Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.

BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardiac diseases. However, the role of systemic extracellular vesicle biogenesis inhibition in HF models is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of tipifarnib, a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a [Ras associated binding protein 27a], nSMase2 [neutral sphingomyelinase 2], and Alix [ALG-2-interacting protein X]) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery were randomly assigned to groups with and without tipifarnib treatment (10 mg/kg 3 times/wk) and monitored for 8 weeks, and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced left ventricular dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of tipifarnib in TAC mice reduced circulating exosomes to baseline and remarkably improved left ventricular functions, hypertrophy, and fibrosis. Tipifarnib treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR 331-5p, which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR 331-5p is crucial for inhibiting the fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR 331-5p that acts as a potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.

Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy.

Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.

Financial burden following adult liver transplantation is common and associated with adverse recipient outcomes.

The financial impact of liver transplantation has been underexplored. We aimed to identify associations between high financial burden (≥10% annual income spent on out-of-pocket medical costs) and work productivity, financial distress (coping behaviors in response to the financial burden), and financial toxicity (health-related quality of life, HRQOL) among adult recipients of liver transplant. Between June 2021 and May 2022, we surveyed 207 adult recipients of liver transplant across 5 US transplant centers. Financial burden and distress were measured by 25 items adapted from national surveys of cancer survivors. Participants also completed the Work Productivity and Activity Impairment and EQ-5D-5L HRQOL questionnaires. In total, 23% of recipients reported high financial burden which was significantly associated with higher daily activity impairment (32.9% vs. 23.3%, p =0.048). In adjusted analyses, the high financial burden was significantly and independently associated with delayed or foregone medical care (adjusted odds ratio, 3.95; 95% CI, 1.85-8.42) and being unable to afford basic necessities (adjusted odds ratio, 5.12; 95% CI: 1.61-16.37). Recipients experiencing high financial burden had significantly lower self-reported HRQOL as measured by the EQ-5D-5L compared to recipients with low financial burden (67.8 vs. 76.1, p =0.008) and an age-matched and sex-matched US general population (67.8 vs. 79.1, p <0.001). In this multicenter cohort study, nearly 1 in 4 adult recipients of liver transplant experienced a high financial burden, which was significantly associated with delayed or foregone medical care and lower self-reported HRQOL. These findings underscore the need to evaluate and address the financial burden in this population before and after transplantation.

Microcystin-LR sensitizes the Oncorhynchus mykiss intestinal epithelium and interacts with paralytic shellfish toxins to alter oxidative balance.

In the context of harmful algal blooms, fish can be exposed to the combined effects of more than one toxin. We studied the effects of consecutive exposure to Microcystin-LR (MCLR) in vivo and paralytic shellfish toxins (PST) ex vivo/in vitro (MCLR+PST) in the rainbow trout Oncorhynchus mykiss's middle intestine. We fed juvenile fish with MCLR incorporated in the feed every 12 h and euthanized them 48 h after the first feeding. Immediately, we removed the middle intestine to make ex vivo and in vitro preparations and exposed them to PST for one hour. We analyzed glutathione (GSH) and glutathione disulfide (GSSG) contents, glutathione S-transferase (GST), glutathione reductase (GR), catalase (CAT), and protein phosphatase 1 (PP1) activities in ex vivo intestinal strips; apical and basolateral ATP-biding cassette subfamily C (Abcc)-mediated transport in ex vivo everted and non- everted sacs; and reactive oxygen species (ROS) production in isolated enterocytes in vitro. MCLR+PST treatment decreased the GSH content, GSH/GSSG ratio, GST activity, and increased ROS production. GR activity remained unchanged, while CAT activity only increased in response to PST. MCLR inhibited PP1 activity and activated Abcc-mediated transport only at the basolateral side of the intestine. Our results show a combined effect of MCLR+PST on the oxidative balance in the O. mykiss middle intestine, which is not affected by the two toxins groups when applied individually. Basolateral Abcc transporters activation by MCLR treatment could lead to an increase in the absorption of toxicants (including MCLR) into the organism. Therefore, MCLR makes the O. mykiss middle intestine more sensitive to possibly co-occurring cyanotoxins like PST.

Occurrence of cancer in Marfan syndrome: Report of two patients with neuroblastoma and review of the literature.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in FBN1, with a hitherto unknown association with cancer. Here, we present two females with MFS who developed pediatric neuroblastoma. Patient 1 presented with neonatal MFS and developed an adrenal neuroblastoma with unfavorable tumor genetics at 10 months of age. Whole genome sequencing revealed a germline de novo missense FBN1 variant (NP_000129.3:p.(Asp1322Asn)), resulting in intron 32 inclusion and exon 32 retention. Patient 2 was diagnosed with classic MFS, caused by a germline de novo frameshift variant in FBN1 (NP_000129.3:p.(Cys805Ter)). At 18 years, she developed high-risk neuroblastoma with a somatic ALK pathogenic variant (NP_004295.2:p.(Arg1275Gln)). We identified 32 reported cases of MFS with cancer in PubMed, yet none with neuroblastoma. Among patients, we observed an early cancer onset and high frequency of MFS complications. We also queried cancer databases for somatic FBN1 variants, finding 49 alterations reported in PeCan, and variants in 2% of patients in cBioPortal. In conclusion, we report the first two patients with MFS and neuroblastoma and highlight an early age at cancer diagnosis in reported patients with MFS. Further epidemiological and functional studies are needed to clarify the growing evidence linking MFS and cancer.

Prevalence and grade of malignancy differences with respect to the area of involvement in multiparametric resonance imaging of the prostate in the diagnosis of prostate cancer using the PI-RADS version 2 classification.

PURPOSE: The peripheral zone is histologically different from the transitional zone. The aim of this study is to analyze the differences between the prevalence and grade of malignancy of mpMRI-targeted biopsies that involve the TZ with respect to the PZ. METHODS: A cross-sectional study of 597 men evaluated for PC screening between February 2016 and October 2022 was conducted. Exclusion criteria were prior BPH surgery, radiotherapy, 5-alpha-reductase inhibitors treatment, UTI, mixed involvement of PZ-TZ or doubts, and central-zone involvement. Hypothesis contrast test was used to study differences proportions of malignancy (ISUP > 0) and significant (ISUP > 1) and high-grade tumor (ISUP > 3) in PI-RADSv2 > 2-targeted biopsies in PZ with respect to TZ, and logistic regression and hypothesis contrast tests were used to study the influence of the area of exposure as an effect-modifying factor in the diagnosis of malignancy with respect to the PI-RADSv2 classification. RESULTS: 473 patients were selected and 573 lesions biopsied (127 PI-RADS3, 346 PI-RADS4 and 100 PI-RADS5). A significant increase was described in the proportion of malignancy and significant and high-grade tumor in PZ compared to TZ (22.6%, 21.3%, and 8.7%, respectively). Significant increase in proportions and malignancy were described in cores targeted to PZ with respect to TZ, highlight the differences between PZ and TZ for ST (37.3%vs23.7% for PI-RADS4, 69.2%vs27.3% for PI-RADS5, respectively). Statistically significant linear trend was described increasing for malignancy, significant and high-grade tumors with respect to the PI-RADSv2 scores (change > 10%). CONCLUSION: Although the prevalence and grade of malignancy in the TZ is lower than in the PZ, PI-RADS4 and 5-targeted biopsies should not be omitted in this location, but PI-RADS3 could be.

Helicobacter bizzozeronii infection in a girl with severe gastric disorders in México: case report.

BACKGROUND: Gastric non-Helicobacter pylori helicobacters (NHPH) naturally colonize the stomach of animals. In humans, infection with these bacteria is associated with chronic active gastritis, peptic ulceration and MALT-lymphoma. H. bizzozeronii belongs to these NHPH and its prevalence in children is unknown. CASE PRESENTATION: This case report describes for the first time a NHPH infection in a 20-month-old girl with severe gastric disorders in Mexico. The patient suffered from melena, epigastric pain, and bloating. Gastroscopy showed presence of a Hiatus Hill grade I, a hemorrhagic gastropathy in the fundus and gastric body, and a Forrest class III ulcer in the fundus. Histopathologic examination revealed a chronic active gastritis with presence of long, spiral-shaped bacilli in the glandular lumen. Biopsies from antrum, body and incisure were negative for presence of H. pylori by culture and PCR, while all biopsies were positive for presence of H. bizzozeronii by PCR. Most likely, infection occurred through intense contact with the family dog. The patient received a triple therapy consisting of a proton pump inhibitor, clarithromycin, and amoxicillin for 14 days, completed with sucralfate for 6 weeks, resulting in the disappearance of her complaints. CONCLUSION: The eradication could not be confirmed, although it was suggested by clear improvement of symptoms. This case report further emphasizes the zoonotic importance of NHPH. It can be advised to routinely check for presence of both H. pylori and NHPH in human patients with gastric complains.

Trypanosoma cruzi Secreted Cyclophilin TcCyP19 as an Early Marker for Trypanocidal Treatment Efficiency.

Cyclophilins (CyPs) are a family of enzymes involved in protein folding. Trypanosoma cruzi, the causative agent of Chagas disease, has a 19-kDa cyclophilin, TcCyP19, that was found to be secreted in parasite stages of the CL Brener clone and recognized by sera from T. cruzi-infected mice and patients. The levels of specific antibodies against TcCyP19 in T. cruzi-infected mice and subjects before and after drug treatment were measured by an in-house enzyme linked immunosorbent assay (ELISA). Mice in the acute and chronic phase of infection, with successful trypanocidal treatments, showed significantly lower anti-TcCyP19 antibody levels than untreated mice. In children and adults chronically infected with T. cruzi, a significant decrease in the anti-TcCyP19 titers was observed after 12 months of etiological treatment. This decrease was maintained in adult chronic patients followed-up 30-38 months post-treatment. These results encourage further studies on TcCyP19 as an early biomarker of trypanocidal treatment efficiency.

Innovative Therapeutic Approaches in Non-Alcoholic Fatty Liver Disease: When Knowing Your Patient Is Key.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic steatosis may result from the dysfunction of multiple pathways and thus multiple molecular triggers involved in the disease have been described. The development of NASH entails the activation of inflammatory and fibrotic processes. Furthermore, NAFLD is also strongly associated with several extra-hepatic comorbidities, i.e., metabolic syndrome, type 2 diabetes mellitus, obesity, hypertension, cardiovascular disease and chronic kidney disease. Due to the heterogeneity of NAFLD presentations and the multifactorial etiology of the disease, clinical trials for NAFLD treatment are testing a wide range of interventions and drugs, with little success. Here, we propose a narrative review of the different phenotypic characteristics of NAFLD patients, whose disease may be triggered by different agents and driven along different pathophysiological pathways. Thus, correct phenotyping of NAFLD patients and personalized treatment is an innovative therapeutic approach that may lead to better therapeutic outcomes.

Profiles of Parents' Preferences for Delivery Formats and Program Features of Parenting Interventions.

Parents are the targeted consumers of parenting interventions but a small body of research has examined parental preferences for program characteristics to incorporate them in the adaptation and implementation of such programs. Furthermore, the relationship between parents' preferences for program characteristics and their cognitions and behaviours has not yet been explored. This study aimed to identify profiles of parental preferences for delivery formats and program features of parenting interventions. Data from 6949 participants from the International Parenting Survey was analysed. Two-step cluster analyses were conducted to determine clusters of delivery formats and program features of parenting interventions. Preferences for delivery formats showed two clusters, a face-to-face cluster and a media-based cluster. In terms of program features, two clusters were also obtained, a personalised cluster and logistic cluster. While these clusters differed in some demographics, parents' report of child emotional and behavioural problems and parent factors were the key differentiating variables.

Delirium in oncological palliative care and clinical cardiology units: A comparative analysis.

OBJECTIVE: The aim of this study was to compare the sociodemographic and clinical characteristics of delirium in patients treated in a clinical cardiology unit (CCU) and an oncological palliative care unit (OPCU) at a high-complexity institution. CONTEXT: Delirium is a neuropsychiatric syndrome with multicausal etiology, associated with increased morbidity and mortality. METHOD: This was a cross-sectional, analytical observational study. CCU and OPCU patients were evaluated for 480 days. The diagnosis was made according to DSM-V. Sociodemographic characteristics, the Karnofsky index, and the Charlson index were evaluated. Possible etiologies were verified. Severity was assessed with the Delirium Severity Scale (DRS-R98). RESULTS: A total of 1,986 patients were evaluated, 205 were eligible, and 110 were included in the study (CCU: 61, OPCU: 49). Delirium prevalence was 11.35% in the CCU and 9.87% in the OPCU. CCU patients were 12 years older (p < 0.03) and a history of dementia (41 vs. 8.2%; p < 0.001). Organ failure was the most frequent etiology of delirium in the CCU (41.0%), and in the OPCU, the etiologies were neoplasms (28.6%), side effect of medication (22.4%), and infections (2.5%). Differences were found in the clinical characteristics of delirium evaluated by DRS-R98, with the condition being more severe and with a higher frequency of psychotic symptoms in OPCU patients. CONCLUSION: Delirium was a common condition in hospitalized patients in the CCU and the OPCU. The clinical characteristics were similar in both groups; however, significant differences were found in OPCU patients in terms of age, personal history of dementia, and opioid use, as well as the severity of delirium and a greater association with psychotic symptoms. These findings have implications for the early implementation of diagnostic and therapeutic strategies.

Exploring the Effects of Organic Matter Characteristics on Fe(II) Oxidation Kinetics in Coastal Seawater.

The iron(II) oxidation kinetic process was studied at 25 stations in coastal seawater of the Macaronesia region (9 around Cape Verde, 11 around the Canary Islands, and 5 around Madeira). In a physicochemical context, experiments were carried out to study the pseudo-first-order oxidation rate constant (k', min-1) over a range of pH (7.8, 7.9, 8.0, and 8.1) and temperature (10, 15, 20, and 25 °C). Deviations from the calculated kcal' at the same T, pH, and S were observed for most of the stations. The measured t1/2 (ln 2/k', min) values at the 25 stations ranged from 1.82 to 3.47 min (mean 1.93 ± 0.76 min) and for all but two stations were lower than the calculated t1/2 of 3.21 ± 0.2 min. In a biogeochemical context, nutrients and variables associated with the organic matter spectral properties (CDOM and FDOM) were analyzed to explain the observed deviations. The application of a multilinear regression model indicated that k' can be described (R = 0.921 and SEE = 0.064 for pH = 8 and T = 25 °C) from a linear combination of three organic variables, k'OM = kcal' -0.11* TDN + 29.9*bDOM + 33.4*C1humic, where TDN is the total dissolved nitrogen, bDOM is the spectral peak obtained from colored dissolved organic matter (DOM) analysis when protein-like or tyrosine-like components are present, and C1humic is the component associated with humic-like compounds obtained from the parallel factor analysis of the fluorescent DOM. Results show that compounds with N in their structures mainly explain the observed k' increase for most of the samples, although other components could also play a relevant role. Experimentally, k' provides the net result between the compounds that accelerate the process and those that slow it down.

Population Structure of Moniliophthora perniciosa in the Main Cacao Producing Departments of Colombia.

The witches' broom (Moniliophthora perniciosa) is considered as one of the main threats for cacao production and, consequently, for chocolate production worldwide. In this work, the genetic diversity and population structure of M. perniciosa were analyzed for 59 isolates collected in five departments of Colombia and using 10 microsatellite markers. Analyses revealed 35 multilocus genotypes and clonal populations structure according to linkage disequilibrium analysis. One of the objectives of this study was to determine whether populations were differentiated by geographic origin or Theobroma cacao host genotype. Analysis of molecular variance, discriminant analysis of principal components, and Bruvo genetic distance suggested that the genetic structure was driven by geographic origin and not by T. cacao genotype. The results of this study were consistent with previous findings obtained in other cocoa-producing countries. Important insights were discussed regarding the dispersal patterns of the pathogen in Colombia and the genetic change of its populations because of different environmental conditions.

Bioconversion of Glycosidic Precursors from Sour Guava (Psidium friedrichsthalianum Nied.) Fruit by the Oral Microbiota into Odor-Active Volatile Compounds.

The ability of the human oral microbiota to hydrolyze the glycosidic aroma precursor extract isolated from sour guava (Psidium friedrichsthalianum Nied.) fruits was studied herein. The glycosidic extract (GP) was incubated with a mixture of the oral microbiota isolated from three individuals' saliva to evaluate the hydrolytic capacity of oral bacteria in the generation of odor-active compounds. The oral microbiota was able to release 1-hexanol from GP, under both aerobic and anaerobic conditions. Additionally, the aroma precursor extracts showed a decrease in the growth of harmful oral bacteria (Streptococcus and Actinomyces). This effect can be considered beneficial to human health because these bacteria have been related to different diseases of the bucco-respiratory tract.

[Perception of the educational environment in residents of medical specialties in Chilean universities]. / Percepción del ambiente educacional de postgrado en residentes de especialidades médicas de universidades chilenas.

BACKGROUND: The Learning Environment (LE) influences the performance of students, learning, social life, mental health, and the future of work. AIM: To assess the learning environment (LE) among medical residents of 64 specialties. MATERIAL AND METHODS: Two validated instruments "Postgraduate Hospital Education Environment Measure" (PHEEM) and "Ambulatory Care Learning Educational Environment" (ACLEEM), and open questions were answered online by 1259 residents from 15 universities. A descriptive and analytical statistical analysis and semantic deductive-inductive analyses of open questions were performed. RESULTS: LE was positive rather than negative (PHEEM of 100.5 points (79-116) and ACLEEM of 138.5 points (120-157)). An age over 32 years, male sex, studying in a private university, being in first year of residence and being in a non-surgical specialty were associated with a better PHEEM score (p < 0.05). For ACLEEM, the first year of specialty, a non-surgical specialty and studying in a private university were associated with better scores (p < 0.05). Two programs had excellent LE (Pathological Anatomy and Ophthalmology) and no specialty had a very poor performance or many problems. Aspects of teaching, clinical activities, and teachers were strengths reported by students. Aspects to improve were teaching, protected times and clinical activities. CONCLUSIONS: LE among medical specialties had more positive than negative features, but with areas that should be improved.

Circulating Cytokine and Chemokine Profiles of Trypanosoma cruzi-Infected Women During Pregnancy and Its Association With Congenital Transmission.

BACKGROUND: Trypanosoma cruzi, the causative agent of Chagas disease, can be transmitted to the offspring of infected women, which constitutes an epidemiologically significant parasite transmission route in nonendemic areas. It is relevant to evaluate differentially expressed factors in T. cruzi-infected pregnant women as potential markers of Chagas congenital transmission. METHODS: Circulating levels of 12 cytokines and chemokines were measured by enzyme-linked immunosorbent assay or cytometric bead array in T. cruzi-infected and uninfected pregnant women in their second trimester of pregnancy and control groups of T. cruzi-infected and uninfected nonpregnant women. RESULTS: Trypanosoma cruzi-infected women showed a proinflammatory Th1-biased profile, with increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-12p70, IL-15, and monokine induced by interferon-gamma (MIG). Uninfected pregnant women presented a biased response towards Th2/Th17/Treg profiles, with increased plasma levels of IL-5, IL-6, IL-1ß, IL-17A, and IL-10. Finally, we identified that high parasitemia together with low levels of TNF-α, IL-15, and IL-17, low TNF-α/IL-10 ratio, and high IL-12p70 levels are factors associated with an increased probability of Chagas congenital transmission. CONCLUSIONS: Trypanosoma cruzi-infected pregnant women who did not transmit the infection to their babies exhibited a distinct proinflammatory cytokine profile that might serve as a potential predictive marker of congenital transmission.

Distinct innate immune responses between sublethal and lethal models of disseminated candidiasis in newborn BALB/c mice.

Invasive candidiasis is associated with a high incidence and mortality rates in infants, especially in preterm newborns. The immunopathogenesis of the mycosis during the neonatal period is poorly understood. Although several in vivo models exist to study invasive candidiasis, the majority of studies employ distinct routes of infection and use 2 to 6 day-old mice that could be less comparable in studying candidiasis in preterm infants. In this study, by using 0-days-old mice we developed a new neonatal murine model of intravenous Candida albicans infection. Using different inoculums of Candida albicans we evaluated survival, dissemination of the fungus, frequency of CD45+ cells, and cytokine production in the liver, brain, and kidneys of newborn and adult BALB/c mice. Unexpectedly, the newborn mice infected with a low inoculum (1×105 cfu per mouse) of Candida albicans survive to the infection. Compared to adult mice, the liver and brain of newborn animals had the greatest fungal burden, fungal invasion and leukocyte infiltrate. A moderate production of TNFα, IL-1ß, IL-6 and IFNγ was detected in tissues of newborn mice infected with a non-lethal inoculum of Candida albicans. In contrast, overproduction of TNFα, IL-1ß, IL-6 and IL-10 was determined when injecting with a lethal inoculum. In agreement, flow cytometry of brain and liver showed an inoculum-dependent CD45+ leukocyte infiltration in newborn mice infected with Candida albicans. Overall, our data shows that Candida albicans infection in newborn mice affects mainly the brain and liver and a 2-fold increase of the inoculum rapidly becomes lethal probably due to massive fungal invasion and exacerbated CD45+ leukocyte infiltrate and cytokine production. This study is the first analysis of innate immune responses in different tissues during early neonatal disseminated candidiasis.

Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. METHODS: Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. RESULTS: IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. CONCLUSIONS: Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.

Trypanosoma cruzi infection in Cyclophilin D deficient mice.

Trypanosoma cruzi is the causative agent of Chagas disease, which is endemic in Latin America and around the world through mother to child transmission. The heart is the organ most frequently affected in the chronic stage of the human infection and depends on mitochondria for the required energy for its activity. Cyclophilins are involved in protein folding and the mitochondrial isoform, Cyclophilin D (CyPD), has a crucial role in the opening of the mitochondrial permeability transition pore. In the present study, we infected CyPD deficient mice, with ablation of the Ppif gene, with T. cruzi parasites and the course of the infection was analyzed. Parasite load, quantified by PCR, was significantly lower in skeletal and cardiac tissues of Ppif-/- mice compared to wild type mice. In vitro cultured cardiomyocytes and macrophages from mice lacking CyPD exhibited lower percentage of infected cells and number of intracellular parasites than those observed for wild type mice. Although histopathological analysis of heart and mRNA of heart cytokines showed differences between T. cruzi-infected mice compared to the uninfected animals, no significant differences were found mice due to the ablation of the Ppif gene. Our results suggest that cells deficient for mitochondrial CyPD, inhibited for the mitochondrial membrane potential collapse, reduces the severity of parasite aggression and spread of cellular infection.

The relationship between positive aspects of caring, anxiety and depression in the caregivers of cancer patients: The mediational role of burden.

OBJECTIVE: The aim of this study was to examine how the burden of caregivers of patients with an advanced oncological illness mediates the relationship between positive aspects of care, depression and anxiety. METHODS: Quantitative study with a cross-sectional design. One hundred informal adult caregivers of patients with advanced oncological illness who attended the pain and palliative care unit or the psychological unit at the Instituto de Cancerologia Clinica las Americas (Medellin, Colombia) completed self-report assessments including positive aspects of care (PAC), burden and anxiety/depression measured using the HADS (Hospitalized Anxiety Depression Scale). The partial least squares Structural Equation Modelling (PLS-SEM) approach was selected to validate the hypotheses of the study. RESULTS: Most of the participants were women (86%), with a mean age of 46.52 years (SD=15.05). Most of the participants reported experiencing both PAC and anxiety. They also scored low for burden. PAC exerted a negative effect on Burden, whereas Burden contributed positively to Anxiety and Depression. The indirect impact of PAC on Anxiety and Depression was significant p < .00. CONCLUSIONS: Positive aspects of care in advanced cancer caregivers constitutes a protective factor against caregiver's burden, depression and anxiety. Health staff can promote caregivers' adaptation and wellbeing emphasizing these PAC.