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Polyhydroxyalkanoates biopolymers to decarbonizing economy and also sustainable future.
In the clinical practice of hematology, the awareness of team-based medical care has become predominant, and effective coordination with other medical staff members and different departments is essential. The transfusion department where I am employed is now responsible for hematopoietic stem cell transplantation in addition to transfusion therapy and, thus, is one of the divisions most closely involved with hematology. The roles of the doctor here range from intra-hospital tasks, such as the management and supervision of transfusion to those outside the hospital, to providing education to medical staffs from other facilities and edification to blood donors. Moreover, owing to the recent rise in the number of patients who require hematopoietic stem cell transplantation and the use of novel cell therapies, such as CAR-T therapy, our role is widening into cell apheresis and cell management. The field of hematology offers several career opportunities; here, I present my own experience of how marriage and childbirth led me to the career path as a hematologist with specialization in transfusion and cell collection.In the present decade, the number of female hematologists and their ratio to the total number of hematologists have increased. This increase in the number of female physicians with various work styles have made physicians aware of diverse career paths. To attain an uninterrupted career, physicians have to overcome obstacles such as severe working environment or intolerance of diversity. The Committee on Studies of Career Education for Female Physicians proposed five learning objectives for all physicians to attain an uninterrupted career professional awareness of the missions of being a physician, ability to make career plans, flexibility to embrace diverse values of the profession, appropriate attitudes toward supports, and recognition of social gender differences. Learning objectives corresponding to the learning period were also proposed. In order to make career plans, residents need to collect the information on specialty training, perceive a variety of individuals as potential role models, and create, review, and change their own career plan. Residents should become familiar with the process for becoming board-certified hematologists through understanding the new training program for hematology residency.Acute lymphoblastic leukemia (ALL) in infants remains an intractable and difficult-to-treat leukemia as compared to other pediatric ALLs, for which considerable progress has been achieved in terms of treatment outcomes in recent years. The leukemic cells in infants with ALL frequently carry chromosome translocations involving 11q23, resulting in the rearrangement and fusion of the MLL (KMT2A) gene. Among many MLL fusion genes, MLL-AF4 (KMT2A-AFF1) fusion is characteristically observed in infants with ALL, representing a hallmark of poor prognosis. In MLL-AF4-positive infants with ALL, first leukemic cells with MLL-AF4 were generated in utero. Analysis of several murine and human leukemia models revealed that the target cells for tumorigenesis by MLL-AF4 were not the hematopoietic progenitor cells of the bone marrow, but the early hematopoietic progenitor cells present in the fetal liver during the embryonic period and possibly the undifferentiated cells prior to the commitment to hematopoietic cells in the fetus. Elucidation of the leukemogenic process of infant ALL with MLL-AF4 may lead to early, pre-symptomatic diagnosis of leukemia, resulting in the improvement of prognosis and prevention of the onset of ALL in infants.Parental age at birth has been investigated in patients diagnosed with pediatric cancer. The Japan Children's Cancer Registry1985-2007 recruited 5,510 patients with leukemia and 8,782 with other cancers. The proportion of patients born to mother and father aged >40 years showed a higher trend in leukemia than that in other cancers (odds ratio [OR] 1.41, p=0.057), especially in 40 years (OR 2.55, p=0.031). We then divided 27,335 patients diagnosed in 1969-2006 into every 8-year birth cohorts to compare proportions of mothers with prenatal medical irradiation. The OR of leukemia was higher than that of other cancers in 1969-1976 (1.25) or 1977-1984 (1.39), which reached statistical significance. We have also studied caregiver's exposure to anticancer drugs. In 15 pediatric patients with cancer who received cyclophosphamide (CPM), the concentration was measured using mothers and medical staff's urine. Five of 7 infants' and 2 of 8 adolescent's mothers showed increased urine CPM levels. CPM was not detected in any medical staff's samples. Maternal exposure to anticancer drugs should also be considered. Efforts of reducing the genotoxicity in both infants and mothers are crucial for pediatric cancer prevention.The development of an inhibitor is a serious complication for patients with hemophilia (PwH). Previous international studies have reported some therapeutic and genetic factors associated with inhibitor development. However, actual situations, such as genetic-background, treatment, and inhibitor development, have remained unclear in PwH in Japan. The Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized in 2008 to establish a nation-wide registry system for PwH in Japan and prospectively investigate the risk factors for inhibitor development. Patients who were newly diagnosed after 2007 without inhibitor and whose treatment was traceable from 0 to 75 exposure days were enrolled in J-HIS2. Of the 386 patients (hemophilia A [HA] 315, hemophilia B [HB] 71) from 46 facilities, inhibitor development was observed in 77 (HA 71, HB 6) by November 2018. Inhibitor development was observed in 31.6% of patients with severe hemophilia A, 6.5% with moderate hemophilia A, and 1.8% with mild hemophilia A. However, it was observed in 15.4% of those with severe hemophilia B. The relative-risk of the F8 null genotype for inhibitor development was higher than that of the non-null one (p less then 0.01). In patients with severe hemophilia A with 25 exposure days of infusions or inhibitor development, prophylaxis was more protective for inhibitor development than non-prophylaxis (p less then 0.01). A simultaneous infusion of FVIII-concentrates and vaccination seemed to exert a limited effect on inhibitor development. History of intracranial hemorrhage appears to be associated with inhibitor development.Blood coagulation factor VIII (FVIII) functions as a cofactor for activated factor IX on the phospholipid membrane in the coagulation reaction. FVIII deficiency causes hemophilia A, and conversely, the thrombotic patients show high FVIII levels. Therefore, FVIII is a key coagulant factor involved in the contradictory pathology of hemorrhage and thrombosis. selleck From the crystal structure of the FVIII molecule and bispecific antibody that substitutes for FVIII cofactor function, FVIIIa function and role on the FXase complex are drawing attention. It has been also supported that a concept that the extrinsic coagulation system involved in the initial phase of the coagulation process, the intrinsic coagulation system involved in the thrombin burst, the anti-coagulation system by activated protein C pathway, and the fibrinolytic system involved the dissolving fibrin clot intertwine each other and progress during the coagulation reaction process. FVIII-related FVIIa coagulation system and FVIII-related plasmin regulation system have been also elucidated. We greatly expect that the developmental elucidation of thrombus formation mechanism (s) centered on FVIII/FVIIIa could lead to the development of more effective new FVIII product and antithrombotic drugs.Genetic complexity and heterogeneity have made drug discovery difficult in human malignancies. In the past few years, we aimed to find vulnerabilities in therapy-resistant and refractory acute myeloid leukemia (AML) through integrative analyses of genomic data, clinical information, and results from in vivo/in vitro cell biological assays. Through analyses, we found that the cells of patients with AML show distinct sensitivity/resistance to small inhibiting molecules for anti-apoptosis and cell cycle/division. In particular, AML cells harboring the IDH1/2 mutations were highly sensitive to BCL-2 inhibition, while inhibition of IAP proteins resulted in efficient elimination of AML cells with varied FLT3, NRAS, and CBL mutations. Linking AML-initiating events with appropriate therapeutic strategies through cellular and genomic analyses might be further translated into nonmyeloid malignancies and solid tumors in the future.Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I. The clinical course of ATL is heterogeneous, and this condition has different types, which are as follows acute, lymphoma, chronic, and smoldering. The chronic type is further subclassified into favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL and favorable chronic and smoldering-type ATL are defined as aggressive and indolent ATL, respectively. Newly identified prognostic indices based on clinical parameters and/or genetic predictors should be incorporated in the stratified treatment approach. The standard of care for aggressive ATL is multiagent chemotherapy, followed by allogeneic hematopoietic stem cell transplantation if applicable. Meanwhile, that for indolent ATL is watchful waiting until progression to the aggressive type. The combination of interferon-α and zidovudine is a treatment option for indolent ATL in other countries, and a confirmatory phase 3 trial is ongoing in Japan. In addition to mogamulizumab, lenalidomide, and brentuximab vedotin, which have been recently utilized in clinical practice, the use of a novel histone deacetylase (HDAC) inhibitor has been filed for approval. Moreover, an EZH1/2 inhibitor has completed the enrollment of a phase 2 trial in Japan. The standard of care for elderly patients should be established because the median age of those with newly diagnosed ATL reaches up to 70 years old.Adult T-cell leukemia-lymphoma (ATL) is a rare disease, and the nationwide surveys conducted in Japan have played an important role in improving our understanding of the clinical features and prognosis of this disease. The diagnostic criteria of clinical subtypes have been proposed based on the surveys conducted on patients with ATL who were diagnosed in the 1980s; the current treatment guideline in Japan is based on this classification of ATL subtypes. In the survey for patients diagnosed between 2000 and 2009, the usefulness of the clinical subtypes was confirmed, and soluble interleukin-2 receptor was identified as a new prognostic factor for chronic- and smoldering-type ATL. We conducted another survey for patients who were diagnosed in 2010 and 2011. The age at diagnosis was higher than that reported in previous trials, and the median patient age at diagnosis was 68 years in the study. The 4-year survival rate was better than that in previous studies on acute- and lymphoma-type disease; however, the prognosis has not improved in chronic- and smoldering-type disease. Further nationwide surveys are expected to improve the treatment strategies for ATL.
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