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Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.
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Untreated release of toxic synthetic and colorful dyes is a serious threat to the environment. Every year, several thousand gallons of dyes are being disposed into the water resources without any sustainable detoxification. The accumulation of hazardous dyes in the environment poses a severe threat to the human health, flora, fauna, and microflora. Therefore, in the present study, a lignin peroxidase enzyme from Pseudomonas fluorescence LiP-RL5 has been employed for the maximal detoxification of selected commercially used dyes. The enzyme production from the microorganism was enhanced ~ 20 folds using statistical optimization tool, response surface methodology. Four different combinations (pH, production time, seed age, and inoculum size) were found to be crucial for the higher production of LiP. The crude enzyme showed decolorization action on commonly used commercial dyes such as Crystal violet, Congo red, Malachite green, and Coomassie brilliant blue. Successful toxicity mitigation of these dyes culminated in the improved seed germination in three plant species, Vigna radiate (20-60%), Cicer arietinum (20-40%), and Phaseolus vulgaris (10-25%). The LiP treated dyes also exhibit reduced bactericidal effects against four common resident microbial species, Escherichia coli (2-10 mm), Bacillus sp. (4-8 mm), Pseudomonas sp. (2-8 mm), and Lactobacillus sp. (2-10 mm). Therefore, apart from the tremendous industrial applications, the LiP from Pseudomonas fluorescence LiP-RL5 could be a potential biocatalyst for the detoxification of synthetic dyes.
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BACKGROUND: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell (PBSC) transplantation for non-Hodgkin lymphoma (NHL). Prior studies report an association between clonal hematopoiesis (CH) in PBSC and risk of t-MN, but small samples precluded examination of risk within specific sub-populations. METHODS: Targeted DNA sequencing was performed to identify CH mutations in PBSC from a retrospective cohort of 984 NHL patients (median age at transplant 57y; range: 18-78). Fine-Gray proportional subdistribution hazard regression models estimated association between number of CH mutations and t-MN, adjusting for demographic, clinical, and therapeutic variables. Secondary analyses evaluated association between CH and t-MN among males and females. RESULTS: CH was identified in PBSC from 366 patients (37.2%). t-MN developed in 60 patients after median follow-up of 5y. Presence of ≥2 mutations conferred increased t-MN risk (adjusted hazard ratio [aHR]=2.10, 95% confidence interval [CI]=1.08-4.11, p=0.029). CH was associated with increased t-MN risk among males (aHR=1.83, 95%CI=1.01-3.31) but not females (aHR=0.56, 95%CI=0.15-2.09). Although prevalence and type of CH mutations in PBSC was comparable, the 8y cumulative incidence of t-MN was higher among males vs. females with CH (12.4% vs. 3.6%) but was similar between males and females without CH (4.9% vs. 3.9%). Expansion of CH clones from PBSC to t-MN was seen only among males. CONCLUSIONS: Presence of CH mutations in PBSC confers increased risk of t-MN after autologous transplantation in male but not female patients with NHL. Factors underlying sex-based differences in risk of CH progression to t-MN merit further investigation.
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BCL-2 inhibitors such as venetoclax offer therapeutic promise in acute myeloid leukemia (AML) and other cancers, but drug resistance poses a significant challenge. It is crucial to understand the mechanisms that regulate venetoclax response. While correlative studies have identified numerous genes linked to venetoclax sensitivity, their direct impact on the drug response remains unclear. In this study, we targeted around 1400 genes upregulated in venetoclax-sensitive primary AML samples and carried out a CRISPR knockout screen to evaluate their direct effects on venetoclax response. Our screen identified the transcription factor ZNF740 as a critical regulator, with its expression consistently predicting venetoclax sensitivity across subtypes of the FAB classification. ZNF740 depletion leads to increased resistance to ventoclax, while its overexpression enhances sensitivity to the drug. Mechanistically, our integrative transcriptomic and genomic analysis identifies NOXA as a direct target of ZNF740, which negatively regulates MCL-1 protein stability. Loss of ZNF740 downregulates NOXA and increases the steady state protein levels of MCL-1 in AML cells. Restoring NOXA expression in ZNF740-depleted cells re-sensitizes AML cells to venetoclax treatment. Furthermore, we demonstrated that dual targeting of MCL-1 and BCL-2 effectively treats ZNF740-deficient AML in vivo. Together, our work systematically elucidates the causal relationship between venetoclax response signature genes and establishes ZNF740 as a novel transcription factor regulating venetoclax sensitivity.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Sulfonamidas/farmacología , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Animales , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Ratones , Resistencia a Antineoplásicos/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Sistemas CRISPR-Cas/genéticaRESUMEN
Melanin is a complex brown pigment, primarily responsible for the skin pigmentation. Therefore, cosmetic industries have always been in search of potent oxidative enzymes useful for melanin degradation, and to promise a fair complexion after using their products. In the present study, lignin peroxidase from Pseudomonas fluorescence LiP-RL5 isolate has been immobilized on super-paramagnetic nanoparticles to enhance its stability and reusability. The chitosan coated enzyme-nanomaterial complex (LiP@MFO-Chit) showed higher melanin decolorization (47.30 ± 2.3 %) compared to the graphene oxide coated nanoparticles (LiP@MFO-GO) (41.60 ± 1.6 %). Synthesized enzyme nanoparticle complexes showed microbicidal effect on skin infection causing pathogen, Pantoea agglomerans with an inhibitory zone of 6.0 ± 0.9 mm and 250 µg/100 µl minimum inhibitory concentration, and a 7.0 ± 1.5 mm zone and 170 µg/100 µl MIC for LiP@MFO-GO and LiP@MFO-Chit, respectively. Antioxidant potential of LiP@MFO-Chit and LiP@MFO-GO nano-conjugates showed a substantial DPPH scavenging activity of 75.7 % and 88.3 %, respectively. Therefore, LiP-nanoparticle hybrid complexes analyzed in this study are not only effective as skin whitening agents but they are potential molecules against various microbial skin infections as well as useful for different other biomedical applications like biorefinery, drug delivery, and dermatology, etc.
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Relapse remains a major cause of treatment failure following allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We retrospectively investigated low-dose decitabine and venetoclax (DEC/VEN) as post-transplant maintenance in 26 older patients with AML and MDS. The cumulative incidence of day 100 gIII-IV acute graft versus host disease (GVHD) and 1-year moderate-severe chronic GVHD was 5% and 26%, respectively. One patient relapsed 14 m after transplant. The 1-year non-relapse mortality and survival were 11% and 84%, respectively. DEC/VEN is a safe and potentially effective strategy to reduce the risk of post-transplant relapse.
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With the discovery of tyrosine kinase inhibitors (TKIs), overall survival in patients with chronic myeloid leukemia (CML) now approaches that of the general population. While these TKIs have proven to be lifesaving, remaining on them lifelong creates both physical and financial burdens for patients. Recently, multiple trials have begun looking into the efficacy of trialing patients off these TKIs to see if they can sustain treatment-free remission (TFR). TFR eligibility is currently limited to a small population of patients with both robust and sustained responses to TKIs. Currently, for those who attempt a trial of TFR, the average success rates are promising, with anywhere from 38 to 54% of patients experiencing sustained TFR. For those who fail to maintain sustained TFR, safety results to date are reassuring, with almost all patients successfully responding to the re-initiation of TKIs, with death and disease progression being very rare complications. Moving forward, research is being conducted to more accurately risk stratify patients at diagnosis and pair them with optimized upfront treatment regimens aimed at increasing candidacy for the trial of TFR.
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Heavy metal pollution is a significant global health concern, posing risks to both the environment and human health. Exposure to heavy metals happens through various channels like contaminated water, food, air, and workplaces, resulting in severe health implications. Heavy metals also disrupt the gut's microbial balance, leading to dysbiosis characterized by a decrease in beneficial microorganisms and proliferation in harmful ones, ultimately exacerbating health problems. Probiotic microorganisms have demonstrated their ability to adsorb and sequester heavy metals, while their exopolysaccharides (EPS) exhibit chelating properties, aiding in mitigating heavy metal toxicity. These beneficial microorganisms aid in restoring gut integrity through processes like biosorption, bioaccumulation, and biotransformation of heavy metals. Incorporating probiotic strains with high affinity for heavy metals into functional foods and supplements presents a practical approach to mitigating heavy metal toxicity while enhancing gut health. Utilizing probiotic microbiota and their exopolysaccharides to address heavy metal toxicity offers a novel method for improving human health through modulation of the gut microbiome. By combining probiotics and exopolysaccharides, a distinctive strategy emerges for mitigating heavy metal toxicity, highlighting promising avenues for therapeutic interventions and health improvements. Further exploration in this domain could lead to groundbreaking therapies and preventive measures, underscoring probiotic microbiota and exopolysaccharides as natural and environmentally friendly solutions to heavy metal toxicity. This, in turn, could enhance public health by safeguarding the gut from environmental contaminants.
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BACKGROUND: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. OBJECTIVES: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients. METHODS: We examined plasma levels of activators, inhibitors, and biomarkers of the coagulation and fibrinolytic pathways in patients aged ≥18 years with newly diagnosed acute leukemia compared with those of normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 with acute promyelocytic leukemia [APL], 253 with non-APL acute myeloid leukemia, and 76 with acute lymphoblastic leukemia) and 30 normal controls. RESULTS: Patients with acute leukemia had higher levels of extracellular vesicle tissue factor (EVTF) activity, phosphatidylserine-positive extracellular vesicles, plasminogen activator inhibitor-1, plasmin-antiplasmin complexes, and cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared with normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 23 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (subdistribution hazard ratio, 2.30; 95% CI, 0.99-5.31), whereas high levels of plasminogen activator inhibitor-1 were associated with increased risk of DVT (subdistribution hazard ratio, 3.00; 95% CI, 0.95-9.47) in these patients. CONCLUSION: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT.
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Biomarcadores , Coagulación Sanguínea , Hemorragia , Leucemia Mieloide Aguda , Tromboembolia Venosa , Humanos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Hemorragia/sangre , Hemorragia/diagnóstico , Tromboembolia Venosa/sangre , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiología , Biomarcadores/sangre , Estudios de Casos y Controles , Anciano , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Factores de Riesgo , Leucemia Promielocítica Aguda/sangre , Leucemia Promielocítica Aguda/complicaciones , Trombosis de la Vena/sangre , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/etiología , Histonas/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Tromboplastina/metabolismo , Tromboplastina/análisis , Adulto Joven , Fosfatidilserinas/sangreRESUMEN
PURPOSE: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available. METHODS: We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients. RESULTS: CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of DNMT3A (n = 25), PPM1D (n = 7), TET2 (n = 7), and TP53 (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSC product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without co-occurring TP53 or PPM1D mutations) did. Presence of TP53 and/or PPM1D mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality. CONCLUSION: The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.
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Hematopoyesis Clonal , Enfermedad de Hodgkin , Mutación , Neoplasias Primarias Secundarias , Trasplante Autólogo , Humanos , Enfermedad de Hodgkin/terapia , Enfermedad de Hodgkin/genética , Adulto , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adolescente , Trasplante Autólogo/efectos adversos , Hematopoyesis Clonal/genética , Adulto Joven , Anciano , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiología , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Proteína p53 Supresora de Tumor/genética , ADN Metiltransferasa 3A , Proteína Fosfatasa 2C/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Dioxigenasas , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
We examined the prevalence, risk factors, and association between pre-frailty and subsequent mortality after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 3346 individuals who underwent BMT between 1974 and 2014 at one of three transplant centers and survived ≥2 years post-BMT. Participants completed the BMTSS survey at a median of 9 years from BMT and were followed for subsequent mortality for a median of 5 years after survey completion. Closest-age and same-sex biological siblings also completed the survey. Previously published self-reported indices (exhaustion, weakness, low energy expenditure, slowness, unintentional weight loss) classified participants as non-frail (0-1 indices) or pre-frail (2 indices). National Death Index was used to determine vital status and cause of death. Overall, 626 (18.7%) BMT survivors were pre-frail. BMT survivors had a 3.2-fold higher odds of being pre-frail (95% CI = 1.9-5.3) compared to siblings. Compared to non-frail survivors, pre-frail survivors had higher hazards of all-cause mortality (adjusted hazard ratio [aHR] = 1.6, 95% CI = 1.4-2.0). Female sex, pre-BMT radiation, smoking, lack of exercise, anxiety, and severe/life-threatening chronic health conditions were associated with pre-frailty. The novel association between pre-frailty and subsequent mortality provides evidence for interventions as pre-frail individuals may transition back to their robust state.
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Trasplante de Médula Ósea , Fragilidad , Humanos , Masculino , Femenino , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/mortalidad , Fragilidad/mortalidad , Persona de Mediana Edad , Factores de Riesgo , Anciano , Adulto , Sobrevivientes , Estudios de Seguimiento , Tasa de Supervivencia , Adulto Joven , AdolescenteRESUMEN
In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3â¯mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.
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Anticuerpos Monoclonales Humanizados , Leucemia Mieloide Aguda , Humanos , Gemtuzumab/uso terapéutico , Quimioterapia de Inducción , Estudios Retrospectivos , Supervivencia sin Enfermedad , Citarabina , Aminoglicósidos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Respuesta Patológica Completa , Factores de Unión al Sitio PrincipalRESUMEN
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Humanos , Crisis Blástica/inducido químicamente , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Cromosoma Filadelfia , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Proteínas de Fusión bcr-abl/genéticaRESUMEN
Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Animales , Ratones , Humanos , Médula Ósea/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide/patología , Cromosoma Filadelfia , Macrófagos/metabolismo , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Microambiente Tumoral/genéticaRESUMEN
We determined the risk of late morbidity and mortality after autologous blood or marrow transplantation (BMT) for lymphoma performed before age 40. The cohort included autologous BMT recipients who had survived ≥2 years after transplantation (N = 583 [HL = 59.9%; NHL = 40.1%]) and a comparison cohort (N = 1070). Participants self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Logistic regression estimated the odds of grade 3-4 conditions in survivors vs. comparison subjects. Proportional subdistribution hazards models identified predictors of grade 3-5 conditions among BMT recipients. Median age at BMT was 30.0 years (range: 2.0-40.0) and median follow-up was 9.8 years (2.0-32.1). Survivors were at a 3-fold higher adjusted odds for grade 3-4 conditions (95% CI = 2.3-4.1) vs. comparison subjects. Factors associated with grade 3-5 conditions among BMT recipients included age at BMT (>30 years: adjusted hazard ratio [aHR] = 2.31; 95% CI = 1.27-4.19; reference: ≤21 years), pre-BMT radiation (aHR = 1.52; 95% CI = 1.13-2.03; reference: non-irradiated), and year of BMT (≥2000: aHR = 0.54; 95% CI = 0.34-0.85; reference: <1990). The 25 years cumulative incidence of relapse-related and non-relapse-related mortality was 18.2% and 25.9%, respectively. The high risk for late morbidity and mortality after autologous BMT for lymphoma performed at age <40 calls for long-term anticipatory risk-based follow-up.
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Trasplante de Médula Ósea , Linfoma , Niño , Humanos , Adolescente , Adulto Joven , Adulto , Trasplante de Médula Ósea/efectos adversos , Médula Ósea , Recurrencia Local de Neoplasia , Linfoma/terapia , Trasplante Autólogo/efectos adversos , MorbilidadRESUMEN
BACKGROUND: Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long-term BMT survivors were evaluated. METHODS: Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2 years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT-related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records. RESULTS: In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%-53% had undergone routine checkups, 37%-38% reported BMT-related visits, and 28%-29% reported transplant/cancer center visits. The presence of severe/life-threatening conditions and chronic graft-vs-host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization. CONCLUSIONS: This study identified vulnerable populations of long-term BMT survivors who would benefit from specialized risk-based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations.
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Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Humanos , Adolescente , Adulto , Trasplante de Médula Ósea , Sobrevivientes , Enfermedad Crónica , Aceptación de la Atención de SaludRESUMEN
Background: Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. Objectives: To evaluate the associations between biomarker levels and bleeding and VTE in acute leukemia patients. Patients/Method: We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to healthy controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and VTE in acute leukemia patients. The study included 358 patients with acute leukemia (29 acute promyelocytic leukemia [APL], 253 non-APL acute myeloid leukemia [AML] and 76 acute lymphoblastic leukemia [ALL]), and 30 healthy controls. Results: Patients with acute leukemia had higher levels of extracellular vesicle (EV) tissue factor (TF) activity, phosphatidylserine-positive EVs, plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes, cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared to healthy controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among the acute leukemia patients. There were 41 bleeding and 37 VTE events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (sHR 2.30, 95%CI 0.99-5.31) whereas high PAI-1 was associated with increased risk of VTE (sHR 3.79, 95%CI 1.40-10.28) in these patients. Conclusions: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and VTE.
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Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.