Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.     

Estratificación basal de riesgo en pacientes mayores de 75 años con infarto y shock cardiogénico referidos para angioplastia primaria

Background and objectivesPatients older than 75 years with ST-segment elevation myocardial infarction undergoing primary angioplasty in cardiogenic shock have high mortality. Identification of preprocedural predictors of short- and long-term mortality could be useful to guide decision-making and further interventions.MethodsWe analyzed a nationwide registry of primary angioplasty in the elderly (ESTROFA MI + 75) comprising 3576 patients. The characteristics and outcomes of the subgroup of patients in cardiogenic shock were analyzed to identify associated factors and prognostic predictors in order to derive a baseline risk prediction score for 1-year mortality. The score was validated in an independent cohort.ResultsA total of 332 patients were included. Baseline independent predictors of mortality were anterior myocardial infarction (HR 2.8, 95%CI, 1.4-6.0; P = .005), ejection fraction < 40% (HR 2.3, 95%CI, 1.14-4.50; P = .018), and time from symptom onset to angioplasty > 6 hours (HR 3.2, 95%CI, 1.6-7.5; P = .001). A score was designed that included these predictive factors (score “6-ANT-40”). Survival at 1 year was 54.5% for patients with score 0, 32.3% for score 1, 27.4% for score 2 and 17% for score 3 (P = .004, c-statistic 0.70). The score was validated in an independent cohort of 124 patients, showing 1-year survival rates of 64.5%, 40.0%, 28.9%, and 22.2%, respectively (P = .008, c-statistic 0.68).ConclusionsA preprocedural score based on 3 simple clinical variables (anterior location, ejection fraction < 40%, and delay time > 6 hours) may be used to estimate survival after primary angioplasty in elderly patients with cardiogenic shock and to guide preinterventional decision-making.     

Dapagliflozin and measures of cardiovascular autonomic function in patients with type 2 diabetes (T2D)

AimsSodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce blood pressure without compensatory heart rate elevation, possibly by modulating sympathetic/parasympathetic activity. This may contribute to their cardiovascular benefits in type 2 diabetes (T2D). We evaluated the effects of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN), cardiac function, and glucose variability (GV) in T2D.MethodsPilot, randomized, two-period crossover trial comparing 12-week DAPA versus 12-week glimepiride treatment on CAN measures (cardiovascular autonomic reflex tests and heart rate variability), B-type natriuretic peptide (BNP), and GV (Abbott's Libre Pro devices) using signed rank tests and mixed models from baseline to 12 weeks within and between each period.ResultsForty-five T2D participants on metformin monotherapy (mean age 57 ± 8 years, duration 7 ± 6 years, HbA1c 7.8 ± 1.3%) were enrolled with 41 completing the trial. There were no differences in CAN indices or BNP with each drug compared to baseline and each other. Participants on DAPA demonstrated greater weight loss, reduced time in hypoglycemia, and improved GV compared to glimepiride.ConclusionsShort term treatment with DAPA did not affect CAN measures or BNP in uncomplicated and relatively healthy T2D participants. Longer prospective studies in patients with advanced disease are needed to better understand relationships between SGLT-2 inhibitors and CAN.Clinical trial registration: NCT02973477     

Protein Content and Methyl Donors in Maternal Diet Interact to Influence the Proliferation Rate and Cell Fate of Neural Stem Cells in Rat Hippocampus

Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation.     

La inervación del disco intervertebral

Until very recently, intervertebral disc innervation was a subject of considerable debate.Nowadays, the introduction of inmunohistochemical techniques associated to specific antibodies and studies with retrograde tracers in nerves have allowed greater understanding of disc innervation in physiological and pathological conditions and also endings characteristics and their patterns of distribution in both situations. The existing controversies regarding structural basis of discogenic pain, have raised the interest of knowing the influence of innervation in back pain from discal origin and its characteristics.Today, we know that pathologic neoinnervation accompanying radial fissures is an important factor in the genesis of discogenic pain; within a complex mechanism in which other neurobiomechemical, inflammatory and biomechanical factors are involved.     

Tumefactive multiple sclerosis requiring emergency craniotomy: Case report and literature review

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by focal neurological dysfunction with a relapsing and remitting course. Tumor-like presentation of MS (or “tumefactive”/“pseudotumoral” presentation) has been described before with a certain frequency; it consists of a large single plaque (>2 cm) with presence of edema and mass effect and it is hard to distinguish from a brain tumor. However, we present a very rare case of a 53-year-old woman with a right temporal mass that turned out to be a MS plaque, who deteriorated within hours (brain herniation with loss of consciousness and unilateral mydriasis) and required an emergency craniotomy. We also present a review of the literature. It appears that only 4 cases of emergency craniotomy/craniectomy required in a patient with a tumor-like MS plaque have been reported before.     

Factors Associated with Prenatal Care and Seeking Assistance in Public Hospitals in Vitória,Espírito Santo,Brazil

Adequate prenatal care provides an opportunity for counseling and reducing the complications associated with pregnancy and delivery. Our objective was to describe the demographic, behavioral, and clinical profile of the pregnant women hospitalized at public maternity hospitals and to identify factors associated with six or more prenatal consultations in Vitória, Brazil. A cross-sectional study of 1,380 women was conducted in public maternity hospitals in Vitória, Brazil. Sixty-seven percent of participants had ≥6 prenatal consultations. Reasons for hospitalization were vaginal delivery (55.7%), cesarean section (32.9%), clinical treatment (7.7%), and abortion/miscarriage (3.7%). Having ≥9 years of schooling (odds ratio, OR = 1.8; 95% confidence interval, CI: 1.1–3.1), being married (OR = 1.9; 95% CI: 1.2–2.9) and delivering at term (OR = 3.6; 95% CI: 1.6–8.2) were significantly independently associated with having ≥6 prenatal consultations. Although higher education, being married, and delivering at term were associated with ≥6 prenatal consultations in this population, the high rate of Cesarean sections demonstrates the need for ongoing educative strategies among health professionals.     

TLR4通路对polyI:C诱导肝癌细胞凋亡的影响

目的:研究TLR4信号通路活化对polyI:C诱导人肝癌细胞系H7402凋亡的影响,并分析其可能的作用机制。方法:用TLR4激动剂LPS处理H7402细胞24 h后,转染polyI:C刺激24 h,然后利用流式细胞术检测细胞凋亡,荧光定量PCR检测凋亡基因及胞内RNA模式识别受体TLR3、MDA5、RIG-I和LGP2的表达,Western blot检测识别受体的蛋白表达水平。结果:LPS预处理,减弱了polyI:C诱导H7402细胞凋亡的作用。同时,促凋亡基因Noxa的表达水平降低。在此过程中polyI:C的胞内识别受体RIG-I、MDA5的基因和蛋白水平表达下调。结论:LPS可能通过降低H7402细胞内dsRNA识别受体的表达,抑制了polyI:C诱导H7402细胞凋亡的作用。     

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent,persistent or metastatic cervical cancer

Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m² as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m²) or cisplatin (50 mg/m²) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5–96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.