrations for the first time for both Fe3O4 particles and Sr-doped Fe3O4 nanoparticles and enclosed the impact of increasing Sr doping content on Fe3O4 nanoparticles.


Sujet(s)
Nanoparticules de magnétite , Nanoparticules , Ibuprofène , Nanoparticules de magnétite/composition chimique , Systèmes de délivrance de médicaments , Composés du fer III/composition chimique , Nanoparticules/composition chimique
8.
Haematologica ; 109(4): 1046-1052, 2024 Apr 01.
Article de Anglais | MEDLINE | ID: mdl-37560812

RÉSUMÉ

Clinical trial eligibility criteria can unfairly exclude patients or unnecessarily expose them to known risks if criteria are not concordant with drug safety. There are few data evaluating the extent to which acute leukemia eligibility criteria are justified. We analyzed criteria and drug safety data for front-line phase II and/or III acute leukemia trials with start dates 1/1/2010-12/31/2019 registered on clinicaltrials.gov. Multivariable analyses assessed concordance between criteria use and safety data (presence of criteria with a safety signal, or absence of criteria without a signal), and differences between criteria and safety-based limits. Of 250 eligible trials, concordant use of ejection fraction criteria was seen in 34.8%, corrected QT level (QTc) in 22.4%, bilirubin in 68.4%, aspartate transaminase/alanine aminotransferase (AST/ALT) in 58.8%, renal function in 68.4%, human immunodeficiency virus (HIV) in 54.8%, and hepatitis B and C in 42.0% and 41.2%. HIV and hepatitis B and C criteria use was concordant with safety data (adjusted Odds Ratios 2.04 [95%CI: 1.13, 3.66], 2.64 [95%CI: 1.38, 5.04], 2.27 [95%CI: 1.20, 4.32]) but organ function criteria were not (all P>0.05); phase III trials were not more concordant. Bilirubin criteria limits were the same as safety-based limits in 16.0% of trials, AST/ALT in 18.1%, and renal function in 13.9%; in 75.7%, 51.4%, and 56.5% of trials, criteria were more restrictive, respectively, by median differences of 0.2, 0.5, and 0.5 times the upper limits of normal. We found limited drug safety justifications for acute leukemia eligibility criteria. These data define criteria use and limits that can be rationally modified to increase patient inclusion and welfare.


Sujet(s)
Infections à VIH , Hépatite B , Leucémies , Humains , Bilirubine , Maladie aigüe , Leucémies/diagnostic , Leucémies/traitement médicamenteux
10.
Ann Surg Oncol ; 30(10): 5965-5973, 2023 Oct.
Article de Anglais | MEDLINE | ID: mdl-37462826

RÉSUMÉ

BACKGROUND: There is no consensus on the use of postoperative antibiotic prophylaxis (PAP) after mastectomy with indwelling drains. We explored the utility of continued PAP in reducing surgical site infection (SSI) rates after mastectomy without immediate reconstruction and with indwelling drains. PATIENTS AND METHODS: A multicenter, two-armed, randomized control superiority trial was conducted in Pakistan. We enrolled all consenting adult patients undergoing mastectomy without immediate reconstruction. All patients received a single preoperative dose of cephalexin within 60 min of incision, and postoperatively were randomized to receive either continued PAP using cephalexin (intervention) or a placebo (control) for the duration of indwelling, closed-suction drains. The primary outcome was the development of SSI within 30 days and 90 days postoperatively. Secondary outcomes included study-drug-associated adverse events. Intention-to-treat analysis was performed using multivariable Cox regression. RESULTS: A total of 369 patients, 180 (48.8%) in the intervention group and 189 (51.2%) in the control group, were included in the final analysis. Overall cumulative SSI rates were 3.5% at 30 days and 4.6% at 90 days postoperatively. PAP was not associated with SSI reduction at 30 (hazard ratio, HR 1.666 [95% confidence interval CI 0.515-5.385]) or 90 (1.575 [0.558-4.448]) days postoperatively, or with study-drug-associated adverse effects (0.529 [0.196-1.428]). CONCLUSIONS: Continuing antibiotic prophylaxis for the duration of indwelling drains after mastectomy without immediate reconstruction offers no additional benefit in terms of SSI reduction. There is a need to update existing guidelines to provide clearer recommendations regarding use of postoperative antibiotic prophylaxis after mastectomy in the setting of indwelling drains.


Sujet(s)
Antibioprophylaxie , Mastectomie , Infection de plaie opératoire , Humains , Infection de plaie opératoire/épidémiologie , Infection de plaie opératoire/prévention et contrôle , Méthode en double aveugle , Pakistan , Soins postopératoires , Résultat thérapeutique , Femelle , Adulte , Adulte d'âge moyen , Sujet âgé
11.
Nat Chem Biol ; 19(2): 239-250, 2023 02.
Article de Anglais | MEDLINE | ID: mdl-36229686

RÉSUMÉ

Membrane lipids control the cellular activity of kinases containing the Src homology 2 (SH2) domain through direct lipid-SH2 domain interactions. Here we report development of new nonlipidic small molecule inhibitors of the lipid-SH2 domain interaction that block the cellular activity of their host proteins. As a pilot study, we evaluated the efficacy of lipid-SH2 domain interaction inhibitors for spleen tyrosine kinase (Syk), which is implicated in hematopoietic malignancies, including acute myeloid leukemia (AML). An optimized inhibitor (WC36) specifically and potently suppressed oncogenic activities of Syk in AML cell lines and patient-derived AML cells. Unlike ATP-competitive Syk inhibitors, WC36 was refractory to de novo and acquired drug resistance due to its ability to block not only the Syk kinase activity, but also its noncatalytic scaffolding function that is linked to drug resistance. Collectively, our study shows that targeting lipid-protein interaction is a powerful approach to developing new small molecule drugs.


Sujet(s)
Leucémie aigüe myéloïde , Protein-tyrosine kinases , Humains , Protein-tyrosine kinases/métabolisme , Protéines et peptides de signalisation intracellulaire/métabolisme , Projets pilotes , Domaine d'homologie SRC , Phosphorylation , Leucémie aigüe myéloïde/traitement médicamenteux , Lipides , Syk kinase/métabolisme
12.
Front Plant Sci ; 13: 1064569, 2022.
Article de Anglais | MEDLINE | ID: mdl-36531405

RÉSUMÉ

Terminal heat stress during reproductive stage in wheat (Triticum aestivum L.) causes pollen grain sterility and has a drastic impact on wheat crop production. Finding genotypes with high pollen viability under heat stress is crucial to cope with the impact of climate change through developing heat-tolerant cultivars. To assess the effect of terminal heat stress on pollen viability in a panel of spring wheat genotypes (N = 200), RCBD (randomized complete block design) field trials were conducted under normal and heat stress conditions for two consecutive years (2020-2021 and 2021-2022). Analysis of variance showed significant variation in genotypes, treatments, and genotype × treatment interaction. Fifty and 46 genotypes were categorized as heat tolerant (HSI pv < 0.5) in the first and second year, respectively. Twelve genotypes, namely, Chenab-70, Pari-73, Pak-81, MH-21, Punjab-76, NIFA-Aman, NUWYT-63, Swabi-1, Nisnan-21, Frontana, Amin-2000, and Pirsabak-2004, were found to be heat tolerant across the years. The violin plot displayed a trend of improvement in heat tolerance (HSI pv < 0.5) over the period of time in many modern wheat varieties. However, some modern wheat varieties released after 2001 such as Janbaz-09 (57%), Ghazi-2019 (57%), and Sindhu-16 (43%) had very low pollen viability under heat stress conditions. The results of phenotypic coefficient of variance (PCV%), genotypic coefficient of variance (GCV%), broad sense heritability (h2 bs), and genetic advance (GA) suggested the major contribution of genetic factors in controlling pollen viability trait. Higher values of h2 bs and GA under heat stress conditions suggested pollen viability as a heat tolerance trait controlled by additive genetic effects. Taken together, these results suggested pollen viability as a useful trait for selection in early generations under elevated temperatures. The genotypes identified as heat tolerant in both years can be used as genetic resources for breeding cultivars with higher pollen viability under elevated temperature conditions.

14.
Blood ; 139(14): 2212-2226, 2022 04 07.
Article de Anglais | MEDLINE | ID: mdl-35061876

RÉSUMÉ

Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.


Sujet(s)
Leucémie aigüe myéloïde , Racisme systémique , Adulte , Ethnies , Disparités de l'état de santé , Hispanique ou Latino , Humains , Leucémie aigüe myéloïde/thérapie ,
15.
J Child Adolesc Trauma ; 14(4): 483-491, 2021 Dec.
Article de Anglais | MEDLINE | ID: mdl-34790282

RÉSUMÉ

Child maltreatment has been identified as a significant problem, both within India and outside. According to UNICEF, over the last decade, there has been a growing recognition about this, but the problem has remained unresolved largely due to being underreported and undocumented. Previous research in this area has reported inconsistent gender differences across the world. Besides, there are shreds of evidence to suggest that childhood maltreatment would be associated with nightmares later in life, but a handful of studies exist in this context. Moreover, there is a paucity of research concerning the interaction effect of gender and group (nightmare sufferer vs non-sufferer) on childhood maltreatment. Owing to the insufficient research and inconsistent findings, the present study aimed to investigate gender differences in childhood maltreatment among nightmare sufferers as compared to non-sufferers. A total of 120 participants were selected from New Delhi. The results of two-way ANOVA suggest that the nightmares later in life would be associated with the abuse and neglect experienced during childhood as nightmare sufferer group reported having higher rates of child abuse and neglect than non-sufferers. It also suggests that male participants in general experience childhood maltreatment more than females; however, emotional abuse was experienced by males only if they belonged to the nightmare sufferer group.

16.
Cureus ; 13(6): e15905, 2021 Jun.
Article de Anglais | MEDLINE | ID: mdl-34336418

RÉSUMÉ

INTRODUCTION: Job satisfaction is vital for the optimal functioning of medical practitioners. Herein, we report our experience of restructuring the internship program by identifying the gaps, developing, implementing strategies to overcome gaps and sharing the results of the pre-implementation and post-implementation audit, as an example for establishing a system for improving intern's work-based learning and satisfaction in a university hospital setting. METHODS: Using Kern's six-step instructional model, a prospective mixed-method study was conducted at Aga Khan University Hospital. In phase 1 (2013) gaps were identified by evaluating various aspects of the internship program. Strategies were developed and implemented to overcome the identified gaps. In phase 2 (2014-2016) the impact of these developmental strategies was assessed. RESULTS: A total of 65 interns, 30 residents, and 22 faculty members participated in phase I, while 71 interns participated in phase II. The reformation of orientation sessions, including practical exposure and content of sessions, opportunities to enhance hands-on experience and supervision in inpatient areas, operating rooms, supervision by fellows, supervision for hands-on procedures, career counseling, and mentorship, led to significant improvement in satisfaction. It was identified that the lack of hands-on opportunities can be overcome by surgical skills-based workshops. These reforms led to an overall rise in intern satisfaction (50% vs 75.4%, p=0.02). CONCLUSION: Periodic restructuring of an existing program helps to improve the work-based learning experience and overall satisfaction among interns. This not only maximizes learning but also eases interns into their postgraduate life and workload subsequently enabling them to become more competent and well-rounded health practitioners.

17.
Front Oncol ; 11: 696532, 2021.
Article de Anglais | MEDLINE | ID: mdl-34381718

RÉSUMÉ

Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.

18.
Cell Death Dis ; 12(7): 704, 2021 07 14.
Article de Anglais | MEDLINE | ID: mdl-34262016

RÉSUMÉ

FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.


Sujet(s)
Antinéoplasiques/pharmacologie , Autophagie/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Protéine M1 à motif en tête de fourche/antagonistes et inhibiteurs , Analyse de profil d'expression de gènes , Tumeurs/traitement médicamenteux , Lignée cellulaire tumorale , Protéine M1 à motif en tête de fourche/génétique , Protéine M1 à motif en tête de fourche/métabolisme , Régulation de l'expression des gènes tumoraux , Réseaux de régulation génique , Humains , Tumeurs/génétique , Tumeurs/métabolisme , Tumeurs/anatomopathologie , Stabilité protéique , Transport des protéines , Protéolyse , RNA-Seq , Transcriptome
19.
J Clin Oncol ; 39(29): 3261-3272, 2021 10 10.
Article de Anglais | MEDLINE | ID: mdl-34156898

RÉSUMÉ

PURPOSE: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.


Sujet(s)
Leucémie aigüe myéloïde/traitement médicamenteux , Progéniteurs myéloïdes/transplantation , Adulte , Sujet âgé , Antifongiques/usage thérapeutique , Femelle , Facteur de stimulation des colonies de granulocytes/usage thérapeutique , Humains , Chimiothérapie d'induction , Mâle , Adulte d'âge moyen , Granulocytes neutrophiles/physiologie , Études prospectives
20.
Cancer Causes Control ; 32(7): 705-712, 2021 Jul.
Article de Anglais | MEDLINE | ID: mdl-33837498

RÉSUMÉ

PURPOSE: Racial disparities in acute myeloid leukemia (AML) have been reported but the relative contribution of disease versus patient-specific factors including comorbidities and access to care is unclear. METHODS: We conducted a retrospective analysis of patient characteristics, treatment patterns and outcomes in a racially diverse patient cohort controlling for cytogenetic risk group. Patients were classified into four groups: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and Other. RESULTS: We evaluated 106 patients from 84 zipcodes incorporating demographics, clinicopathologic features, treatment patterns and outcomes. We identified significant differences in BMI and geographic poverty based on ethnoracial group, while prognostic mutations in NPM1 and FLT3 did not differ significantly. Utilization of intensive chemotherapy and transplant rate did not differ by ethnoracial group. However, there was a significantly higher use of alternate donor transplants in minority populations. There was a notably increased rate of clinical trial enrollment in NHW patients compared to other groups. In log-rank analysis, NHW patients had increased overall survival (OS) compared to NHB, Hispanic and Other patients (31.6 months vs. 16.7 months vs. 14.3 months, vs 18.1 months, p = 0.021). In bivariate analysis, overall survival was negatively influenced by advanced age and race. Obesity and zip code poverty levels approached statistical significance in predicting OS. In multivariate analysis, the only factors independently influencing OS were race and allogeneic stem cell transplant. CONCLUSION: These results suggest that race impacts survival in intermediate-risk AML, highlighting the need to dissect biologic and nonbiologic factors that contribute to this disparity.


Sujet(s)
/statistiques et données numériques , Hispanique ou Latino/statistiques et données numériques , Leucémie aigüe myéloïde/mortalité , Évaluation des résultats des patients , /statistiques et données numériques , Adulte , Sujet âgé , Allogreffes , Marqueurs biologiques tumoraux/génétique , Études de cohortes , Humains , Leucémie aigüe myéloïde/ethnologie , Leucémie aigüe myéloïde/thérapie , Mâle , Adulte d'âge moyen , Minorités/statistiques et données numériques , Mutation , Nucléophosmine , Études rétrospectives , Facteurs de risque , Analyse de survie , Résultat thérapeutique
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