ABSTRACT
Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.
Subject(s)
Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 14 , DNA-Binding Proteins/genetics , Genetic Loci , Kidney Neoplasms/genetics , STAT3 Transcription Factor/genetics , Transcription Factors/genetics , Carcinogenesis/genetics , Carcinogenesis/immunology , Carcinogenesis/pathology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , Cell Line, Tumor , Chromatin/chemistry , Chromatin/immunology , Chromatin Assembly and Disassembly/immunology , Cytokines/genetics , Cytokines/immunology , DNA-Binding Proteins/immunology , Gene Expression Regulation , Genetic Predisposition to Disease , Genome, Human , Genome-Wide Association Study , High-Throughput Nucleotide Sequencing , Humans , Immunotherapy/methods , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Polymorphism, Single Nucleotide , STAT3 Transcription Factor/immunology , T-Lymphocytes, Cytotoxic , Transcription Factors/immunologyABSTRACT
BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies. METHODS AND RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells. CONCLUSION: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.
Subject(s)
Leukocytes, Mononuclear , RecQ Helicases , Adult , Female , Humans , Male , DNA Helicases/genetics , DNA Helicases/metabolism , DNA Repair/genetics , Leukocytes, Mononuclear/metabolism , RecQ Helicases/genetics , RecQ Helicases/metabolism , Telomere/metabolism , Telomere/genetics , Telomere Homeostasis/geneticsABSTRACT
INTRODUCTION: Allogeneic Hematopoietic Stem Cells Transplantation (allo-HSCT) is capable of curing patients with neoplastic or non-neoplastic hematologic disorders or of prolonging their survival. This study assessed if the insertion of the clinical pharmacist in the allo-HSCT team modified the outcomes: transplantation-related mortality, grafting failure, incidence of Graft versus Host Disease, hospitalization time, time for grafting, number of readmissions, number of drug-related problems (DRPs), adherence and knowledge about pharmacotherapy. METHODS: Interventional study with historical control carried out in an allo-HSCT unit, in which the intervention group (IG) included 33 individuals who received pharmacotherapy follow-up. Control Group (CG) consisted of 28 individuals. RESULTS: A total of 250 DRPs were identified, 59 team's doubts were clarified, and 309 interventions were conducted in the IG. The DRPs mainly arose from safety (51.60%) and effectiveness (38.40%) problems. A mean of 9.36 (SD = 6.97) interventions per patient was obtained, mainly including dose reductions (19.09%), adjustments in administration time (18.12%), educational activities (15.21%) and drug removal (10.68%). Clinical significance of the interventions was considered high (75.7% extremely significant, very significant or significant), as well as their acceptability (89.7% accepted). Each patient attended a mean of 4.68 pharmaceutical consultations (SD = 1.91) after hospital discharge, presenting increase in knowledge (p = 0.0001) and in adherence (p = 0.0115). There was no evidence of differences between the groups in the other outcomes analyzed. CONCLUSIONS: The pharmacotherapy follow-up allowed detecting several DRPs and performing interventions of high clinical relevance and acceptability, in addition to improving adherence and individualizing the pharmacotherapy.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Pharmacists , Hematopoietic Stem Cell Transplantation/adverse effects , Hospitalization , Graft vs Host Disease/prevention & control , Graft vs Host Disease/etiology , Hematopoietic Stem Cells , Retrospective StudiesABSTRACT
BACKGROUND: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is currently one of the most effective therapies in onco-hematology. For the treatment of the disease and prevention of such complications, a complex pharmacotherapeutic regimen is employed. Non-compliance is prevalent among adolescents and young adults with chronic hematological diseases, being reported by up to 50% of the patients. OBJECTIVE: To evaluate the results of pharmacotherapeutic follow-up on medication compliance and on the knowledge about pharmacotherapy of patients who underwent allo-HSCT. METHODS: A single-arm, open-label and non-randomized intervention study developed in an allo-HSCT outpatient clinic. The participants attended pharmaceutical consultations and had their knowledge about pharmacotherapy and medication compliance measured by MedTake and Brief Medication Questionnaire (BMQ), respectively. RESULTS: A total of 27 patients attended pharmaceutical consultations (4.81 consultations/patient; SD = 1.80). There was an improvement in medication compliance and in knowledge between the first and last consultations (p < 0.05). In the final consultation, 70.37% of the patients showed compliance, with a knowledge rate of 98.35% (SD = 3.63). Non-compliant individuals presented a greater tendency to hospital readmissions. There was no relationship between medication compliance and sociodemographic variables, graft-versus-host disease, and knowledge about pharmacotherapy. CONCLUSIONS: Pharmacotherapeutic follow-up contributed to improving medication compliance. Knowledge about pharmacotherapy alone does not translate into behaviors, which corroborates the complexity of the biopsychosocial factors associated with medication compliance.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Adolescent , Young Adult , Humans , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/drug therapy , Graft vs Host Disease/prevention & control , Graft vs Host Disease/etiology , Medication Adherence , Pharmaceutical Preparations , Retrospective StudiesABSTRACT
INTRODUCTION: Cancer-associated-cachexia represents a systemic syndrome of unintended weight-loss (WL) and systemic inflammation, affecting >80% patients with pancreatic adenocarcinoma (PA). We aimed to evaluate the association of weight change (WC) with survival of patients treated with chemotherapy (ChT) for PA and the influence of disease staging. We also studied the prognostic and predictive value of inflammation-based scores. METHODS: Observational, retrospective cohort study. Individuals were divided into two cohorts, according to WC (WL ≥5% vs. non-WL <5%) after ChT. Main endpoints were weight change and survival time. Statistical analysis was performed using Stata software. RESULTS: Sixty-five patients were included (median age 69; 48% female), 60% with advanced disease. At 3 months after ChT start, 54% experienced WL. Advanced disease independently predicted WL (OR 2.10; 95% CI, 1.11-19.6; p = 0.041). With median follow-up of 14.8 mo, median survival time of patients with WL was 18.5 mo, vs. 33.2 vs. for non-WL (HR 2.28; 95% CI, 1.15-4.52; p = 0.019). In patients with early-stage disease, WL was associated with decreased survival time (21.9 vs. 67.6 mo; HR 23.68; 95% CI 2.39-234.75; p = 0.007), while the association of WL on survival time in advanced disease was not significant (HR 0.74; 95% CI, 0.34-1.60; p = 0.449). The multivariate survival model showed that WL (HR 1.11, 95% CI 1.03-1.20, p = 0.005) and cachexia (HR 3.76, 95% CI 1.07-13-18), p = 0.041) were associated with survival time, as well as location in body or tail (HR 3.05; 95% CI, 1.75-5.31; p < 0.001) and high Neutrophil-to-lymphocyte ratio (NLR) at 3 months (HR 6.20; 95% CI, 2.59-14.87; p < 0.001). CONCLUSION: WL was an independent prognostic factor for survival. Particularly in early stage disease, interventions targeting this modifiable factor may translate into better outcomes for PA patients. NLR may be a surrogate marker of systemic inflammatory status in this setting.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Weight Loss , Adenocarcinoma/complications , Adenocarcinoma/drug therapy , Aged , Biomarkers , Female , Humans , Inflammation , Lymphocytes , Male , Neoplasm Staging , Neutrophils , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/drug therapy , Prognosis , Retrospective StudiesABSTRACT
Severe aplastic anemia (SAA) is a life-threatening disease that can be cured with allogeneic cell transplantation (HCT). Haploidentical donor transplantation with post-transplantation cyclophosphamide (haplo-PTCy) is an option for patients lacking an HLA-matched donor. We analyzed 87 patients who underwent haplo-PTCy between 2010 and 2019. The median patient age was 14 years (range, 1 to 69 years), most were heavily transfused, and all received previous immunosuppression (25% without antithymocyte globulin). Almost two-thirds (63%) received standard fludarabine (Flu)/cyclophosphamide (Cy) 29/total body irradiation (TBI) 200 cGy conditioning, and the remaining patients received an augmented conditioning: Flu/Cy29/TBI 300-400 (16%), Flu/Cy50/TBI 200 (10%), or Flu/Cy50/TBI 400 (10%). All patients received PTCy-based graft-versus-host disease (GVHD) prophylaxis. Most grafts (93%) were bone marrow (BM). The median duration of follow-up was 2 years and 2 months. The median time to neutrophil recovery was 17 days. Primary graft failure occurred in 15% of the patients, and secondary or poor graft function occurred in 5%. The incidences of grade II-IV acute GVHD was 14%, and that of chronic GVHD was 9%. Two-year overall survival and event-free survival (EFS) were 79% and 70%, respectively. EFS was higher for patients who received augmented Flu/Cy/TBI (hazard ratio [HR], .28; P = .02), and those who received higher BM CD34 cell doses (>3.2 × 10E6/kg) (HR, .29; P = .004). The presence of donor-specific antibodies before HSCT was associated with lower EFS (HR, 3.92; P = .01). Graft failure (HR, 7.20; P < .0001) was associated with an elevated risk of death. Cytomegalovirus reactivation was frequent (62%). Haploidentical HCT for SAA is a feasible procedure; outcomes are improved with augmented conditioning regimens and BM grafts with higher CD34 cell doses.
Subject(s)
Anemia, Aplastic , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Aged , Anemia, Aplastic/therapy , Child , Child, Preschool , Cyclophosphamide/therapeutic use , Graft vs Host Disease/prevention & control , Humans , Infant , Middle Aged , Transplantation Conditioning , Young AdultABSTRACT
Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll-like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34-0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53-6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.
Subject(s)
Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/microbiology , Bacterial Infections/genetics , Toll-Like Receptor 2/genetics , Adolescent , Adult , Africa/epidemiology , Aged , Anemia, Sickle Cell/epidemiology , Anemia, Sickle Cell/immunology , Bacterial Infections/epidemiology , Bacterial Infections/immunology , Brazil/epidemiology , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Male , Middle Aged , Young AdultABSTRACT
We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and ≥4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3.4 × 107/kg. In multivariable analysis, patients receiving CBUs with GG-CTLA4 genotype had poorer neutrophil recovery (hazard ratio [HR], 1.33; P = .02), increased nonrelapse mortality (NRM) (HR, 1.50; P < .01), and inferior disease-free survival (HR, 1.41; P = .02). We performed the same analysis in a more homogeneous subset of cohort 1 (cohort 2, n = 305) of patients who received transplants for acute leukemia, all given a myeloablative conditioning regimen, and with available allele HLA typing (HLA-A, -B, -C, and -DRB1). In this more homogeneous but smaller cohort, we were able to demonstrate that GG-CTLA4-CBU was associated with increased NRM (HR, 1.85; P = .01). Use of GG-CTLA4-CBU was associated with higher mortality after CBT, which may be a useful criterion for CBU selection, when multiple CBUs are available.
Subject(s)
CTLA-4 Antigen/immunology , Cord Blood Stem Cell Transplantation , HLA Antigens/immunology , Hematologic Neoplasms/genetics , Polymorphism, Genetic , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/immunology , Adolescent , Adult , Alleles , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/immunology , CTLA-4 Antigen/genetics , Child , Child, Preschool , Disease-Free Survival , Female , Fetal Blood/cytology , Fetal Blood/immunology , Fetal Blood/transplantation , Gene Expression , Genotype , HLA Antigens/genetics , Hematologic Neoplasms/immunology , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Histocompatibility Testing , Humans , Infant , Male , Middle Aged , Myeloablative Agonists/therapeutic use , NLR Proteins , Proportional Hazards Models , Protein Isoforms/genetics , Protein Isoforms/immunology , Retrospective Studies , Transplantation Conditioning , Unrelated DonorsABSTRACT
CD4+ T-helper subsets drive autoimmune chronic graft-versus-host disease, a major complication after allogeneic bone marrow transplantation. However, it remains unclear how specific T-helper subsets contribute to chronic graft-versus-host disease. T-helper type 1 cells are one of the major disease-mediating T-cell subsets and require interferon-γ signaling and Tbet expression for their function. Regulatory T cells on the other hand can inhibit T-helper type 1 cell-mediated responses. Using an established murine model that isolates the autoimmune component of graft-versus-host disease, we hypothesized that T-helper type 1 cells would restrict FoxP3-driven regulatory T cells. Upon transfer into immune-deficient syngeneic hosts, alloreactive Tbx21-/-CD4+ T cells led to marked increases in FoxP3+ cells and reduced clinical evidence of autoimmunity. To evaluate whether peripheral induction contributed to regulatory T-cell predominance, we adoptively transferred Tbx21-/- T cells that consisted of fate mapping for FoxP3: recipients of flow-purified effector cells that were Foxp3- and Tbx21-/- had enhanced T-regulatory-cell predominance during autoimmune graft-versus-host disease. These data directly demonstrated that peripheral T-regulatory-cell induction was inhibited by Tbet. Finally, Tbx21-/- T-regulatory cells cross-regulated autoimmune wild-type T-effector-cell cytokine production in vivo The Tbet pathway therefore directly impairs T-regulatory-cell reconstitution and is consequently a feasible target in efforts to prevent autoimmune graft-versus-host disease.
Subject(s)
Forkhead Transcription Factors/metabolism , Graft vs Host Disease/immunology , T-Box Domain Proteins/immunology , Animals , Autoimmunity , CD4-Positive T-Lymphocytes/immunology , Graft vs Host Disease/prevention & control , Mice , T-Box Domain Proteins/deficiency , T-Box Domain Proteins/genetics , T-Lymphocyte Subsets , T-Lymphocytes, Regulatory/immunologySubject(s)
Alemtuzumab/therapeutic use , Histiocytic Sarcoma/drug therapy , Alemtuzumab/pharmacology , Child , Humans , MaleABSTRACT
Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD.
Subject(s)
Bone Marrow Transplantation , Cord Blood Stem Cell Transplantation , Graft vs Host Disease/mortality , Graft vs Host Disease/therapy , Leukemia/mortality , Leukemia/therapy , Transplantation Conditioning , Acute Disease , Adolescent , Adult , Allografts , Child , Child, Preschool , Chronic Disease , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/etiology , Humans , Infant , Living Donors , Male , Survival RateSubject(s)
Anemia, Sickle Cell/therapy , Blood Transfusion , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Allografts , Anemia, Sickle Cell/blood , Child , Child, Preschool , Female , Humans , MaleABSTRACT
Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.
ABSTRACT
Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.
Subject(s)
Developing Countries , Genetic Therapy , Translational Research, Biomedical , HumansABSTRACT
Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has donor specific anti-HLA antibodies.
Subject(s)
Autoantibodies/blood , Graft Survival/immunology , HLA Antigens/blood , Hematopoietic Stem Cell Transplantation/trends , Tissue Donors , Transplantation Conditioning/trends , Adolescent , Adult , Aged , Autoantibodies/biosynthesis , Child , Child, Preschool , Female , Fetal Blood/cytology , Fetal Blood/immunology , Follow-Up Studies , France , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation/mortality , Histocompatibility/genetics , Histocompatibility/immunology , Humans , Infant , Male , Middle Aged , Retrospective Studies , Societies, Medical/trends , Survival Rate/trends , Transplantation Conditioning/mortality , Treatment Outcome , Young AdultABSTRACT
Objective To evaluate the postoperative functional and radiographic outcomes of the shoulder of patients submitted to transosseous suturing of a greater tuberosity fracture (GTF) through an anterolateral route and the influence of the glenohumeral dislocation on these outcomes. Methods We conducted a retrospective study and functional assessment using the Constant-Murley score. The distance between the greater tuberosity and the joint surface of the proximal humerus (in true anteroposterior radiographs) after the union was calculated. We used the Fisher exact test for the categorical independent variables, and the Student t or Mann-Whitney test for the non-categorical variables. Results In total, 26 patients met the inclusion criteria, and 38% of the sample presented an association between glenohumeral dislocation and GTF. The mean Constant-Murley score was of 82.5 + 8.02 points. The presence of an associated dislocation did not alter the functional outcome. The mean distance between the greater tuberosity of the humerus and the joint surface of the humeral head after the union was of 9 ± 4.3 mm below the articular line of the humeral head. The dislocation led to a lower level of reduction, but this did not influence the Constant-Murley score. Conclusion The cases of GTF submitted to surgical treatment with transosseous sutures had good functional outcomes. The presence of dislocation made the anatomical reduction of the greater tuberosity difficult. However, it did not influence the Constant-Murley score.
ABSTRACT
Applying surfactants to reduce the interfacial tension (IFT) on water/oil interfaces is a proven technique. The search for new surfactants and delivery strategies is an ongoing research area with applications in many fields such as drug delivery through nanoemulsions and enhanced oil recovery. Experimentally, the combination of hyperbranched polyglycerol (HPG) with cetyltrimethylammonium bromide (CTAB) substantially reduced the observed IFT of oil/water interface, 0.9 mN/m, while HPG alone was 5.80 mN/m and CTAB alone IFT was 8.08 mN/m. Previous simulations in an aqueous solution showed that HPG is a surfactant carrier. Complementarily, in this work, we performed classical molecular dynamics simulations on combinations of CTAB and HPG with one aliphatic chain to investigate further the interaction of this pair in oil interfaces and propose the mechanism of IFT decrease. Basically, from our results, one can observe that the IFT reduction comes from a combination of effects that have not been observed for other dual systems: (i) Due to the CTAB-HPG strong interaction, a weakening of their specific and isolated interactions with the water and oil phases occurs. (ii) Aggregates enlarge the interfacial area, turning it into a less ordered interface. (iii) The spread of individual molecules charge profiles leads to the much lower interfacial tension observed with the CTAB+HPG systems.
ABSTRACT
BACKGROUND: Steroid-refractory acute graft-vs.-host disease (SR-aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation with a dismal prognosis and for which there is no consensus-based second-line therapy. Ruxolitinib is not easily accessible in many countries. A possible therapy is the administration of mesenchymal stromal cells (MSCs). METHODS: In this retrospective study, 52 patients with severe SR-aGVHD were treated with MSCs from umbilical cord (UC-MSCs) in nine institutions. RESULTS: The median (range) age was 12.5 (0.3-65) years and the mean ± SD dose (×106/kg) was 4.73 ± 1.3 per infusion (median of four infusions). Overall (OR) and complete response (CR) rates on day 28 were 63.5% and 36.6%, respectively. Children (n = 35) had better OR (71.5% vs. 47.1%, p = 0.12), CR (48.6% vs. 11.8%, p = 0.03), overall survival (p = 0.0006), and relapse-free survival (p = 0.0014) than adults (n = 17). Acute adverse events (all of them mild or moderate) were detected in 32.7% of patients, with no significant difference in children and adult groups (p = 1.0). CONCLUSIONS: UC-MSCs are a feasible alternative therapy for SR-aGVHD, especially in children. The safety profile is favorable.
ABSTRACT
BACKGROUND: The application of CPAP has been used to minimize postoperative pulmonary complications after lung resection surgery. The aim of this study was to quantify both the CPAP effects upon lung function and functional capacity in early postoperative lung resection, as well as to evaluate if CPAP prolongs air leak through the chest drain. METHODS: Thirty patients in the postoperative period of lung resection were allocated into 2 groups: an experimental group, consisting of 15 patients who underwent a 10 cm H(2)O CPAP, and a 15 patient control group, who performed breathing exercises. Arterial blood gas analysis, peak expiratory flow (PEF), respiratory muscle strength, spirometry, and 6-min walk test (6MWT) were assessed in the preoperative period, and repeated postoperatively on the first and on the seventh day (6MWT was repeated only on the seventh day). RESULTS: Significant increases in PEF, muscle strength, and FEV(1) between the first and seventh postoperative day were observed, both in the experimental and in the control group, whereas FVC and P(aO(2)) increased significantly between the first and seventh postoperative day only in the experimental group. The average loss in 6-min walk distance (6MWD) from preoperative to postoperative day 7 in the experimental group was significantly lower than in control group. When comparing the 2 groups, only 6MWD was statistically different (P < .001). There was no air leakage increase through the drain with the early use of CPAP. CONCLUSION: When compared to breathing exercises, CPAP increases the 6MWD in postoperative lung resection patients, without prolonging air leak through the chest drain.
Subject(s)
Continuous Positive Airway Pressure , Exercise Test , Pneumonectomy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Lung Diseases/physiopathology , Lung Diseases/surgery , Male , Middle Aged , Pneumonectomy/rehabilitation , Postoperative Period , Recovery of Function , Respiratory Function Tests , Young AdultABSTRACT
INTRODUCTION: The optimization of oral health before allogeneic hematopoietic cell transplantation (HCT) is important for preventing infectious complications during treatment. OBJECTIVE: The objective of this study was to evaluate the oral health condition and dental treatments performed in patients in pre-allogeneic HCT. METHOD: The records of patients treated during 2018 at a Brazilian HCT service were reviewed. The following oral health data were obtained: 1. Decayed, missing and filled teeth / correlated index for primary dentition (DMFT/dmft); 2. Quality of oral hygiene and 3. Dental pathologies: 3.1 Periodontal infectious focus, 3.2 Endodontic infectious focus and 3.3 Carie incidence. All dental procedures performed were surveyed. RESULTS: Thirty-three patients were included, with a mean age of 28.42 (±16.37), 20 male (60%) and 13 female. The average DMFT/dmft found in this study was 10.24 (± 8.37), similar to the index found in the population in southeastern Brazil. The younger study population presented a DMFT/dmft considered high, when compared to the general population. A total of 27.2% of the patients had active caries lesions, 33.3%, foci of periodontal infection, 15.1%, endodontic infectious focus and 40%, poor oral hygiene. Almost half of the patients (48.4%) had to undergo dental intervention, 24.2% needing periodontal scaling, 21.2%, fillings and 12.1%, tooth extractions. CONCLUSION: We conclude that the studied population had an important incidence of dental pathologies and infectious conditions that could complicate throughout HCT, especially in younger patients, therefore presenting a high demand for dental treatment in the pre-HCT. Studies that assess the impact of dental conditioning on the outcomes of HCT with an emphasis on dental infectious complications, days of hospitalization and survival are necessary."