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The Glasgow prognostic score (GPS) and CAR-HEMATOTOX (CAR-HT) score identify multiple myeloma (MM) patients at high risk for immune-mediated toxicity and early mortality with cellular immunotherapy. However, their association with outcomes in patients receiving T-cell redirecting bispecific antibodies (bsAb) is unclear. This multi-centre retrospective study examines the association of baseline GPS and CAR-HT scores with outcomes in 126 MM patients treated with bsAb. Overall, 19% were identified as GPS high risk but did not experience increased toxicity or mortality. Conversely, high-risk CAR-HT patients had a higher incidence of infections and inferior survival, suggesting a need for aggressive infection mitigation strategies.
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PURPOSE: Novel agents such as PI3K and mTOR inhibitors (PI3K/mTORi) have expanded treatment options in metastatic breast cancer (MBC). Nevertheless, mortality rates remain disproportionately high for Black patients and patients with lower socioeconomic status. Furthermore, clinical trials for these novel agents lacked diversity, so their toxicity profile in minority populations is uncertain. METHODS: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database for patients with HR+, HER2- MBC. Multivariable logistic regression was used to evaluate factors associated with PI3K/mTORi use and toxicity outcomes. RESULTS: A total of 9169 patients with MBC were included in our analysis, of which 1780 (19.4%) received a PI3K/mTORi. We estimated the conditional total effect of insurance through Medicaid, and found lower odds of use of PI3K/mTORi among patients on Medicaid compared to those with commercial insurance (OR 0.73, 95% CI 0.54-0.99, p = 0.049). Odds of PI3K/mTORi use were higher for patients treated at an academic center (OR 1.28, CI 1.06-1.55, p = 0.01). Modeled as a controlled direct effect, Black/African American (Black/AA) race had no impact on odds of PI3K/mTOR use. Black/AA patients had twice the odds of developing hyperglycemia on PI3K/mTORi compared to White patients (OR 2.02, CI 1.24-3.39, p < 0.01). CONCLUSION: This analysis of real-world data suggests that the use of PI3K/mTORi is influenced by socioeconomic factors. We also found racial disparities in toxicity outcomes, with Black/AA patients having twice the risk of hyperglycemia. Our findings call for greater efforts to ensure access to novel treatments and improve their tolerability in diverse populations.
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Neoplasias da Mama , Inibidores de MTOR , Inibidores de Fosfoinositídeo-3 Quinase , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Idoso , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Estudos Retrospectivos , Inibidores de MTOR/uso terapêutico , Disparidades em Assistência à Saúde/estatística & dados numéricos , Adulto , Metástase Neoplásica , Resultado do Tratamento , Serina-Treonina Quinases TOR/antagonistas & inibidores , Estados Unidos/epidemiologiaRESUMO
Many of the daily systemic medications (parenteral and oral) used to treat various diseases are known to cause ocular toxicities - leading to vision loss. How these medications gain entry into the eye despite the ocular barriers is an important question to be addressed. Various reports show almost 30-40 % of systemic drugs causing ocular toxicity are organic cation in nature. We hypothesize these systemic drugs (cations) are non-specifically recognized as endogenous substrates by organic cation transporter (OCT1) in the lacrimal gland, thereby facilitating its entry into the anterior eye segment. Therefore, we studied the expression and localization of OCT1 in the lacrimal gland of rabbits. Further, to prove our hypothesis, OCT1 substrates (known as well as predicted from our previous Artificial Intelligence study) were administered intravenously in the presence and absence of topically administered OCT1 blockers. Our findings show, OCT1 gene and protein expression in the lacrimal gland, with its localization in the terminal acinar cells. The tear levels of intravenously administered substrates decreased in the presence of topical OCT1 blockers, indicating - a) the entry of systemic drugs into the eye via lacrimal secretion and b) OCT1 in the lacrimal gland is involved in the drug transport (substrates) from blood to the eye. Though the role of transporters in toxicity is well-known, the current study opens a new avenue for understanding the role of transporters in ocular toxicity.
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This study examines perceived source credibility of health information in a moment of TGD health disinformation. Through thematic analysis of in-depth interviews with 30 transgender and gender diverse (TGD) individuals, findings suggest health information is marred by anti-TGD legislation, a sociopolitical force that bleeds into health information spaces. Disinformation and TGD health communication are intertwined in complex ways, whereby disinformation can undermine trust in healthcare institutions, lead to harmful behaviors, and contribute to the spread of diseases. Health communication practitioners need to center the safety and humanity of TGD people, addressing TGD health disinformation.
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Comunicação em Saúde , Pessoas Transgênero , Confiança , Humanos , Feminino , Pessoas Transgênero/psicologia , Pessoas Transgênero/estatística & dados numéricos , Masculino , Comunicação em Saúde/métodos , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Pesquisa QualitativaRESUMO
Multi-level, place-based interventions have proven effective at promoting a range of health behaviors, including tobacco control and discouraging the uptake of tobacco products. This paper describes the implementation and impact of a 3-year, multi-level tobacco prevention and control program at a community-college minority-serving institution (MSI) on the Texas Gulf Coast within the context of a broader multi-sector, cross-functional health coalition. The intervention studied included a tobacco-free policy, a large-scale communication campaign highlighting parts of the intervention and prevention and cessation resources. The intervention was bolstered by the support of a community-led Steering Committee and tobacco control experts. Results from the first 3 years of implementation show that tobacco-free policies were largely supported by community members, awareness of the policy increased over time, and tobacco prevention and cessation resources were successfully embedded into campus norms. This multi-component approach shows how a community college was able to effectively reach students and staff on their campus to increase awareness of both the campus tobacco-free policy and the availability of tobacco prevention and cessation resources. Additionally, it also offers lessons for future tobacco prevention and control work in higher education.
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Grupos Minoritários , Texas , Humanos , Prevenção do Hábito de Fumar , Avaliação de Programas e Projetos de Saúde , Universidades , Feminino , Masculino , Adulto , Promoção da Saúde/organização & administração , Abandono do Hábito de Fumar , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Post-coronavirus disease (COVID) persistence of symptoms and the development of complications have become frequently encountered clinical problems due to multiple waves of the pandemic over the past 3 years across the world. Identifying risk factors would enable us to direct our limited resources toward the subgroups requiring long-term follow-up and treatment. With this prospective observational study, we aim to establish a statistical correlation between the persistence of symptoms and four of the most attributed risk factors for prolonged recovery: severity of acute illness, elderly age, presence of multiple comorbidities, and female gender in the Indian population. MATERIALS AND METHODS: Three hundred patients with positive COVID reverse transcription polymerase chain reaction (RTPCR) or antigen tests were enrolled over 10 months (from December 2020, after obtaining ethical clearance, to October 2021). Symptoms were recorded at baseline and followed up with a predesigned questionnaire to assess their persistence at 1-, 2-, and 4-month intervals post-COVID recovery. Appropriate statistical analysis [Pearson's correlation/analysis of variance (ANOVA) test] was used to establish the correlation between the persistence of symptoms and their severity with the presence of risk factors. RESULTS: Severity of acute illness was the single most important determining factor of persistence of symptoms as well as their severity in our study (p < 0.001) at each follow-up interval. The correlation observed between average number or severity of persistent symptoms increased with female gender, increasing age-group and presence of multiple comorbidities was not significant statistically (p > 0.05) with exception of persistent fatigue in females at 2-month interval. INTERPRETATION AND CONCLUSION: Persistent symptoms and its prevalence recorded so far represents tip of the iceberg of patients suffering with long COVID. Patients with history of severe acute illness should be followed up closely for prompt identification and rehabilitation of these cases as it had maximum bearing on the outcome of these patients.
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COVID-19 , Comorbidade , Índice de Gravidade de Doença , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índia/epidemiologia , Adulto , Fatores Etários , Fatores de Risco , Fatores Sexuais , Idoso , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Adulto JovemRESUMO
BACKGROUND: Survival outcomes in metastatic breast cancer (MBC) have improved due to novel agents such as CDK4/6 inhibitors (CDK4/6i). Nevertheless, Black patients and patients with lower socioeconomic status (SES) continue to bear a disproportionate mortality burden. METHODS: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database (FHD). A dataset was constructed to include Black/African-American (Black/AA) and White patients with hormone receptor (HR)-positive, HER2-negative MBC. Outcomes included CDK4/6i use (overall and first-line), and rates of leukopenia, dose reduction, and time on treatment for first-line CDK4/6i. Multivariable logistic regression was used to evaluate factors associated with use and outcomes. RESULTS: A total of 6802 patients with MBC were included, of which 5187 (76.3%) received CDK4/6i. Of those, 3186 (61.4%) received CDK4/6i first-line. Overall, 86.7% of patients were categorized as White and 13.3% as Black/AA; 22.4% were > 75 years old; 12.6% were treated at an academic site; 3.3% had Medicaid insurance. In addition to advanced age and poorer performance status, lower use of CDK4/6i was associated with Black/AA vs White race (72.9% vs 76.8%; OR 0.83, 95% CI 0.70-0.99, p = 0.04) and Medicaid vs commercial insurance (69.6% vs 77.4%; OR: 0.68, 95% CI 0.49-0.95, p = 0.02). Odds of CDK4/6i use were twofold higher for patients treated at an academic center (p < 0.001). Rates of CDK4/6i-induced leukopenia and dose reductions did not differ significantly by race, insurance type, or treatment site. Time on CDK4/6i was significantly lower among Medicaid patients (395 days) than patients with commercial insurance (558 days) or Medicare (643 days) (p = 0.03). CONCLUSION: This analysis of real-world data suggests that Black race and lower SES are associated with decreased CDK4/6i use. However, among patients treated with CDK4/6i, subsequent toxicity outcomes are similar. Efforts to ensure access to these life-prolonging medications are warranted.
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Neoplasias da Mama , Leucopenia , Estados Unidos/epidemiologia , Humanos , Idoso , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Medicare , Estudos Retrospectivos , Determinantes Sociais da Saúde , Quinase 4 Dependente de CiclinaRESUMO
The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.
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Imidazóis , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ciclização , AcilaçãoRESUMO
A 30-year-old, previously healthy adult male received equine rabies immunoglobulins (Ig) (ERIG) along with anti-rabies vaccinations as per protocol for postexposure prophylaxis after an unprovoked rabid dog bite of grade three wound over the shin of the left lower limb. On the 8th day, he developed urticarial rashes beginning from the site of the wound, which gradually became a widespread maculopapular rash. Development of the rash was followed by low-grade fever, nonspecific arthralgias and soreness in the throat. A diagnosis of serum sickness-like illness was made based on history, temporal correlation of administration of ERIG and development of symptoms. He responded well to antihistaminic and a short course of injectable steroids. The purpose of this article is to increase awareness regarding the clinical presentation and management of this rare yet potentially curable adverse event if identified timely.
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Imunoglobulinas , Raiva , Doença do Soro , Adulto , Animais , Cães , Humanos , Masculino , Mordeduras e Picadas/complicações , Mordeduras e Picadas/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Imunoglobulinas/uso terapêutico , Profilaxia Pós-Exposição/métodos , Raiva/tratamento farmacológico , Vacina Antirrábica/efeitos adversos , Vacina Antirrábica/uso terapêuticoRESUMO
PURPOSE: Bone pain is a common presenting symptom of multiple myeloma (MM) and is frequently treated with opioids in addition to myeloma directed therapy. With improved response and survival with modern myeloma therapy, it is important to re-examine the role of opioids in managing symptomatic myeloma. PATIENTS AND METHODS: We performed a retrospective analysis of patients with myeloma at Rutgers Cancer Institute of New Jersey (RCINJ) who received an ASCT between January 1, 2012, and December 30, 2017, and who had subsequent follow-up (a total of 138 patients). We sought information specifically from the visits after induction therapy but prior to ASCT, at 100 days and 1-year post-ASCT follow-up visits. We compared opioid users and non-users in relation to treatment response, co-morbid conditions, and symptoms. We also examined amounts, duration, and odds of continued opioid use. RESULTS: At the time of the first analysis (before transplant), 34.8% of patients were using opioids and opioid use was more frequent in younger patients and, as expected, in patients with bone lesions. At 1 year, 31.9% of patients were still using opioids and continued opioid use was not correlated with disease response. Of the patients using opioids at the time of transplant, 58% either maintained their opioid dose or increased it at 1-year post-transplant. CONCLUSIONS: This retrospective analysis shows that despite a small decrease in opioid use over time, opioid use remains frequent in MM patients and is correlated with younger age and bone involvement but not with response to therapy. Over half the patients using opioids at the time of transplant continued or increased opioid use over the following year. With increasing survival in myeloma patients, further attention is required to distinguish cancer pain from chronic pain in cancer patients.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Analgésicos Opioides/efeitos adversos , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Estudos Retrospectivos , Transplante AutólogoRESUMO
AIMS: Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. METHODS: Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK-based predictions with observed PK profiles. RESULTS: Predicted exposure (AUC0-6h ) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0-6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. CONCLUSION: A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure-response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.
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Indometacina , Modelos Biológicos , Feminino , Feto , Humanos , Indometacina/efeitos adversos , Recém-Nascido , Gravidez , Terceiro Trimestre da Gravidez , Trimestres da GravidezRESUMO
CONTEXT: Fatigue is the most prominent feature of long COVID. With the increasing burden of long COVID cases post-acute phase of illness after recurrent waves of the pandemic, understanding its pathophysiology is of paramount importance. Such fatigue and post-viral illness could be associated with features of neuroimmune exhaustion and thus be a part of a larger syndrome such as myalgic encephalomyelitis (ME). Identifying the proportion of patients having ME from those experiencing fatigue would bring us one step closer to understanding the pathophysiology. International consensus criteria (ICC) originally published in English (ICC-E) is a valid and reliable tool for identifying cases of ME. However, a validated Hindi version of ICC-E is not available. : To develop and validate an equivalent version of ICC-E in the native Hindi language (ICC-H) to suit Indian patients and health care workers even at peripheries and to make conducting large scales surveys more feasible. SUBJECTS AND METHODS: Once permission from the ethics board was granted, guidelines given by MAPI Research Trust were followed and ICC-H was developed from ICC-E, in the following steps: (a) translation to Hindi, (b) back translation, (c) comparison between the translated and back-translated version performed by experts, and (d) pre-pilot test in the intended population. The ICC-H was applied to 53 bilingual individuals knowing both Hindi and English. STATISTICAL ANALYSIS USED: The distribution of Hindi and English questionnaires was analyzed using the Chi-square test and Spearman's correlation coefficient was used for correlation between answers of each question. RESULTS: The score of individual items and its global score was highly correlated with each other (p<0.001). The scores of individual components and global scores of ICC-H at baseline and original ICC-E after 4 weeks did not differ significantly. CONCLUSION: This study shows that the ICC-H is a valid and reliable instrument for the assessment of ME. ICC-H can be used for Hindi speaking population for identifying cases of ME. Key Messages There is a significant overlap in symptoms of long COVID and ME, with fatigue being a major component in both. Understanding the prevalence of ME in the post-acute phase of COVID illness can bring us a step closer to understanding its pathophysiology. In a multilingual country like ours, regionally translated criteria are a must for conducting large-scale surveys.
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COVID-19 , Síndrome de Fadiga Crônica , Humanos , Comparação Transcultural , Consenso , Síndrome de COVID-19 Pós-Aguda , Idioma , Inquéritos e Questionários , Reprodutibilidade dos Testes , Fadiga/etiologiaRESUMO
BACKGROUND: Despite consensus guidelines, concern about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has dissuaded patients with cancer from seeking medical care. Studies have shown that contaminated surfaces may contain viable virus for up to 72 hours in laboratory settings. The purpose of this study was to investigate contamination of SARS-CoV-2 on commonly used environmental surfaces in a tertiary cancer care center. METHODS: This study evaluated the incidence of SARS-CoV-2 viral RNA in high-touch outpatient and inpatient cancer center spaces. Surfaces were tested over a 2-week period after patient or staff exposure but before scheduled disinfection services according to the World Health Organization protocols for coronavirus disease 2019 (COVID-19) surface sampling. Samples were analyzed via reverse transcriptase-polymerase chain reaction for the presence of SARS-CoV-2 RNA. RESULTS: Two hundred four environmental samples were obtained from inpatient and outpatient oncology clinics and infusion suites, and they were categorized as 1) public areas, 2) staff areas, or 3) medical equipment. One hundred thirty surfaces from 2 outpatient hematology and oncology clinics and 36 surfaces from an inpatient leukemia/lymphoma/chimeric antigen receptor T-cell unit were examined, and all 166 samples were negative for SARS-CoV-2. One of 38 samples (2.6%) from COVID-19+ inpatient units was positive. Altogether, the positive test rate for SARS-CoV-2 RNA across all surfaces was 0.5% (1 of 204). CONCLUSIONS: This prospective, systematic quality assurance investigation of real-world environmental surfaces, performed in inpatient and outpatient hematology/oncology units, revealed overall negligible detection of SARS-CoV-2 RNA when strict mitigation strategies against COVID-19 transmission were instituted. LAY SUMMARY: The potential risks of nosocomial infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have deterred patients with cancer from seeking timely care despite consensus guidelines. This study has found negligible rates of environmental contamination with SARS-CoV-2 across a multitude of commonly used surfaces in outpatient and inpatient hematology/oncology settings with adherence to strict infection control protocols.
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COVID-19/diagnóstico , Infecção Hospitalar/diagnóstico , Neoplasias/terapia , SARS-CoV-2/isolamento & purificação , Centros de Atenção Terciária , COVID-19/transmissão , COVID-19/virologia , Infecção Hospitalar/transmissão , Infecção Hospitalar/virologia , Desinfecção/métodos , Monitoramento Ambiental/métodos , Humanos , Pacientes Internados/estatística & dados numéricos , Neoplasias/diagnóstico , Pacientes Ambulatoriais/estatística & dados numéricos , Estudos Prospectivos , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Propriedades de SuperfícieRESUMO
Diagnosis and treatment of breast cancer in pregnancy can result in morbidity and mortality for the mother and fetus. Many new paclitaxel nanoformulations commercially available worldwide for breast cancer treatment are being adopted due to favorable dosing regimens and side effect profiles, but their transplacental transport and resultant fetal exposure remain unknown. Here, we examine three formulations: Taxol (paclitaxel dissolved in Kolliphor EL and ethanol); Abraxane (albumin nanoparticle); and Genexol-PM (polymeric micelle). In the ex vivo dually perfused human placental cotyledon, placental accumulation of Genexol-PM is higher than Taxol, and both nanoformulations have lower maternal concentrations of paclitaxel over time. In vitro studies of these formulations and fluorescent nanoparticle analogs demonstrate that Genexol-PM allows paclitaxel to overcome P-glycoprotein efflux, but Abraxane behaves as a free drug formulation. We anticipate that these findings will impact future development of rational and safe treatment strategies for pregnancy-associated breast cancer and other diseases.
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Antineoplásicos Fitogênicos/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Paclitaxel/química , Paclitaxel Ligado a Albumina/química , Albuminas/química , Linhagem Celular Tumoral , Composição de Medicamentos , Feminino , Humanos , Micelas , Nanopartículas/química , Paclitaxel/farmacologia , Placenta/citologia , Polietilenoglicóis/química , GravidezRESUMO
Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication.
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Fator de Transcrição E2F1/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Neoplásico/metabolismo , Regulação para Cima , Animais , Proliferação de Células , Sobrevivência Celular , Fator de Transcrição E2F1/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos Knockout , MicroRNAs/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , RNA Neoplásico/genética , Transdução de SinaisRESUMO
Aberrantly expressed cytokines in the bone marrow (BM) niche are increasingly recognized as critical mediators of survival and expansion of leukemic stem cells. To identify regulators of primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34+ CD38low chronic phase CML cells. Out of the 313 unique human cytokines evaluated, 11 were found to expand cell numbers ≥2-fold in a 7-day culture. Focusing on novel positive regulators of primitive CML cells, the myostatin antagonist myostatin propeptide gave the largest increase in cell expansion and was chosen for further studies. Herein, we demonstrate that myostatin propeptide expands primitive CML and normal BM cells, as shown by increased colony-forming capacity. For primary CML samples, retention of CD34-expression was also seen after culture. Furthermore, we show expression of MSTN by CML mesenchymal stromal cells, and that myostatin propeptide has a direct and instant effect on CML cells, independent of myostatin, by demonstrating binding of myostatin propeptide to the cell surface and increased phosphorylation of STAT5 and SMAD2/3. In summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.
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Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antígenos CD34 , Medula Óssea , Células Cultivadas , Citocinas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Miostatina/genéticaRESUMO
PURPOSE OF REVIEW: Pregnancy-associated lymphoma (PAL) is an uncommon entity that lacks detailed prospective data. It poses significant management challenges that incorporate maternal and fetal risks associated with treatment or delayed intervention. Herein, we review the current literature for the diagnosis, management, and supportive care strategies for PAL. RECENT FINDINGS: Establishment of a multidisciplinary team, including hematology-oncology, maternal-fetal medicine, and neonatology, is critical in the management of PAL. For staging, ultrasound and MRI are preferred modalities with use of computerized tomography in select situations. Data for the safety and effectiveness of therapy for PAL is largely based on retrospective studies. The timing of lymphoma-directed antenatal systemic therapy depends on the trimester, gestational age, lymphoma subtype and aggressiveness, and patient wishes. Therapy in the first trimester is usually not advocated, while treatment in the second and third trimesters appears to result in similar outcomes for PAL compared with non-pregnant patients with lymphoma. An overarching goal in most PAL cases should be to plan for delivery at term (i.e., gestational age > 37 weeks). For supportive care, most antiemetics, including agents such as neurokinin-1 receptor antagonists, have been used safely during pregnancy. For prevention or treatment of infections, particular antibiotics (i.e., macrolides, cephalosporins, penicillins, metronidazole), antivirals (i.e., acyclovir, valacyclovir, famciclovir), and antifungals (amphotericin B) have demonstrated safety and with use of growth factors reserved for treatment of neutropenia (vs. primary prophylaxis). Therapy for PAL should be individualized with goals of care that balance maternal and fetal well-being, which should include a multidisciplinary care team and overall intent for term delivery in most cases.
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Linfoma/diagnóstico , Linfoma/terapia , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/terapia , Feminino , Humanos , Gravidez , Trimestres da GravidezRESUMO
Hydrogen sulfide removal is a long-standing economic and environmental challenge faced by the oil and gas industries. H2S separation processes using reactive and non-reactive absorption and adsorption, membranes, and cryogenic distillation are reviewed. A detailed discussion is presented on new developments in adsorbents, such as ionic liquids, metal oxides, metals, metal-organic frameworks, zeolites, carbon-based materials, and composite materials; and membrane technologies for H2S removal. This Review attempts to exhaustively compile the existing literature on sour gas sweetening and to identify promising areas for future developments in the field.
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Individuals suffering from autoimmune disorders possess a hyperactive cellular phenotype where tolerance to self-antigens is lost. Autophagy has been implicated in both the induction and prevention of autoimmunity, and modulators of this cellular recycling process hold high potential for the treatment of autoimmune diseases. In this study, we determine the effects of a loss of autophagy in dendritic cells (DCs), as well as both B cells and DCs, in a TLR7-mediated model of autoimmunity, similar to systemic lupus erythematosus, where both cell types are critical for disease. Although a loss of DC autophagy slowed disease, the combined loss of autophagy in both cell types resulted in a lethal sepsis-like environment, which included tissue inflammation and hyperproduction of inflammasome-associated cytokines. Ablation of B cell signaling reversed this phenotype, indicating that activation of these cells is an essential step in disease induction. Thus, autophagy plays a dichotomous role in this model of disease.
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Autoimunidade , Autofagia/fisiologia , Linfócitos B/fisiologia , Células Dendríticas/fisiologia , Inflamação/etiologia , Glicoproteínas de Membrana/fisiologia , Receptor 7 Toll-Like/fisiologia , Animais , Interleucina-18/biossíntese , Lúpus Eritematoso Sistêmico/etiologia , Linfadenopatia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Esplenomegalia/etiologiaRESUMO
Hepatic mucormycosis is a disease caused by a ubiquitous fungus which is especially important in patients with hematologic malignancies. We present a case of an adult patient with acute myeloid leukemia who developed the infection after undergoing chemotherapy. His successful management was an integrated approach of a minimally invasive surgical resection with anti-fungal therapy. We describe the management of this patient and a review of the literature.