Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia

Simple Summary In solid tumors, the altered expression of embryonic genes such as the SLIT-ROBO family has been associated with poor prognosis, while little is known about their role in acute myeloid leukemia (AML). Previous studies reported frequent hypermethylation of SLIT2 mediated by the methyltransferase enzyme EZH2 and more recently the PML protein, which are commonly found to be aberrantly expressed in AML. Here, we aim to assess retrospectively the clinical relevance of the SLIT2 gene in acute promyelocytic leukemia, a homogenous subtype of AML. We demonstrated that reduced SLIT2 expression was associated with high leukocyte counts and reduced overall survival in different APL cohorts. STLI2 treatment decreased APL growth, while SLIT2 knockdown accelerated cell cycle progression and proliferation. Finally, reduced expression of SLIT2 in murine APL blasts resulted in fatal leukemia associated with increased leukocyte counts in vivo. These findings demonstrate that SLIT2 can be considered as a prognostic marker in APL, and a potential candidate for clinical studies of a more heterogeneous disease, such as AML. The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2(high) transcript levels were associated with cell cycle arrest, while SLIT2(low) APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p <0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated

Indivíduos fisicamente ativos submetidos ao tratamento com Tribulus terrestris versus placebo

The purpose of the present study is to evaluate anthropometric, biochemical, hormonal and performance differences among physically active individuals who utilize (or not) Tribulus terrestris (TT) supplementation.&nbsp; The cohort is composed of 32 subjects divided into two groups: 1) 8 males and 8 females individuals who are physically active and utilize Tribulus terrestres; 2) 8 males and 8 females individuals who are physically active and utilize placebo. Inclusion criteria for all subjects consisted of age requirement within the range of 18 and 40 years old, a history of at least 6 months of physical activity and absence of any drug treatment/consumption. Analysis of body composition, physical performance test and blood collection for subsequent hormonal and biochemical tests were collected. Data were processed and analyzed based on descriptive statistical tests and one-way-ANOVA. Results were considered statistically significant when p&lt;0.05. Results show significant increase in testosterone levels for both females and males treated with TT, decreased levels of body fat among the treated women, increased libido for treated individuals and enhanced strength among treated women. Biochemical parameters among all groups were within normal limits.O objetivo do presente estudo é avaliar as diferenças antropométricas, bioquímicas, hormonais ede desempenho entre indivíduos fisicamente ativos que utilizam (ou não) a suplementação comTribulus terrestris (TT). A coorte é composta por 32 indivíduos divididos em dois grupos: 1) 8indivíduos do sexo masculino e 8 do sexo feminino, fisicamente ativos e que utilizam Tribulusterrestres; 2) 8 indivíduos do sexo masculino e 8 do sexo feminino que são fisicamente ativos eutilizam placebo. Os critérios de inclusão para todos os sujeitos consistiram na exigência de idadeentre 18 e 40 anos, histórico de pelo menos 6 meses de atividade física e ausência de qualquertratamento / consumo de drogas. Análise da composição corporal, teste de desempenho físico ecoleta de sangue para testes hormonais e bioquímicos subsequentes foram coletados. Os dadosforam processados e analisados com base em testes estatísticos descritivos e ANOVA one-way. Osresultados foram considerados estatisticamente significantes quando p &amp;lt;0,05. Os resultadosmostram aumento significativo nos níveis de testosterona para mulheres e homens tratados comTT, diminuição dos níveis de gordura corporal entre as mulheres tratadas, aumento da libido paraindivíduos tratados e aumento da força entre mulheres tratadas. Parâmetros bioquímicos entretodos os grupos estavam dentro dos limites normais

Two Year Cosmology Large Angular Scale Surveyor (CLASS) Observations: Long Timescale Stability Achieved with a Front-End Variable-delay Polarization Modulator at 40 GHz

The Cosmology Large Angular Scale Surveyor (CLASS) is a four-telescope array observing the largest angular scales ($2 \lesssim \ell \lesssim 200$) of the cosmic microwave background (CMB) polarization. These scales encode information about reionization and inflation during the early universe. The instrument stability necessary to observe these angular scales from the ground is achieved through the use of a variable-delay polarization modulator (VPM) as the first optical element in each of the CLASS telescopes. Here we develop a demodulation scheme used to extract the polarization timestreams from the CLASS data and apply this method to selected data from the first two years of observations by the 40 GHz CLASS telescope. These timestreams are used to measure the $1/f$ noise and temperature-to-polarization ($T\rightarrow P$) leakage present in the CLASS data. We find a median knee frequency for the pair-differenced demodulated linear polarization of 15.12 mHz and a $T\rightarrow P$ leakage of $<3.8\times10^{-4}$ (95\% confidence) across the focal plane. We examine the sources of $1/f$ noise present in the data and find the component of $1/f$ due to atmospheric precipitable water vapor (PWV) has an amplitude of $203 \pm 12 \mathrm{\mu K_{RJ}\sqrt{s}}$ for 1 mm of PWV when evaluated at 10 mHz; accounting for $\sim32\%$ of the $1/f$ noise in the central pixels of the focal plane. The low level of $T\rightarrow P$ leakage and $1/f$ noise achieved through the use of a front-end polarization modulator enables the observation of the largest scales of the CMB polarization from the ground by the CLASS telescopes.Comment: Submitted to Ap

Effects of the interaction between dark energy and dark matter on cosmological parameters

We examine the effects of possible phenomenological interactions between dark energy and dark matter on cosmological parameters and their efficiency in solving the coincidence problem. We work with two simple parameterizations of the dynamical dark energy equation of state and the constant dark energy equation of state. Using observational data coming from the new 182 Gold type Ia supernova samples, the shift parameter of the Cosmic Microwave Background given by the three-year Wilkinson Microwave Anisotropy Probe observations, and the baryon acoustic oscillation measurement from the Sloan Digital Sky Survey, we perform a statistical joint analysis of different forms of phenomenological interactions between dark energy and dark matter.Comment: revised version, accepted for publication in JCA

Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p&nbsp;=&nbsp;0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Age, Successive Waves, Immunization, and Mortality in Elderly COVID-19 Haematological Patients: EPICOVIDEHA Findings

Introduction: elderly patients with haematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection impact in different age groups remains unstudied in detail. Methods: We analysed elderly patients (age groups: 65-70, 71-75, 76-80 and &gt;80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with haematological malignancy. results: the study included data from 3,603 elderly patients (aged 65 or older) with haematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves.tThe 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukaemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusions: These data underscore the heterogeneity of elderly haematological patients, highlight the different impact of COVID waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated