BRAF V600E-Positive Multisite Langerhans Cell Histiocytosis in a Preterm Neonate

Hemorrhagic pustules with a “blueberry muffin” appearance accompanied by respiratory failure in a neonate present a challenging differential diagnosis that includes infections and neoplasms. We present a case of multiorgan, multisite Langerhans cell histiocytosis (LCH), positive for the oncogenic BRAF V600E mutation, in a preterm neonate. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. This case is unusual in that the newborn presented with severe multiorgan involvement. Due to the rare incidence, wide spectrum of clinical manifestations, and high mortality rate, clinicians must maintain a high index of suspicion for LCH

Online Professional Development’s Effect on Teachers’ Technology Self-Efficacy and Continuance Intention to Use Pear Deck

Districts and schools are spending millions of dollars on technology, training, and professional development each year; however, a disconnect between technology use and good pedagogy remains. The one-shot, sit-and-get professional development model has not provided North Lake Intermediate School’s teachers the necessary skills and knowledge to prepare students for the 21st century through the use of innovative technologies. The purpose of this action research study was to investigate how a TPACK-focused online professional development experience influenced teachers’ development of technology self-efficacy and intention to integrate the technology tool, Pear Deck, and measure changes in their attitudes toward Pear Deck. The innovation in this study was a TPACK-focused, online, asynchronous professional development. Participants had access to optional pre-learning material and discussion forums, an asynchronous professional development presentation, and personalized feedback reports in response to their reflection questions. A convergent mixed-methods design yielded supplementary sources of data: quantitative data gathered through a modified TAM pre and post survey and lesson plans and qualitative data from teacher reflections and semi-structured interviews. Analyzing and converging interview data revealed the impact of online teacher professional development on intermediate teachers’ technology self-efficacy, changes in attitudes toward Pear Deck, and continuance intentions to integrate Pear Deck. Implications from this study include providing asynchronous TPACK-focused online professional development to positively impacts teachers’ technology self-efficacy, attitudes toward Pear Deck, and continuance intentions. However, further studies should be done to address how external barriers may be overcome

Mudança dos hábitos nutricionais dos hipertensos e diabéticos da equipe de saúde da família Pedra Furados em Nova Era - MG

O Diabetes Mellitus e a HAS são condições crônicas de alta prevalência e difícil controle. São consideradas fatores de risco modificáveis para doenças cardiovasculares, as quais são responsáveis por um alto número de internações e configuram a principal causa de morte no Brasil. Este trabalho tem por objetivo propor ações educativas para empreender mudanças nos hábitos alimentares, direcionadas a usuários com Diabetes Mellitus e Hipertensão Arterial na saúde da família em Nova Era - MG. Para elaboração da proposta de intervenção, foram executadas três etapas: diagnóstico situacional, revisão bibliográfica e elaboração do plano de ação, utilizando o planejamento estratégico situacional. Verificou-se na literatura que a educação do paciente com hipertensão e diabético sobre sua patologia, a seriedade das complicações, os mecanismos de prevenção, além das técnicas de autocuidado, são elementos indispensáveis para um tratamento adequado da doença. Na intervenção pretende se realizar educação em saúde pelos integrantes da equipe, assim como reforçar o sistema de autocuidado dos pacientes e capacitação primeiramente dos profissionais participantes. Os resultados obtidos por meio da implantação de programas efetivos de educação são notadamente positivos. Este projeto almeja proporcionar a tais usuários um controle mais eficaz da doença e uma melhora na qualidade de vida dos mesmos, apoiando-se na prevenção, no estímulo ao autocuidado, na promoção da adoção e hábitos no estilo de vida e na participação em seu tratament

Mudança dos hábitos nutricionais dos hipertensos e diabéticos da equipe de saúde da família Pedra Furados em Nova Era - MG

O Diabetes Mellitus e a HAS são condições crônicas de alta prevalência e difícil controle. São consideradas fatores de risco modificáveis para doenças cardiovasculares, as quais são responsáveis por um alto número de internações e configuram a principal causa de morte no Brasil. Este trabalho tem por objetivo propor ações educativas para empreender mudanças nos hábitos alimentares, direcionadas a usuários com Diabetes Mellitus e Hipertensão Arterial na saúde da família em Nova Era - MG. Para elaboração da proposta de intervenção, foram executadas três etapas: diagnóstico situacional, revisão bibliográfica e elaboração do plano de ação, utilizando o planejamento estratégico situacional. Verificou-se na literatura que a educação do paciente com hipertensão e diabético sobre sua patologia, a seriedade das complicações, os mecanismos de prevenção, além das técnicas de autocuidado, são elementos indispensáveis para um tratamento adequado da doença. Na intervenção pretende se realizar educação em saúde pelos integrantes da equipe, assim como reforçar o sistema de autocuidado dos pacientes e capacitação primeiramente dos profissionais participantes. Os resultados obtidos por meio da implantação de programas efetivos de educação são notadamente positivos. Este projeto almeja proporcionar a tais usuários um controle mais eficaz da doença e uma melhora na qualidade de vida dos mesmos, apoiando-se na prevenção, no estímulo ao autocuidado, na promoção da adoção e hábitos no estilo de vida e na participação em seu tratament

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondria) apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, FED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia.

PURPOSE: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML. EXPERIMENTAL DESIGN: ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens. RESULTS: Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23-0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19-0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05-3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96-4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score-based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002). CONCLUSIONS: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen

Treating and triggering hyperinflammation: tackling hemophagocytic lymphohistiocytosis and HLH-like syndromes in the pediatric cell therapy and critical care setting

Hemophagocytic lymphohistiocytosis (HLH) describes a severe, hyperinflammatory syndrome that can originate from diverse etiologies, often requiring critical care level management. Primary HLH, initially described in the 1940s, derives from genetic defects that result in uncontrolled immune activation. Although chemotherapy and immunosuppressive agents can temporarily quell inflammation, allogeneic hematopoietic cell transplantation (HCT) is the only curative option. In 2025, HCT is indicated for primary HLH and some etiologies of secondary HLH but remains challenging due to both disease and transplant-related inflammation. Additionally, new cellular therapy approaches to treat malignancy, such as chimeric antigen receptor T cells, can trigger a spectrum of hyperinflammatory complications. Herein, we review the pathophysiology, diagnosis, and evolving management approaches of primary and secondary HLH, ultimately informing our management of hyperinflammation in the setting of new cell therapies

Emapalumab in children with primary hemophagocytic lymphohistiocytosis

Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. RESULTS At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P=0.02 and P=0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. CONCLUSIONS Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis