Panel‑based next‑generation sequencing facilitates the characterization of childhood acute myeloid leukemia in clinical settings

Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30‑40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next‑generation sequencing (NGS) of >150 cancer‑related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT, GATA1, WT1, PTPN11, JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations (FLT3‑ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel‑based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel‑based NGS approach into the clinical setting may allow for a patient‑oriented strategy of precision treatment for childhood AML

ACTN1 Mutations Cause Congenital Macrothrombocytopenia

Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP

Prognostic prediction by hypermetabolism varies depending on the nutritional status in early amyotrophic lateral sclerosis.

To examine whether hypermetabolism could predict the prognosis of early amyotrophic lateral sclerosis (ALS) patients with differing nutritional profiles. This single-center, retrospective study examined the prognosis of ALS patients with hypermetabolism in relation to their nutritional status at hospitalization. The metabolic state was estimated by the ratio of measured resting energy expenditure (mREE) to lean soft tissue mass (LSTM) (mREE/LSTM), wherein patients with ratios ≥ 38 were defined as hypermetabolic. Malnutrition was defined as %ideal body weight < 0.9. Forty-eight patients were enrolled in this study. The hypermetabolic group had shorter survival in the normal-weight group but more prolonged survival in the malnutrition group. Multiplication of nutritional and metabolic factors, such as [(body mass index (BMI) - 19.8) × (mREE/LSTM - 38)], designated as BMI-muscle metabolism index (BMM index), successfully predicted the prognosis in the group with a high BMM index (≥ 1), which showed shorter survival and a faster rate of weight loss and functional decline. Multivariate analysis using the Cox model showed high BMM index was an independent poor prognostic factor (hazard ratio: 4.05; p = 0.025). Prognostic prediction by hypermetabolism varies depending on the nutritional status in ALS, and the BMM index is a consistent prognostic factor

Occupational therapy using a robotic-assisted glove ameliorates finger dexterity and modulates functional connectivity in amyotrophic lateral sclerosis.

Introduction:Although rehabilitation is recommended for amyotrophic lateral sclerosis (ALS), improvement of functional decline has hardly been achieved. We investigated the effect of occupational therapy that uses a robotic-assisted glove (RAG) on hand dexterity and the functional connectivities found in the brain of ALS patients.Method:Ten patients diagnosed with ALS and admitted to the Shiga University of Medical Science (SUMS) Hospital from December 2018 to December 2021 participated in the study. These participants chose the hand side to wear RAG and exercised for two weeks. A sham movement was performed on the other side. We administered several functional assessments, including the Simple Test for Evaluating Hand Function (STEF), grip strength, pinch meter for grip strength, Canadian occupational performance measure (COPM), as well as nerve conduction study (NCS) before and after the exercise, and evaluated the results. We also analyzed six patients\u27 resting-state functional magnetic resonance imaging (rs-fMRI).Results:Two-week robotic rehabilitation improved the STEF, grip strength, and COPM scores when compared with those of the other side. However, no significant effect was observed in the pinch meter and the NCS results. The rs-fMRI data analysis revealed that the robotic rehabilitation augmented two functional connectivities between the left pallidum-right supplementary motor cortex and right insular cortex-right sensorimotor network among the patients, which had beneficial effects.Conclusion:The occupational therapy using RAG displayed improved hand dexterity. The enhanced functional connectivities around the sensorimotor network might be associated with the improvement in hand dexterity because of the RAG

Factors Affecting Energy Metabolism and Prognosis in Patients with Amyotrophic Lateral Sclerosis.

Background/aims:Nutritional status is a factor affecting prognosis in patients with amyotrophic lateral sclerosis (ALS). Here, we aimed to clarify the factors associated with hypermetabolism and the prognosticators of ALS.Methods:Forty-two inpatients (22 men, 20 women) diagnosed with ALS according to the revised El-Escorial criteria were investigated. The following data were retrospectively analyzed: anthropometric measurements, blood biochemistry, disease severity, basal energy expenditure (BEE), resting energy expenditure (REE) measured by indirect calorimetry, spirometry, and bioelectrical impedance analysis. Single and multiple regression analysis was performed to examine factors affecting REE and metabolic changes (defined as the ratio of REE to fat-free mass [FFM]). The Kaplan-Meier method was used to examine factors associated with the occurrence of cumulative events (death or tracheostomy).Results:Among the 42 inpatients, REE was significantly higher than BEE, indicating hypermetabolism in ALS. Multiple regression analysis revealed that REE/FFM is strongly associated with the skeletal muscle index (-3.746 to -1.532, p < 0.0001) and percent forced vital capacity (%FVC) (-0.172 to -0.021, p = 0.013). Moreover, both the skeletal muscle index and %FVC were significant prognosticators associated with the occurrence of cumulative events.Conclusions:Energy metabolism was elevated in ALS, and respiratory status and muscle mass were associated with the hypermetabolism and poor prognosis. Adequate nutritional support may improve outcomes in ALS by preventing deterioration of respiratory status and reduction in muscle mass

Side-Channel Attack using Order 4 Element against Curve25519 on ATmega328P

International audienc

タハツセイ ケッカン キョウサク ヤ ツイコツ ドウミャクリュウトウ ノ タサイナ ケッカン ビョウヘン オ テイシタ neuropsychiatric systemic lupus erythematosus ノ 1レイ

症例は42 歳女性，約20 年前に全身性エリテマトーデス（systemic lupus erythematosus，以下SLE と略記）と診断された．ステロイド誘発性精神障害のためステロイド漸減中に錯乱状態を主とする神経精神SLE（neuropsychiatric SLE，以下NPSLE と略記）を発症し，MRI では右側頭葉皮質を中心に急性期梗塞像，複数の脳主幹動脈で亜急性に変動する狭窄と拡張，右椎骨動脈瘤形成を認めた．シクロホスファミド静注療法等を早期から導入し動脈瘤は拡大なく血管狭窄は改善した．NPSLE における血管攣縮と拡張，動脈瘤形成は稀であるが，疾患活動性の指標となり，強固な免疫治療を検討する必要性があると考え報告した．A 42 years old female suffered from systemic lupus erythematosus (SLE) about 20 years ago. While steroid was tapered for a steroid-induced psychiatric disorder, she presented with an acute confusional state and was diagnosed with neuropsychiatric SLE (NPSLE). MRI showed acute infarction mainly in the cortex of the right temporal lobe and MRA demonstrated dynamic subacute morphological changes such as stenosis and dilation in several major intracrainal arteries. The right vertebral artery diffusely dilated and subsequently formed an aneurysm in a week. Contrast-enhanced MRI vessel-wall imaging showed a remarkable enhancement of the aneurysm wall, which might indicate an unstable unruptured aneurysm. The prompt introduction of intravenous cyclophosphamide improved both clinical and radiological signs. Our case indicates that intensive immunosuppressive treatments should be considered in NPSLE patients with varying vasospasm and aneurysm, indicating exacerbated disease activity

Additional file 1 of Intestinal metabolites predict treatment resistance of patients with depression and anxiety

Supplementary Material 1: Supplemental Figure 1. Comparison of Bray-Curtis dissimilarity between replicates and between different participants; Supplemental Figure 2. Comparison of normalized bacterial abundance among intestinal bacteria; Supplemental Figure 3. Prediction of treatment responders and non-responders based on the baseline HAM-A scores or the abundance of Odoribacter; Supplemental Figure 4. Changes in the levels of the identified metabolites over time; Supplemental Figure 5. Fecal levels of short-chain fatty acids are not associated with the treatment responses of patients with depression and anxiet