In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

Integrated transcriptome and proteome analysis indicates potential biomarkers of prostate cancer in offspring of pregnant rats exposed to a phthalate mixture during gestation and lactation.

As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.

Recombinant human TIM-3 ectodomain expressed in bacteria and recovered from inclusion bodies as a stable and active molecule.

Introduction: Microbial systems, such as Escherichia coli, as host recombinant expression is the most versatile and the cheapest system for protein production, however, several obstacles still remain, such as recovery of soluble and functional proteins from inclusion bodies, elimination of lipopolysaccharides (LPS) contamination, incomplete synthesis, degradation by proteases, and the lack of post-translational modifications, which becomes even more complex when comes to membrane proteins, because they are difficult not only to produce but also to keep in solution in its active state. T-cell Immunoglobulin and Mucin domain 3 (TIM-3) is a type I transmembrane protein that is predominantly expressed on the surface of T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages, playing a role as a negative immune checkpoint receptor. TIM-3 comprises a single ectodomain for interaction with immune system soluble and cellular components, a transmembrane domain, and a cytoplasmic tail, responsible for the binding of signaling and scaffolding molecules. TIM-3 pathway holds potential as a therapeutic target for immunotherapy against tumors, autoimmunity, chronic virus infections, and various malignancies, however, many aspects of the biology of this receptor are still incompletely understood, especially regarding its ligands. Methods: Here we overcome, for the first time, the challenge of the production of active immune checkpoint protein recovered from bacterial cytoplasmic inclusion bodies, being able to obtain an active, and non-glycosylated TIM-3 ectodomain (TIM-3-ECD), which can be used as a tool to better understand the interactions and roles of this immune checkpoint. The TIM-3 refolding was obtained by the association of high pressure and alkaline pH. Results: The purified TIM-3-ECD showed the correct secondary structure and was recognized from anti-TIM-3 structural-dependent antibodies likewise commercial TIM-3-ECD was produced by a mammal cells system. Furthermore, immunofluorescence showed the ability of TIM-3-ECD to bind to the surface of lung cancer A549 cells and to provide an additional boost for the expression of the lymphocyte activation marker CD69 in anti-CD3/CD28 activated human PBMC. Discussion: Taken together these results validated a methodology able to obtain active checkpoint proteins from bacterial inclusion bodies, which will be helpful to further investigate the interactions of this and others not yet explored immune checkpoints.

A model for preservation of thymocyte-depleted thymus.

DiGeorge syndrome is a disorder caused by a microdeletion on the long arm of chromosome 22. Approximately 1% of patients diagnosed with DiGeorge syndrome may have an absence of a functional thymus, which characterizes the complete form of the syndrome. These patients require urgent treatment to reconstitute T cell immunity. Thymus transplantation is a promising investigational procedure for reconstitution of thymic function in infants with congenital athymia. Here, we demonstrate a possible optimization of the preparation of thymus slices for transplantation through prior depletion of thymocytes and leukocyte cell lineages followed by cryopreservation with cryoprotective media (5% dextran FP 40, 5% Me2SO, and 5% FBS) while preserving tissue architecture. Thymus fragments were stored in liquid nitrogen at -196°C for 30 days or one year. The tissue architecture of the fragments was preserved, including the distinction between medullary thymic epithelial cells (TECs), cortical TECs, and Hassall bodies. Moreover, depleted thymus fragments cryopreserved for one year were recolonized by intrathymic injections of 3×106 thymocytes per mL, demonstrating the capability of these fragments to support T cell development. Thus, this technique opens up the possibility of freezing and storing large volumes of thymus tissue for immediate transplantation into patients with DiGeorge syndrome or atypical (Omenn-like) phenotype.

A model for preservation of thymocyte-depleted thymus

DiGeorge syndrome is a disorder caused by a microdeletion on the long arm of chromosome 22. Approximately 1% of patients diagnosed with DiGeorge syndrome may have an absence of a functional thymus, which characterizes the complete form of the syndrome. These patients require urgent treatment to reconstitute T cell immunity. Thymus transplantation is a promising investigational procedure for reconstitution of thymic function in infants with congenital athymia. Here, we demonstrate a possible optimization of the preparation of thymus slices for transplantation through prior depletion of thymocytes and leukocyte cell lineages followed by cryopreservation with cryoprotective media (5% dextran FP 40, 5% Me2SO, and 5% FBS) while preserving tissue architecture. Thymus fragments were stored in liquid nitrogen at -196°C for 30 days or one year. The tissue architecture of the fragments was preserved, including the distinction between medullary thymic epithelial cells (TECs), cortical TECs, and Hassall bodies. Moreover, depleted thymus fragments cryopreserved for one year were recolonized by intrathymic injections of 3×106 thymocytes per mL, demonstrating the capability of these fragments to support T cell development. Thus, this technique opens up the possibility of freezing and storing large volumes of thymus tissue for immediate transplantation into patients with DiGeorge syndrome or atypical (Omenn-like) phenotype.

Age, Blasts, Performance Status and Lenalidomide Therapy Influence the Outcome of Myelodysplastic Syndrome With Isolated Del(5q): A Study of 58 South American Patients.

BACKGROUND: Myelodysplastic Syndrome (MDS) with isolated deletion 5q is associated with a low risk to leukemic evolution and long overall survival (OS); it comprises 3%-4.5% of MDS cases in Latin America classified according to the World Health Organization 2008. This study aims to describe clinical, laboratory and the outcome of patients according to the newest World Health Organization 2016 proposal. METHODS: We retrospectively reviewed patients from four Brazilian (BR) and four Argentinean (AR) centers diagnosed between 1999 and 2019. RESULTS: The 58 patients (16-AR and 42-BR) presented a median age of 67 (IQR 61-75) years old, women predominance (70.7%) and transfusion dependency (62.5%) at diagnosis. Median hemoglobin level was 8.1g/dL, 27.5% and 44.4% presented thrombocytosis and neutropenia, respectively. Bone marrow (BM) was predominantly hypercellular (43.1%) with 66% showing dysplasia >1 lineage and 37.9% with >2% of blasts. Deletion 5q was mostly isolated (79.3%) and a variety of abnormalities were observed in remaining cases. Most patients were treated with erythropoietin-stimulating agents (ESA), 18 with lenalidomide and 15 with thalidomide. Median follow-up was 7.6 years, with a median OS of 3.5 years and an 8-years leukemic evolution rate of 18.4%. Multivariate analysis showed that age >75 years (HR 2.19), ECOG ≥2 (HR 5.76), BM blasts >2% (HR 2.92) and lenalidomide treatment (HR 0.25) independently influenced the OS. CONCLUSION: Older age, worse performance status and higher percentage of blasts, that can be easily assessed, were associated to a worse prognosis. Also, our results corroborate the protective influence of lenalidomide in terms of OS in this South American series.

Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia.

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.

Evaluating the menopausal transition with the STRAW + 10 in a Brazilian cohort of women with HIV, 2015-2016.

BACKGROUND: Menopausal transition is a physiological process encompassing hormonal and body changes that impact women's health and life quality. This period may be characterized by the Stages of Reproductive Aging Workshop (STRAW + 10) criteria using menstrual patterns. Use of the STRAW + 10 is uncertain in HIV infection. We aimed to characterize menopausal transition in women with HIV (WWH) using the STRAW + 10 criteria, hormonal measures and menopause symptoms. METHODS: We performed a cross-sectional study, nested to the HIV-Infected Women's Cohort, in Rio de Janeiro, Brazil. Eligible women included those aged 30 years or older, without clinical or surgical menopause, hormonal contraception, replacement therapy and ovarian disorders. We conducted face-to-face interviews and collected blood samples for follicle stimulating hormone (FSH) and estradiol measures. RESULTS: We enrolled 328 WWH (28.3% of women in the cohort). The distribution of age, hormonal levels and reported symptoms per each STRAW + 10 stage was consistent with the expected distribution in the menopausal transition. Age and FSH significantly increased and estradiol decreased from stage -2 (7 + days of menstrual delay) to stage +2 (8 + years of amenorrhea). CONCLUSIONS: The present results support use of the STRAW + 10 to characterize the menopausal transition of WWH with good clinical and immunological control.

Pituitary neuroendocrine tumors and differentiated thyroid cancer: do metabolic and inflammatory risk factors play roles?

PURPOSE: It is postulated that patients with different types of pituitary neuroendocrine tumors (PitNETs) may present a higher incidence of cancer. Factors underlying individuals becoming overweight, such as insulin resistance, hyperleptinemia, and low-grade inflammation, may play a role in the risk of differentiated thyroid carcinoma (DTC) in such patients. This study aimed to investigate the frequency of and obesity-related risk factors associated with DTC in patients with PitNETs. METHODS: This cross-sectional study involved 149 patients with nonacromegalic PitNETs (AG group), 71 patients with acromegaly (ACRO group), and 156 controls (CG group). All participants underwent insulin and blood glucose measurements with the determination of the homeostatic model assessment-insulin resistance (HOMA-IR) index, leptin, and high-sensitivity C-reactive protein (hsCRP), and they also underwent thyroid ultrasound. Clinically significant nodules were biopsied for subsequent cytopathological evaluation, and participants were operated on when indicated. RESULTS: Patients in the AG group had high levels of insulin resistance and significantly higher levels of leptin and hsCRP compared with those of patients in the ACRO group. There were no cases of DTC in the AG group; two findings, one incidental, of DTC occurred in the CG group, and three cases of DTC were present in the ACRO group. Acromegaly was associated with DTC after adjusted analysis. CONCLUSIONS: Our findings in patients with nonacromegalic PitNETs do not indicate a high risk for DTC despite the presence of metabolic and inflammatory risk factors for neoplastic events. In contrast, acromegaly promotes a greater risk of DTC.

Effects of dietary fibre intake in chemotherapy-induced mucositis in murine model.

Mucositis is an inflammation of the gastrointestinal mucosa resulting from high doses of radio/chemotherapy treatment and may lead to interruption of antineoplasic therapy. Soluble fibres, like pectin, increase SCFA production, which play a role in gut homoeostasis and inflammation suppression. Due to the properties of pectin, the aim of the present study was to evaluate the effect of a high-fibre (HF) diet on chemotherapy-induced mucositis in a murine model. C57/BL6 mice received control (AIN93M), HF, low/zero fibre (LF) diets for 10 d prior to mucositis challenging with irinotecan (75 mg/kg), or they were treated with acetate added to drinking water 5 d prior to and during the mucositis induction. Mice that received the HF diet showed decreased immune cells influx and improved histopathological parameters in the intestine, compared with mice that received the normal diet. Furthermore, the HF diet decreased intestinal permeability induced in the mucositis model when compared with the control group. This effect was not observed for acetate alone, which did not improve gut permeability. For instance, mice that received the LF diet had worsened gut permeability, compared with mice that received the normal diet and mucositis. The effects of the HF and LF diets were shown to modulate the intestinal microbiota, in which the LF diet increased the levels of Enterobacteriaceae, a group associated with gut inflammation, whereas the HF diet decreased this group and increased Lactobacillus and Bifidobacterium (SCFA producers) levels. In conclusion, the results demonstrated the importance of dietary fibre intake in the modulation of gut microbiota composition and homoeostasis maintenance during mucositis in this model.

Marco Técnico de Referencia para la Interoperabilidad de Expedientes Clínicos Electrónicos: Modelo del Dominio / Technical Reference Framework for the Interoperability of Electronic Medical Record: Domain Model

Resumen El objetivo de esta investigación es la modelación del dominio de un marco técnico de compartición e interacción de un expediente clínico electrónico (ECE) entre diversas instituciones de salud, públicas o privadas, como primer paso para lograr un marco técnico de refererencia para la interoperabilidad de sistemas de ECE en México. Se ha utilizado el proceso sistemático KMOS-RE para obterner los diversos artefactos que conforman el modelo: el léxico extendido del conocimiento del domino, los modelos conceptuales del dominio de aplicación y del dominio de la solución y los modelos de estados. Debido a que el diseño e implementación de los sistemas de ECE de cada una de las instituciones de salud se generan de manera independiente, realizar un marco técnico de referencia representa un gran desafío y una gran oportunidad, ya que ofrecerá ventajas importantes, como el hecho de contar con la información clínica de manera oportuna en cualquier institución de salud, la posibilidad de que el propio paciente acceda a su información y la facilidad de realizar investigación clínica a partir de los datos compartidos. Aún cuando la modelación de un dominio es dinámica, el contar con un modelo del dominio lo más preciso posible en este punto, facilitará los siguientes pasos para lograr el marco técnico de referencia propuesto.

Abstract This paper presents the domain modeling of a technical framework of sharing and interaction of an electronic medical record among different healthcare institutions, both public or private, as a first step to establish a technical reference framework for the interoperability of electronic medical record systems in Mexico. The artefact that make up the domain model were carried out using the KMOS-RE systematic process. Through this process, the following components have been obtained: the knowledge domain extended lexicon, the conceptual models, one for the application domain and another for the solution domain, as well as the state models. Since the design and implementation of the electronic medical record systems of different healthcare institutions are generated independently, having a technical reference framework represents a great challenge but also a great opportunity, since it will offer important advantages, such as having the clinical information in a timely manner in any healthcare institution, the possibility of the patient accessing their own information and the ease of conducting clinical research from the shared data. Even when a domain modeling is a dynamic task, having a precise domain model at this point will facilitate the next steps to achieve the proposed technical reference framework.

Correction: Long-term clinical outcomes in a cohort of patients with solitary plasmacytoma treated in the modern era.

[This corrects the article DOI: 10.1371/journal.pone.0219857.].

Long-term clinical outcomes in a cohort of patients with solitary plasmacytoma treated in the modern era.

BACKGROUND: The risk of recurrence of solitary plasmacytoma (SP)/progression to MM is well established, but patient, imaging and treatment factors influencing risk of progression require further evaluation. METHODS: This is a retrospective analysis of 66 SP patients (23 UK, 43 Brazil) diagnosed 1989-2016. Patient baseline characteristics were recorded. The incidence of progression to MM was calculated, including biochemical and imaging findings and the treatment modality received. Survival estimates were determined by Kaplan-Meier analyses. RESULTS: With a median follow-up of 53.6 months the 5 year overall survival (OS) was 90.7% (95%CI 79-96%). The median progression free survival (PFS) from diagnosis was 61 months. Cumulative incidence of progression to MM was 49.9% at 5 years (95% CI 35.6-62.6%) and was significantly higher with bone plasmacytoma (47.2%, 95%CI 31.9-61.1%), than an extramedullary location (8.3%, 95%CI 0.4-32.3%, Gray test p = 0.0095)). The majority of patients with solitary bony plasmacytoma (SBP) received radiotherapy (RT) (51/53, 96.2%) whereas most extramedullary cases were treated with surgical resection (7/13, 53.8%). A small proportion of SBP patients received additional upfront chemotherapy, with 5/6 in remission after a median follow-up (FU) of 10 years. The diagnostic yield of surveillance functional FU imaging without other indications of relapse/progression was low. The positive predictive value of functional FU imaging was high but with a low negative predictive value, especially in cases of suspected relapse/progression. CONCLUSION: Our data suggests functional imaging should be used if clinical suspicion of relapse/progression, rather than a routine surveillance tool, and upfront adjuvant chemotherapy is worthy of prospective evaluation.

Attrition at the final donor stage among unrelated haematopoietic stem cell donors: the British Bone Marrow Registry experience.

OBJECTIVES: To investigate attrition at the finally selected donor stage among British Bone Marrow Registry (BBMR) donors, all recruited from blood donors. BACKGROUND: The success of searches for unrelated stem cell donors relies on the existence of large international donor registries and the availability of registered donors when matched with a patient. Withdrawal of donors may adversely affect patient outcomes. MATERIALS/METHODS: Data on 2942 planned donations were analysed to assess donor-related deferral rates and associated factors. RESULTS: Overall, 20·2% of requests were cancelled. Transplant centres activated more than half of the cancellations (52·6%). Donor reasons accounted for 46·7% of cancellations (9·4% of requests), of which 61·7% happened for medical and 38·3% for personal reasons. Medical ineligibility of the donor was associated with increasing age (odds ratio [OR] = 1·36, P = 0·011) and peripheral blood stem cell source (OR = 2·22, P = 0·006), and there was some evidence of association with low blood donation reliability (OR = 1·52, P = 0·054). The blood donor reliability score relates to blood donation, and the score worsens if donors consistently fail to attend a donation session when invited. Withdrawal on personal grounds showed associations with donor age (OR = 1·72, P = 0·017, 30-40 years vs other ages), peripheral blood stem cell source (OR = 2·43, P = 0·010) and low blood donor reliability (OR = 1·94, P = 0·007). CONCLUSIONS: To our knowledge, this is the first report on all-cause cancellation at the finally-selected donor stage for international stem cell donor provision, showing 9·4% donor-related cancellation rate. Scores associated with blood donation reliability may be useful to predict stem cell donor withdrawal.

Prevalence of children exposed to secondhand smoke at home and in the car in Azores (Portugal).

OBJECTIVES: To identify the prevalence of exposure to secondhand smoke (SHS) at home and in the car among children attending the 4th grade in Azores. METHODS: This is a cross-sectional study that assessed children's exposure to SHS in a convenience sample of school children attending the 4th grade in all primary schools of Azores. The entire population of 4th graders from all elementary schools in Azores were asked to participate in the study (n=2463) in 2017. A validated self-reported questionnaire was administered to 2092 students who delivered the signed informed consent form. We analyzed frequencies, contingency tables, and performed Chi-square tests. RESULTS: Results showed that 56.1% (95% CI 54.0-58.2) children reported having, at least, one smoking parent. Overall exposure to SHS at home was 38.4% (95% CI 36.3-40.6), and overall exposure to SHS in the car was 27.6% (95% CI 25.8-29.3). Children whose parents were smokers reported being more exposed to SHS at home (63.6%; 95% CI 58.6-68.3) than children whose parents were non-smokers (32.3%; 95% CI 30.2-34.6). CONCLUSION: The results showed that the children's exposure to SHS in Azores is high and it tends to be higher than the prevalence found in mainland Portugal. Having parents who smoke is a major risk factor for children's exposure to SHS at home. These data justify a population-wide intervention plan for preventing tobacco consumption and children's exposure to SHS in Azores.

Epidemiology, risk factors and outcomes of multi-drug-resistant bloodstream infections in haematopoietic stem cell transplant recipients: importance of previous gut colonization.

BACKGROUND: Bloodstream infections (BSI) are a major complication in the early phase of a haematopoietic stem cell transplant (HSCT). AIM: To describe the incidence and risk factors for BSI occurring in the pre-engraftment phase of HSCT, and its impact on mortality. METHODS: Clinical variables of 232 HSCT patients were analysed retrospectively between 2014 and 2015. Univariate Cox regression analyses were performed to test the association between each covariate and the outcome. Covariates with P < 0.10 on univariate analysis were included in a multiple Cox regression analysis using a backward elimination method. FINDINGS: The cumulative incidence of BSI was 25.4%, mainly caused by Gram-negative bacteria (GNB) (55.2%). Approximately 40.5% of the patients had gut colonization by multi-drug-resistant (MDR) bacteria (vancomycin-resistant enterococcus and carbapenem-resistant GNB). Among patients colonized by MDR GNB, 20% developed an overt BSI due to MDR bacteria with the same pattern of sensitivity. Of the 13 deaths related to infection, 10 were patients with BSI caused by MDR GNB. The independent risk factors for BSI were gut colonization by MDR bacteria including GNB (P < 0.001) and duration of neutropenia >10 days (P = 0.005), and those associated with BSI caused by MDR bacteria were age >62 years (P = 0.03), use of total parenteral nutrition (TPN) (P < 0.001) and previous gut colonization by MDR GNB (P = 0.002). CONCLUSIONS: Previous gut colonization by MDR was an independent risk factor for BSI, together with TPN and age, and had an impact on outcome. These findings suggest that gut decolonization may be a potential strategy to prevent BSI.

Mieloma múltiplo em cão com apresentação clínica atípica de paralisia facial bilateral: relato de caso / Multiple Myeloma in dog with atypical clinical presentation of bilateral facial paralysis: case report

Objetivou-se com o presente trabalho relatar um caso de mieloma múltiplo (MM) em uma cadela com apresentação clínica atípica de rigidez da musculatura facial. Foram realizados hemogramas seriados, exames bioquímicos, sumário de urina, sorologia para leishmaniose, radiografias de crânio, citologia de medula óssea e eletroforese de proteínas séricas. O infiltrado plasmocitário em medula óssea >20%, a gamopatia monoclonal e as lesões compatíveis com lise óssea, observados no mielograma, eletroforese de proteínas e exame radiográfico, respectivamente, foram determinantes para conclusão diagnóstica de MM. A doença pode ter uma apresentação clínica variável em cães e representar um desafio ao diagnóstico na clínica de animais de companhia, principalmente em áreas endêmicas de doenças infecciosas que se manifestam com apresentações clínicas e laboratoriais semelhantes.(AU)

This paper reports a case of multiple myeloma (MM) in a bitch with atypical clinical presentation of rigidity of the facial muscles. Hemogram, biochemical tests, urinalysis, serology for leishmaniasis, skull radiography, bone marrow cytology and serum protein electrophoresis were performed. The plasma cell infiltration in bone marrow was >20 %, the monoclonal gammopathy and lesions compatible with bone lysis observed in the myelogram, protein electrophoresis and radiographic examination respectively, were decisive for diagnostic conclusion of MM. The disease may have a variable clinical presentation in dogs and pose a challenge for diagnosis in the pet clinic, especially in endemic areas of infectious diseases that present with similar clinical and laboratory presentations.(AU)

Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe de Moelle Osseuse et Thérapie Cellulaire and Eurocord.

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

Outcomes of UCB transplantation are comparable in FLT3+ AML: results of CIBMTR, EUROCORD and EBMT collaborative analysis.

Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FMS-like tyrosine kinase 3+ (FLT3+) acute myeloid leukemia (AML), which has poor prognosis because of high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126) (hazard ratio (HR) 0.86, P=0.54) and URD (n=91) (HR 0.81, P=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, P=0.02), but not vs URD (HR 1.72, P=0.07). All three cohorts had statistically nonsignificant 3-year LFS: 39% (95% confidence interval (CI): 30-47) after UCB, 43% (95% CI: 30-54) after sibling and 50% (95% CI: 40-60) after URD. Chronic graft-versus-host disease rates were significantly lower after UCB compared with either sibling (HR 0.59, P=0.03) or URD (HR 0.49, P=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2 (second CR). UCB is a suitable option for adults with FLT3+ AML in the absence of an human leukocyte antigen-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common, thus allowing HCT in CR1 (first CR) when outcomes are best.