Psychometric Properties and Measurement Invariance of the Herth Hope Index in Spanish Cancer Patients.

BACKGROUND: The aim of this study was to evaluate the psychometric properties, differential item functioning, factorial invariance, and convergent validity of the Spanish version of the Herth Hope Index (HHI) in patients with cancer. METHOD: Exploratory and confirmatory factor analyses were conducted to explore the scale, dimensionality, functioning of items, test for strong measurement invariance across sex, age, tumor site, and expected survival, and an extended structural equation model to assess external validity in a cross-sectional, multicenter, prospective study of 863 cancer patients from 15 Spanish hospitals. RESULTS: The results do not support the original 3-factor scale but instead suggest a one-factor structure, which explained 62% of the common variance. Scores from the unidimensional structure exhibited satisfactory reliability (ω = .88). A strong invariance solution demonstrated excellent fit across sex, age, tumor site, and survival. HHI exhibited substantial associations with resilience coping strategies and spiritual well-being. CONCLUSIONS: The findings of our study contribute to the diversity of earlier empirical findings regarding the construct of hope. Despite this, our results indicate that the Spanish version of the HHI is a short, easy-to-administer, valid, reliable tool for evaluating cancer patients' levels of hope.

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids.

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 µM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite's plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Using the emotional functioning in clinical practice to detect psychological distress in patients with advanced thoracic and colorectal cancer.

PURPOSE: Patients with advanced cancer suffer significant decline of their psychological state. A rapid and reliable evaluation of this state is essential to detect and treat it and improve quality of life. The aim was to probe the usefulness of the emotional function (EF) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EF-EORTC-QLQ-C30) to assess psychological distress in cancer patients. METHODS: This is a multicenter, prospective, observational study involving 15 Spanish hospitals. Patients diagnosed with unresectable advanced thoracic or colorectal cancer were included. Participants completed the Brief Symptom Inventory 18 (BSI-18), the current the gold standard, and the EF-EORTC-QLQ-C30 to assess their psychological distress prior to initiating systemic antineoplastic treatment. Accuracy, sensitivity, positive predictive value (PPV), specificity, and negative predictive value (NPV) were calculated. RESULTS: The sample comprised 639 patients: 283 with advanced thoracic cancer and 356 with advanced colorectal cancer. According to the BSI scale, 74% and 66% displayed psychological distress with an EF-EORTC-QLQ-C30 accuracy of 79% and 76% in detecting psychological distress in individuals with advanced thoracic and colorectal cancer, respectively. Sensitivity was 79 and 75% and specificity was 79 and 77% with a PPV of 92 and 86% and a NPV of 56 and 61% (scale cut-off point, 75) for patients with advanced thoracic and colorectal cancer, respectively. The mean AUC for thoracic cancer was 0.84 and, for colorectal cancer, it was 0.85. CONCLUSION: This study reveals that the EF-EORTC-QLQ-C30 subscale is a simple and effective tool for detecting psychological distress in people with advanced cancer.

Psychological distress and resilience in patients with advanced cancer during the Covid-19 pandemic: the mediating role of spirituality.

BACKGROUND: The purpose of this study was to investigate the sociodemographic factors related to psychological distress, spirituality, and resilience, and to examine the mediating role of spirituality with respect to psychological distress and resilience in patients with advanced, unresectable cancer during the Covid-19 pandemic. METHODS: A prospective, cross-sectional design was adopted. Data were collected from 636 participants with advanced cancer at 15 tertiary hospitals in Spain between February 2019 and December 2021. Participants completed self-report measures: Brief Resilient Coping Scale (BRCS), Brief Symptom Inventory (BSI-18), and Spiritual well-being (FACIT-Sp). Hierarchical linear regression models were used to explore the mediating role of spirituality. RESULTS: Spirituality was significantly different according to the person's age and marital status. Psychological distress accounted for 12% of the variance in resilience (ß = - 0.32, p < 0.001) and spirituality, another 15% (ß =0.48, p < 0.001). Spirituality acted as a partial mediator in the relationship between psychological distress and resilience in individuals with advanced cancer. CONCLUSIONS: Both psychological distress and spirituality played a role in resilience in cases of advanced cancer. Spirituality can help promote subjective well-being and increased resilience in these subjects.

Measurement properties of the Spanish version of the brief resilient coping scale (BRCS) in cancer patients.

Background/Objective: Resilience is the capacity to adaptively confront stress. The aim of this study was to evaluate the psychometric properties, convergent validity, and factorial invariance of the Spanish version of the Brief Resilient Coping Scale (BRCS). Method: Exploratory and confirmatory factor analyses based on a cross-validation were conducted to explore the scale's dimensionality and test for strong (scalar) measurement invariance across gender, age, tumor site, and survival, by fitting multiple-group confirmatory solutions. An extended structural equation model was used to assess external validity. Prospective, multicenter cohort study of 636 patients who completed the BRCS, Satisfaction with Life Scale (SWLS), and Spiritual well-being (FACIT-sp) scales. Results: The data supported a unidimensional structure. The BRCS is a very short, narrow bandwidth measure, with items demonstrating high discriminating power. A strong invariance solution demonstrated excellent fit across gender, age, tumor site, and survival. Scores derived from the unidimensional structure exhibited satisfactory degrees of reliability (ω = .86) and determinacy (FDI = .94). BRCS revealed substantial associations with satisfaction with life and spirituality well-being (all p < .001), factors widely related to resilience, particularly in cancer patients. Conclusions: The Spanish version of the BRCS is a reliable, valid resilience measure in advanced cancer.

Resilience, Social Support, and Anxious Preoccupation in Patients with Advanced Cancer during COVID-19 Pandemic.

This study examines the mediating role of social support between anxious preoccupation and resilience in patients with cancer during COVID-19. NEOetic_SEOM is a prospective, multicenter study involving individuals with advanced, unresectable cancer who completed the following scales: Resilience (BCRS), Social Support (Duke-UNC-11), and anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer (M-MAC) before starting antineoplastic treatment. Between March 2020 and July 2021, 507 patients (55% male; mean age, 65) were recruited. No differences in resilience were observed based on sociodemographic or clinical characteristics. Social support in people with advanced, unresectable cancer promotes both decreased anxious preoccupation and greater resilience.

A prospective, randomized, blinded, placebo-controlled multisite clinical study of bedinvetmab, a canine monoclonal antibody targeting nerve growth factor, in dogs with osteoarthritis.

OBJECTIVE: Bedinvetmab is a canine monoclonal antibody targeting nerve growth factor. This study evaluated the efficacy and safety of bedinvetmab for alleviation of pain associated with osteoarthritis in dogs. STUDY DESIGN: Double-blind, randomized, multicentre, placebo-controlled study. ANIMALS: Client-owned dogs (n = 287) with osteoarthritis. METHODS: Dogs were randomized (1:1) to subcutaneous injection with placebo (saline, n = 146) or bedinvetmab (0.5-1.0 mg kg-1, n = 141) administered monthly. After 3 months, 89 bedinvetmab-treated dogs that responded positively based on owner and veterinarian assessments were administered up to six additional doses of bedinvetmab in a single-armed open-label continuation phase. The primary efficacy end point was treatment success based on the owner-assessed canine brief pain inventory (CBPI) on day 28. Treatment success was defined as ≥ 1 reduction in pain severity score (0-10) and ≥ 2 in pain interference score (0-10). RESULTS: Percentage treatment success was significantly greater in the bedinvetmab group than in the placebo group from day 7 through all assessed time points (p ≤ 0.0025). On day 28, 43.5% of dogs achieved treatment success with bedinvetmab compared with placebo (16.9%) (p = 0.0017). Treatment success continued through days 56 (50.8%) and 84 (48.2%) in the bedinvetmab group and was < 25% in the placebo group at all time points. Sustained efficacy was demonstrated in the continuation phase. Adverse health events occurred at similar frequencies in both groups. They were considered typical for a population of dogs with osteoarthritis and not related to study treatment. Treatment with bedinvetmab demonstrated a significant effect on all three components of CBPI-pain interference, pain severity, quality of life. CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated the effectiveness and safety of bedinvetmab administered monthly for up to 9 months at 0.5-1.0 mg kg-1 for alleviation of pain associated with canine osteoarthritis.

Early antibody response and clinical outcome in experimental canine leishmaniasis.

Infected dogs are the main reservoir of zoonotic visceral leishmaniasis, a widespread parasitic disease caused by Leishmania infantum. Therefore, the control of canine infections is required to reduce the incidence of human cases. Disease outcome in dogs depends on the fine balance between parasite virulence and efficacy of the immune system. Thus, knowledge of early response could yield relevant information for diagnosis and follow-up. In our study, 20 Beagle dogs were intravenously infected with 108 amastigotes of a fresh isolate of L. infantum and monitored along 16 weeks post inoculation. Specific antibody response and clinical evolution of infected animals were highly variable. Immunofluorescence antibody test (IFAT) and enzyme linked immunosorbent assay (ELISA) were useful to assess infection status, although only ELISA with promastigote-coated plates and, particularly, western blotting (WB) allowed an early diagnosis. Prominent antigens were identified by mass peptide fingerprinting. Chaperonin HSP60, 32 and 30 KDa antigens were recognized by all dogs on week 10 post infection. This suggests that these antigens may be valuable for early diagnosis. Advanced infection showed, in addition, reactivity to HSP83 and HSP70. Disease outcome did not show a clear relationship with ELISA or IFAT titers. Correlation between the clinical status and the combined reactivity to some antigens sustains their use for diagnosis and follow-up.

SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent.

Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (1), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure-activity relationship studies around hit compound 1. The pivaloyl derivative (13) showed significant anti-T. brucei activity (EC50 = 1.1 µM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondrial toxicity, cytochrome P450 and hERG inhibition) were determined for compound 1 and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.

In-Vitro Activity of Silybin and Related Flavonolignans against Leishmania infantum and L. donovani.

Flavonolignans from the seeds of the milk thistle (Silybum marianum) have been extensively used in folk medicine for centuries. Confirmation of their properties as hepatoprotective, antioxidant and anticancer has been obtained using standardized extracts and purified flavonolignans. Information on their potential effect on Leishmania is very scarce. We have investigated the effect of silymarin, silybin and related flavonolignans on the multiplication of promastigotes in vitro and ex vivo on intracellular amastigotes of L. infantum (Li) and L. donovani (Ld), causative agents of human and canine visceral leishmaniasis (VL). In addition, the potential synergistic effect of the most active molecule and well-established antileishmanial drugs against promastigotes was explored. Dehydroisosilybin A elicited the highest inhibition against Ld and Li promastigotes with an approximate IC50 of 90.23 µM. This molecule showed a moderate synergism with amphotericin B (AmB) but not with SbIII or paromomycin, although it was ineffective against amastigotes. Antileishmanial activity on intracellular amastigotes of the two diastereoisomers of dehydrosilybin (10 µM) was comparable to that elicited by 0.1 µM AmB. Antiproliferative activity and safety of flavonolignans suggest the interest of exploring their potential value in combination therapy against VL.

Pharmacokinetics and disposition of miltefosine in healthy mice and hamsters experimentally infected with Leishmania infantum.

Miltefosine is the only currently available oral drug for treatment of leishmaniasis. However, information on the pharmacokinetics (PK) of miltefosine is relatively scarce in animals. PK parameters and disposition of the molecule was determined in healthy NMRI mice and Syrian hamsters infected and treated with different miltefosine doses and regimens. Long half-life of the molecule was confirmed and differential pattern of accumulation of the drug was observed in analyzed organs in mice and hamster. Long treatment schedules produced miltefosine levels over IC50 value against L. infantum intracellular amastigotes for at least 24 days in spleen and liver of infected hamsters. The observed differential pattern of organ accumulation of the drug in mice and hamster supports the relevance of both species for translational research on chemotherapy of leishmaniasis.

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 µM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 µM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.

Allicin Induces Calcium and Mitochondrial Dysregulation Causing Necrotic Death in Leishmania.

BACKGROUND: Allicin has shown antileishmanial activity in vitro and in vivo. However the mechanism of action underlying its antiproliferative effect against Leishmania has been virtually unexplored. In this paper, we present the results obtained in L.infantum and a mechanistic basis is proposed. METHODOLOGY/PRINCIPAL FINDING: Exposure of the parasites to allicin led to high Ca2+ levels and mitochondrial reactive oxygen species (ROS), collapse of the mitochondrial membrane potential, reduced production of ATP and elevation of cytosolic ROS. The incubation of the promastigotes with SYTOX Green revealed that decrease of ATP was not associated with plasma membrane permeabilization. Annexin V and propidium iodide (PI) staining indicated that allicin did not induce phospholipids exposure on the plasma membrane. Moreover, DNA agarose gel electrophoresis and TUNEL analysis demonstrated that allicin did not provoke DNA fragmentation. Analysis of the cell cycle with PI staining showed that allicin induced cell cycle arrest in the G2/M phase. CONCLUSIONS/SIGNIFICANCE: We conclude that allicin induces dysregulation of calcium homeostasis and oxidative stress, uncontrolled by the antioxidant defense of the cell, which leads to mitochondrial dysfunction and a bioenergetic catastrophe leading to cell necrosis and cell cycle arrest in the premitotic phase.

TAp73 is one of the genes responsible for the lack of response to chemotherapy depending on B-Raf mutational status.

BACKGROUND: Although there have been many studies on the p73 gene, some of its functions still remain unclear. There is little research on the relationship between p73 gene transcription and its protein expression and the response to certain drugs such as oxaliplatin and cetuximab, which are drugs currently used in colorectal cancer.The purpose of this study was to evaluate the impact of TAp73 expression on oxaliplatin and cetuximab-based chemotherapy in colorectal cancer cell lines with different K-Ras and B-Raf mutational status. METHODS: TAp73 was analyzed in three colorectal tumor cell lines HT-29, SW-480 and Caco-2. mRNA TAp73 was determined using Real time PCR; TAp73 protein by immunoblotting and cell viability was analyzed by the MTT method. RESULTS: We found that mRNA and TAp73 protein were decreased in cells treated with oxaliplatin (in monotherapy or combined with cetuximab) when B-Raf is mutated. This was statistically significant and was also associated with higher cell viability after the treatment. CONCLUSIONS: Here, for the first time we report, that there is a signaling loop between B-Raf activation and p73 function.Low expression of TAp73 in colorectal cancer cell lines with mutated B-Raf may be involved in the lack of response to oxaliplatin in monotherapy or combined with cetuximab.

Task switching and novelty processing activate a common neural network for cognitive control.

The abrupt onset of a novel event captures attention away from, and disrupts, ongoing task performance. Less obvious is that intentional task switching compares with novelty-induced behavioral distraction. Here we explore the hypothesis that intentional task switching and attentional capture by a novel distracter both activate a common neural network involved in processing contextual novelty [Barcelo, F., Periáñez, J. A., & Knight, R. T. Think differently: A brain orienting response to task novelty. NeuroReport, 13, 1887-1892, 2002.]. Event-related potentials were recorded in two task-cueing paradigms while 16 subjects sorted cards following either two (color or shape; two-task condition) or three (color, shape, or number; three-task condition) rules of action. Each card was preceded by a familiar tone cueing the subject either to switch or to repeat the previous rule. Novel sound distracters were interspersed in one of two blocks of trials in each condition. Both novel sounds and task-switch cues impaired responses to the following visual target. Novel sounds elicited novelty P3 potentials with their usual peak latency and frontal-central scalp distribution. Familiar tonal switch cues in the three- and two-task conditions elicited brain potentials with a similar latency and morphology as the novelty P3, but with relatively smaller amplitudes over frontal scalp regions. Covariance and principal component analyses revealed a sustained frontal negative potential that was distorting concurrent novelty P3 activity to the tonal switch cues. When this frontal negativity was statistically removed, P3 potentials to novel sounds and task-switch cues showed similar scalp topographies. The degree of activation in the novelty P3 network seemed to be a function of the information (entropy) conveyed by the eliciting stimulus for response selection, over and above its relative novelty, probability of occurrence, task relevance, or feedback value. We conclude that novelty P3 reflects transient activation in a neural network involved in updating task set information for goal-directed action selection and might thus constitute one key element in a central bottleneck for attentional control.