Subtypes of Familial Hemophagocytic Lymphohistiocytosis in Japan Based on Genetic and Functional Analyses of Cytotoxic T Lymphocytes

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of infancy or early childhood. To clarify the incidence and subtypes of FHL in Japan, we performed genetic and functional analyses of cytotoxic T lymphocytes (CTLs) in Japanese patients with FHL. DESIGN AND METHODS: Among the Japanese children with hemophagocytic lymphohistiocytosis (HLH) registered at our laboratory, those with more than one of the following findings were eligible for study entry under a diagnosis of FHL: positive for known genetic mutations, a family history of HLH, and impaired CTL-mediated cytotoxicity. Mutations of the newly identified causative gene for FHL5, STXBP2, and the cytotoxicity and degranulation activity of CTLs in FHL patients, were analyzed. RESULTS: Among 31 FHL patients who satisfied the above criteria, PRF1 mutation was detected in 17 (FHL2) and UNC13D mutation was in 10 (FHL3). In 2 other patients, 3 novel mutations of STXBP2 gene were confirmed (FHL5). Finally, the remaining 2 were classified as having FHL with unknown genetic mutations. In all FHL patients, CTL-mediated cytotoxicity was low or deficient, and degranulation activity was also low or absent except FHL2 patients. In 2 patients with unknown genetic mutations, the cytotoxicity and degranulation activity of CTLs appeared to be deficient in one patient and moderately impaired in the other. CONCLUSIONS: FHL can be diagnosed and classified on the basis of CTL-mediated cytotoxicity, degranulation activity, and genetic analysis. Based on the data obtained from functional analysis of CTLs, other unknown gene(s) responsible for FHL remain to be identified

Spatial and temporal genetic heterogeneity of epidermal growth factor receptor gene status in a patient with non-small cell lung cancer: a case report

<p>Abstract</p> <p>Introduction</p> <p>To date, an epidermal growth factor receptor-activating mutation is recognized as a genetic hallmark that predicts a good response to treatment with epidermal growth factor receptor tyrosine kinase inhibitor. However, there has been less long-term observation of the mutational status within the same patient. To the best of our knowledge, this is the first case report which illustrates the instability of the genetic status of pulmonary adenocarcinoma cells.</p> <p>Case presentation</p> <p>A 64-year-old Japanese woman with advanced lung adenocarcinoma had been undergoing various anticancer treatments, including epidermal growth factor receptor tyrosine kinase inhibitor, for seven years. She had been receiving locoregional treatment in addition to systemic treatment. She maintained a good performance status until seven years after the initial diagnosis, although she had local and distant recurrences. We analyzed the genetic status of the epidermal growth factor receptor gene in a series of specimens obtained from various tumor-containing lesions throughout the therapeutic period. The results of the genetic analyses clearly showed that the spatial and temporal genetic heterogeneity of the epidermal growth factor receptor gene status originated from an identical tumor ancestor.</p> <p>Conclusions</p> <p>An alternative paradigm to determine a therapeutic strategy for a patient with lung cancer should be considered given the genetic heterogeneity and instability of tumor cells.</p

Knockdown of the Drosophila Fused in Sarcoma (FUS) Homologue Causes Deficient Locomotive Behavior and Shortening of Motoneuron Terminal Branches

Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation. Cabeza (Caz) is a Drosophila orthologue of human FUS. Here, we generated Drosophila models with Caz knockdown, and investigated their phenotypes. In wild-type Drosophila, Caz was strongly expressed in the central nervous system of larvae and adults. Caz did not colocalize with a presynaptic marker, suggesting that Caz physiologically functions in neuronal cell bodies and/or their axons. Fly models with neuron-specific Caz knockdown exhibited reduced climbing ability in adulthood and anatomical defects in presynaptic terminals of motoneurons in third instar larvae. Our results demonstrated that decreased expression of Drosophila Caz is sufficient to cause degeneration of motoneurons and locomotive disability in the absence of abnormal cytoplasmic Caz aggregates, suggesting that the pathogenic mechanism underlying FUS-related ALS should be ascribed more to the loss of physiological FUS functions in the nucleus than to the toxicity of cytoplasmic FUS aggregates. Since the Caz-knockdown Drosophila model we presented recapitulates key features of human ALS, it would be a suitable animal model for the screening of genes and chemicals that might modify the pathogenic processes that lead to the degeneration of motoneurons in ALS

Long-term efficacy and safety of tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: final analysis of phase IIb results

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Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652)

Space-time Extended Finite Element Method with Applications to Fluid-structure Interaction Problems

This thesis presents a space-time extended finite element method (space-time XFEM) based on the Heaviside enrichment for transient problems with moving interfaces, and its applications to the fluid-structure interaction (FSI) analysis. The Heaviside-enriched XFEM is a promising method to discretize partial differential equations with discontinuities in space. However, significant approximation errors are introduced by time stepping schemes when the interface geometry changes in time. The proposed space-time XFEM applies the finite element discretization and the Heaviside enrichment in both space and time with elements forming a space-time slab. A simple space-time scheme is introduced to integrate the weak form of the governing equations. This scheme considers spatial intersection configuration at multiple temporal integration points. Standard spatial integration techniques can be applied for each spatial configuration. Nitsche's method and the face-oriented ghost-penalty method are extended to the proposed space-time XFEM formulation. The stability, accuracy and flexibility of the space-time XFEM for various interface conditions including moving interfaces are demonstrated with structural and fluid problems. Moreover, the space-time XFEM enables analyzing complex FSI problems using moving interfaces, such as FSI with contact. Two FSI methods using moving interfaces (full-Eulerian FSI and Lagrangian-immersed FSI) are studied. The Lagrangian-immersed FSI method is a mixed formulation of Lagrangian and Eulerian descriptions. As solid and fluid meshes are independently defined, the FSI is computed between non-matching interfaces based on Nitsche's method and projection techniques adopted from computational contact mechanics. The stabilized Lagrange multiplier method is used for contact. Numerical examples of FSI and FSI-contact problems provide insight into the characteristics of the combination of the space-time XFEM and the Lagrangian-immersed FSI method. The proposed combination is a promising method which has the versatility for various multi-physics simulations and the applicability such as optimization

Reporting quality of randomized controlled trials in patients with HIV on antiretroviral therapy: a systematic review

Abstract Background To allow for correct evaluation of clinical trial results, readers require comprehensive, clear, and highly transparent information on the methodology used and the results obtained. This study aimed to evaluate the quality of reporting in articles on randomized controlled trials (RCTs) of antiretroviral therapy (ART) in the field of HIV/AIDS. Methods We searched for original articles on RCTs of ART developed in the field of HIV/AIDS in PubMed database by 5 April 2016. Searched articles were divided into three groups based on the revision year in which the Consolidated Standards of Reporting Trials (CONSORT) guidelines were published: Period 1 (1996–2001); Period 2 (2002–2010); and Period 3 (2011–2016). We evaluated the articles using the reporting rates of the 37 items in the CONSORT 2010 checklist, five items in the protocol deviation, and the three items in the ethics. Results Fifty-two articles were extracted and included in this study. Many of the reporting rates calculated using the CONSORT 2010 checklist showed a significantly increasing trend over the successive periods (65% in Period 1, 67% in Period 2, 79% in Period 3; p 80% in Period 3) among the five items. The reporting rates for obtaining informed consent and approval by the ethics committee or institutional review board were high (>88%), regardless of the time period assessed. Conclusion In terms of representative RCT articles in the field of HIV/AIDS, the reporting rate of the items defined by CONSORT was approximately 70%, improving over the successive CONSORT statement revision periods

Febrile neutropenia in a patient with non-small-cell lung cancer treated with atezolizumab: A case reportLearning points

Hematological immune-related adverse events (hem-irAEs) related to immunotherapy have not been extensively characterized, and there is no report of neutropenia caused by atezolizumab administration. Herein, we report a case of febrile neutropenia caused by a hem-irAEs due to atezolizumab, which was treated with granulocyte-colony stimulating factor (G-CSF) and antibiotic prophylaxis. It is important that oncologists be aware of the hematological toxicities of immune checkpoint inhibitors (ICIs). Furthermore, antibiotics and G-CSF should be administered until absolute neutrophil count recovery in cases of febrile neutropenia complicated by atezolizumab. Systemic corticosteroids should not be administered because they can accentuate the risk of infection