Children Hunger 2/13/1985 News Release Selct Committee on Hunger U.S. House of Representatives H2-507 School Lunch for Millions of Poor Children Threatened

Children Hunger 2/13/1985 News Release Selct Committee on Hunger U.S. House of Representatives H2-507 School Lunch for Millions of Poor Children Threatene

Taksimarkkinoiden suorituskyvyn mittarit:mittaristo markkinoiden suorituskyvyn jatkuvaan mittaamiseen

Tiivistelmä. Taksimarkkinat vapautuivat pääosin kilpailulle heinäkuussa 2018, jolloin uuden liikennepalvelulain toinen vaihe astui voimaan. Lain säätämisen yhteydessä eduskunta edellytti, että lain vaikutuksia seurataan tiiviisti ja mikäli tarve vaatii, tulee valtioneuvoston ryhtyä toimiin sääntelyn muuttamiseksi. Vaikutusten arvioinnin tunnistettiin kuuluvan Liikenne- ja viestintäministeriön hallinnonalalle ja erityisesti Liikenne- ja viestintävirasto Traficomille. Tämän työn tarkoituksena on osaltaan vastata vaikutusten arviointitarpeisiin ja luoda kehikko taksimarkkinoiden pitkän aikavälin seurantaa varten. Tutkielman tavoitteena on täydentää teoreettiseen ja empiiriseen aineistoon pohjaten aikaisempaa strategisen johdon laskentatoimen tutkimuskenttää ulkoisten markkinoiden seurannan osalta suomalaisessa julkishallinnon organisaatiossa. Aikaisemman kirjallisuuden perusteella luodaan ensin kokonaiskuva strategisesta johdon laskentatoimesta, minkä jälkeen pureudutaan syvemmin kokonaisvaltaiseen suorituskyvyn mittaamiseen, joka on yksi strategisen johdon laskentatoimen osa-alueista. Tämän jälkeen toteutetaan empiirinen tapaustutkimus, jossa hyödynnetään konstruktiivista tutkimusotetta. Tutkimus on laadullinen ja tutkimusaineisto kerättiin teemahaastatteluin sekä analysoimalla sisällönanalyysin keinoin organisaation julkisia aineistoja. Tutkimuksen kohteena on Liikenne- ja viestintävirasto Traficom, mutta teoreettinen viitekehys huomioon ottaen myös Liikenne- ja viestintäministeriötä käsitellään tutkielmassa. Liikenne- ja viestintäministeriön hallinnonalalla ja Traficomissa seurataan yleisesti tavoitteiden asettamisessa ja mittaamisessa strategisen johdon laskentatoimen kirjallisuudessa ehdotettuja käytäntöjä. Tavoitteet johdetaan strategiasta ja niiden toteutumista mitataan sekä rahamääräisillä että ei-rahamääräisillä mittareilla. Strategiaa myös kommunikoidaan aktiivisesti organisaatiossa eteenpäin. Taksimarkkinoiden seuranta ei kuitenkaan täytä strategisen johdon laskentatoimen teoriassa esitettyjä käytäntöjä. Nykyiset seurantatyökalut ovat hyödyllisiä ja tarkoituksenmukaisia, mutta eivät sellaisenaan täytä teoriassa esitettyjä kokonaisvaltaisen suorituskyvyn mittaamisen piirteitä. Tutkielmassa rakennetaankin teoreettiseen viitekehykseen, empiiriseen aineistoon ja organisaation sekä sidosryhmien tarpeisiin pohjaten kokonaisvaltainen suorituskykymittaristo, joka koostuu kolmen eri mittariston organisaatiolle sopivimmista puolista. Tämän tutkielman tulokset eivät ole yleistettävissä, sillä suorituskykymittaristo on rakennettu niin spesifin osa-alueen suorituskyvyn mittaamiseen, että organisaation strategia ja tarpeet huomioiden sitä ei voida sellaisenaan siirtää muun organisaation käyttöön. Tutkimus tarjoaa kuitenkin hyödyllistä informaatiota strategisen johdon laskentatoimen sovelluksista sekä suorituskyvyn mittaamisesta ulkoisen markkinan osalta suomalaisessa julkisorganisaatiossa

Gemtuzumab-Ozogamicin-Related Impaired Hemoglobin-Haptoglobin Scavenging as On-Target/Off-Tumor Toxicity of Anti-CD33 AML Therapy : A Report of Two Cases

Gemtuzumab-ozogamicin (GO) is a humanized anti-CD33 antibody, which is conjugated to a cytotoxic calicheamicin. It is used to treat acute myeloid leukemia (AML) in combination with chemotherapy. We describe here two GO-treated acute myeloid leukemia (AML) cases: both patients suffered from a toxic syndrome, which manifested as impaired hemoglobin-haptoglobin scavenging and accumulation of hemolysis-related products. Our observations and earlier reports indicated that the reaction was caused by GO-targeted destruction of CD33 + CD163+ monocytes/macrophages, which are responsible for the clearance of hemoglobin-haptoglobin complexes. The rise of plasma lactate dehydrogenase was an early sign of the reaction, and both patients had high levels of free plasma hemoglobin, but plasma haptoglobin and bilirubin levels were paradoxically normal. Symptoms included septic fever and abnormalities in cardiac tests and in the case of the first patient, severe neurological symptoms which required intensive care unit admittance. Therapeutic plasma exchanges supported the patients until the recovery of normal hematopoiesis. The symptoms may be easily confounded with infectious complications-related organ damage. Regarding the increasing use of gemtuzumab-ozogamicin and other emerging CD33-targeted cell therapies, we want to highlight this mostly unknown and probably underdiagnosed toxicity.Peer reviewe

Increased myeloid cell hypoxia-inducible factor-1 delays obliterative airway disease in the mouse

BACKGROUND: Obliterative bronchiolitis after lung transplantation is characterized by chronic airway inflammation leading to the obliteration of small airways. Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular responses to hypoxia and inflammation. The Von Hippel-Lindau protein (pVHL) drives the degradation of oxygen-sensitive subunit HIF-1 alpha that controls the activity of HIF-1. We investigated the effect of myeloid cell targeted gene deletion of HIF-1 alpha or its negative regulator pVHL on the development of obliterative airway disease (OAD) in the recipients of tracheal allografts, a mouse model for obliterative bronchiolitis after lung transplantation. METHODS: Tracheal allografts were heterotopically transplanted from BALB/c donor mice to fully major histocompatibility complex mismatched recipient mice with HIF-1 alpha or VHL gene deletion in myeloid cells. The recipients were left non-immunosuppressed or received tacrolimus daily. Histologic, immunohistochemical, and real-time reverse transcription polymerase chain reaction analyses were performed at 3, 10, and 30 days. RESULTS: In the absence of immunosuppression, myeloid cell-specific VHL deficiency of the recipient mice improved epithelial recovery, decreased inflammatory cell infiltration and expression of pro-inflammatory cytokines, increased regulatory forkhead box P3 messenger RNA expression, and reduced OAD development in tracheal allografts. In the presence of tacrolimus immunosuppression, loss of HIF-1 alpha activity in myeloid cells of the recipient by HIF-1 alpha gene deletion accelerated OAD development in mouse tracheal allografts. CONCLUSIONS: Activity of the HIF-pathway affects the development of allograft rejection, and our results suggest that myeloid cell-specific VHL-deficiency that potentially increases HIF-activity decreases allograft inflammation and the subsequent development of OAD in mouse tracheal allografts. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.Peer reviewe

Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia

Despite recent progress in acute lymphoblastic leukemia (ALL) therapies, a significant subset of adult and pediatric ALL patients has a dismal prognosis. Better understanding of leukemogenesis and recognition of germline genetic changes may provide new tools for treating patients. Given that hematopoietic stem cell transplantation, often from a family member, is a major form of treatment in ALL, acknowledging the possibility of hereditary predisposition is of special importance. Reports of comprehensive germline analyses performed in adult ALL patients are scarce. Aiming at fulfilling this gap of knowledge, we investigated variants in 93 genes predisposing to hematologic malignancies and 70 other cancer-predisposing genes from exome data obtained from 61 adult and 87 pediatric ALL patients. Our results show that pathogenic (P) or likely pathogenic (LP) germline variants in genes associated with predisposition to ALL or other cancers are prevalent in ALL patients: 8% of adults and 11% of children. Comparison of P/LP germline variants in patients to population-matched controls (gnomAD Finns) revealed a 2.6-fold enrichment in ALL cases (CI 95% 1.5-4.2, p = 0.00071). Acknowledging inherited factors is crucial, especially when considering hematopoietic stem cell transplantation and planning post-therapy follow-up. Harmful germline variants may also predispose patients to excessive toxicity potentially compromising the outcome. We propose integrating germline genetics into precise ALL patient care and providing families genetic counseling.Peer reviewe

Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4(+) T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n=134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4(+) T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies. Chronic graft versus host disease (cGvHD) is a major cause of morbidity and mortality in allogeneic bone marrow transplantation. Here the authors identify a recurrent activating mTOR mutation in expanded donor T-cell clones of 3 cGvHD patients, which suggests somatic mutations may contribute to GvHD pathogenesis and opens avenues to targeted therapies.Peer reviewe

Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia

The prevalence and functional impact of somatic mutations in nonleukemic T cells is not well characterized, although clonal T-cell expansions are common. In immune-mediated aplastic anemia (AA), cytotoxic T-cell expansions are shown to participate in disease pathogenesis. We investigated the mutation profiles of T cells in AA by a custom panel of 2533 genes. We sequenced CD4+ and CD8+ T cells of 24 AA patients and compared the results to 20 healthy controls and whole-exome sequencing of 37 patients with AA. Somatic variants were common both in patients and healthy controls but enriched to AA patients' CD8+ T cells, which accumulated most mutations on JAK-STAT and MAPK pathways. Mutation burden was associated with CD8+ T-cell clonality, assessed by T-cell receptor beta sequencing. To understand the effect of mutations, we performed single-cell sequencing of AA patients carrying STAT3 or other mutations in CD8+ T cells. STAT3 mutated clone was cytotoxic, clearly distinguishable from other CD8+ T cells, and attenuated by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation of their role in the pathogenesis of AA.Peer reviewe

Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4+ T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.</p