Kinetics and Risk Factors of Relapse after Allogeneic Stem Cell Transplantation in Children with Leukemia: A Long-Term Follow-Up Single-Center Study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment for high-risk hematological malignancies in the pediatric population, but relapse remains the leading cause of death. We analyzed risk factors associated with relapse.Data from 353 allo-HSCTs from 1989 to 2015 in our center were studied retrospectively. We performed a multivariate analysis of pre- and postransplantation variables and developed a predictive risk score for relapse using the significant factors in this training cohort. The results were confirmed in a validation cohort of 90 allo-HSCTs done in our institution from 2016 to the present.A total of 104 patients relapsed after allo-HSCT, with a relapse cumulative incidence of 31 ± 2%. In multivariate analysis, only 2 variables influenced relapse: disease phase (advanced versus early, HR, 2.84; 95% CI, 1.76 to 4.57; P?=?.001) and presence of chronic graft-versus-host disease (GVHD) (acute GVHD versus chronic GVHD [HR, 4.27; 95% CI, 1.99 to 9.15; P?=?.0001] and no GVHD versus chronic GVHD [HR, 6.86; 95% CI, 3.63 to 12.97] P?=?.0001]. Applying the personalized risk score (0 to 3), the relapse cumulative incidence was 70 ± 5% in patients with a score of 3 (without GVHD and in the advanced phase) compared with 6 ± 4% in patients with a score of 0 (with chronic GVHD and in an early phase). This score has been verified in the validation set. With a median follow-up of 54 months, the disease-free survival (DFS) and overall survival rate were 37 ± 3% and 45 ± 4%, respectively.The association of GVHD with the graft-versus-leukemia effect is clearly established in our study, and the form of GVHD associated with less relapse and the best DFS is the classical form of chronic GVHD according to the National Institutes of Health classification. The proposed relapse risk score was validated in an independent cohort and allows personalization of the prognosis.     

Potential application of small myristoylated protein-3 evaluated as recombinant antigen and a synthetic peptide containing its linear B-cell epitope for the serodiagnosis of canine visceral and human tegumentary leishmaniasis

Serological tests are important tools for the diagnosis of Leishmania infection. However, they are not effective markers to diagnose asymptomatic cases of visceral leishmaniasis (VL) and patients developing tegumentary leishmaniasis (TL), since antileishmanial antibodies can be encountered in low levels resulting in false-negative results in the serological trials. In this context, antigens able to be recognized by antibodies in sera from both VL and TL patients will be desirable to be employed in a more sensitivity and specific diagnosis of disease. In the present study, a conserved Leishmania protein, small myristoylated protein-3 (SMP-3), which was showed to be conserved in different Leishmania species and an effective vaccine candidate against Leishmania infantum infection in a murine model, was cloned and the recombinant protein was evaluated as a serological marker for the diagnosis of human TL and canine VL. In addition, a linear B cell-specific epitope (MQKDEESGEFKCEL) was identified, synthetized and also investigated as a serological marker. As antigen controls, rA2 protein and antigenic Leishmania extracts (SLA) were used. Results showed that ELISA-rSMP-3 and ELISA-Peptide presented sensitivity and specificity values higher than 90% in both diseases in humans and canids, having identified all asymptomatic cases and did not present cross-reaction with cross-reactivity diseases in both mammalian hosts. On the other hand, sensitivity and specificity values were worst when rA2 or SLA were used as antigens in humans and dogs. In conclusion, results showed the efficacy and Leishmania SMP-3 protein, employed as a recombinant antigen or a B cell epitope, for the improvement of the serodiagnosis of human TL and canine VL. This candidate can be tested in other diagnostic platforms, such as rapid immunochromatographic dipstick tests, aiming its use in epidemiological studies in remote areas where laboratories are not readily accessible for conventional assays.     

A biomarker for tegumentary and visceral leishmaniasis based on a recombinant Leishmania hypothetical protein

The measures for leishmaniasis control include the precise diagnosis of disease. However, although several recombinant antigens have been tested with this biotechnological purpose, no effective product exists, which could detects patients with the active disease, as well as differentiates them from cured and treated patients. In this study, a conserved Leishmania hypothetical protein, which was identified in Leishmania infantum parasites, but evaluated to presents high homology in the amino acid sequences between distinct parasite species, was evaluated for the diagnosis of tegumentary and visceral leishmaniasis. In addition, PBMCs collected from treated and untreated mucosal leishmaniasis (ML) and visceral leishmaniasis (VL) patients, as well as in healthy subjects living in endemic region of disease, were in vitro stimulated, when IFN-γ, IL-4 and IL-10 levels were evaluated in the cell supernatant. Regarding the serological analyses, ELISA experiments using the recombinant protein (rLiHyL) and a human serological panel revealed high sensitivity and specificity values to detect both diseases, while control antigens showed worst results. Regarding the cellular response, results showed that rLiHyL-stimulated cells produced higher IFN-γ and lower IL-4 and IL-10 levels in the supernatants. Also, the anti-protein antibody production was evaluated in these patients, and data showed higher IgG2 and lower IgG1 levels found in the treated patients and healthy controls, demonstrating the stimulation of a Th1-type response induced by the rLiHyL protein. In conclusion, this hypothetical protein can be considered as antigenic in TL and VL, as well as a vaccine candidate to be tested in future studies to protect against disease.     

Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant

We investigated the Central Nervous System (CNS) and skeletal muscle tissue from A woman was clinically diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 22. Neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration and skeletal muscle denervation. Analysis of the patient's Deoxyribonucleic acid (DNA) revealed a AGT>GGT change resulting in an S375G substitution in the C‐terminal region of TDP‐43. This variant was previously reported as being benign. Considering the early onset and severity of the disease in this patient, we tested the effects of this genetic variant on TDP‐43 localization, pre‐mRNA splicing activity and toxicity, in parallel with the effects on known neighboring disease‐associated mutations. In cell lines, expressed in culture, S375G TDP‐43 appeared to be more significantly localized in the nucleus and to exert higher toxicity than wild‐type TDP‐43. Strikingly, a phosphomimic mutant at the same residue (S375E) showed a strong tendency to accumulate in the cytoplasm, especially under stress conditions, and molecular dynamics simulations suggest that phosphorylation of this residue can disrupt TDP‐43 intermolecular interactions. The results of the current study highlight the importance of phosphorylation and regulation of TDP‐43 nuclear‐cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS.     

A unique telomere DNA expansion phenotype in human retinal rod photoreceptors associated with aging and disease

We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non‐neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non‐telomerase‐mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra‐bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus‐positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human‐specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra‐bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus‐positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus‐positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus‐positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina.     

Long-term health outcomes of childhood sexual abuse and peer sexual contact among an urban sample of behaviourally bisexual Latino men

While previous research indicates high rates of childhood sexual abuse among Latino men who have sex with men, few studies have examined the long-term health outcomes of childhood sexual abuse specifically among behaviourally bisexual Latino men. In a sample of 148 behaviourally bisexual Latino men in New York City, we examined associations between childhood sexual abuse and multiple dimensions of adult health: sexual risk behaviours; sexually transmitted infections incidence; polydrug use; depressive symptoms; and perceived stress. We compared outcomes between those with histories of childhood sexual abuse, those reporting peer sexual contact prior to age 13 and those with no sexual contact prior to age 13. Over one-fifth (22.3%) reported a history of childhood sexual abuse, which was significantly associated with engaging in receptive condomless anal intercourse (aOR = 3.59, p < .01, SE = 2.0), high perceived stress (aOR = 2.48, p < .06, SE = 1.13) and clinically significant depressive symptoms (aOR = 2.7, p < .05, SE = 1.25). Across all variables, peer sexual contact did not impact these outcomes, underscoring a key distinction between abusive and non-abusive early sexual experiences. We recommend that sexual abuse prevention policies and programmes better engage Latino youth, and that practitioners serving this population across diverse areas of practice incorporate childhood sexual abuse screening and culturally appropriate treatment and care into practice.     

Prevalence and correlates of diabetes and metabolic syndrome in a rural indigenous community in Baja California,Mexico

Background

Diabetes is a leading cause of morbidity and mortality in Mexico and understudied among indigenous populations. This study aimed to determine the prevalence and identify correlates of Type 2 diabetes mellitus (Type 2 DM) and metabolic syndrome (MetS) in a rural, indigenous community in Northwestern Mexico.

Methods

A cross-sectional study was conducted in the community of San Quintin, Baja California, Mexico, among a sample of households. A total of 275 participants (≥18?years old) underwent a questionnaire, physical examination, and serologic test. Prevalence and adjusted odds ratio (AOR), using logistic regression modeling, were estimated with 95% confidence intervals (95% CI).

Results

The prevalence of Type 2 DM and MetS was 21.8 and 53.1%, respectively. Mean?±?standard deviation (SD) age and body mass index of study participants was 35.8?±?13.0?years and 28.7?±?5.6?kg/m², respectively. Participants were 75% female and 60.7% self-identified as indigenous. Thirty-seven percent of adults had high blood pressure. After controlling for age, higher educational attainment had a protective effect on Type 2 DM (AOR?=?0.39; 95% CI 0.20, 0.77). Additionally, the presence of MetS was associated with being female (AOR?=?2.27; 95% CI 1.23, 4.14) and having lower educational attainment (AOR?=?0.62; 95% CI 0.37, 0.94).

Conclusions

The prevalence of Type 2 DM and MetS was high in this rural and indigenous population, and education was shown to play a critical role. These findings support the need for community-inclusive health-promoting interventions in rural communities.