Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine.

T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322 treatment stimulated T cell cytotoxicity through the increased presence of granzyme B, perforin, and interferon-gamma. Additional immune profiling indicated TILT-322 increased gamma delta T cell activation and impacted other cell types such as natural killer cells and natural killer-like T cells that are traditionally involved in cancer immunotherapy. TILT-322 treatment also decreased the proportion of exhausted CD8+ T cells as demarked by immune checkpoint expression in ovarian ascites samples. Overall, our data showed that TILT-322 treatment led to an enhanced T cell activation and reversed T cell exhaustion translating into high antitumor efficacy when given locally or intravenously. The analysis of blood and tumors isolated from an in vivo patient-derived ovarian cancer xenograft model suggested TILT-322 mediated tumor control through improved T cell functions. Therefore, TILT-322 is a promising novel anti-tumor agent for clinical translation.

Detecting non-content-based response styles in survey data: An application of mixture factor analysis.

It is common for some participants in self-report surveys to be careless, inattentive, or lacking in effort. Data quality can be severely compromised by responses that are not based on item content (non-content-based [nCB] responses), leading to strong biases in the results of data analysis and misinterpretation of individual scores. In this study, we propose a specification of factor mixture analysis (FMA) to detect nCB responses. We investigated the usefulness and effectiveness of the FMA model in detecting nCB responses using both simulated data (Study 1) and real data (Study 2). In the first study, FMA showed reasonably robust sensitivity (.60 to .86) and excellent specificity (.96 to .99) on mixed-worded scales, suggesting that FMA had superior properties as a screening tool under different sample conditions. However, FMA performance was poor on scales composed of only positive items because of the difficulty in distinguishing acquiescent patterns from valid responses representing high levels of the trait. In Study 2 (real data), FMA detected a minority of cases (6.5%) with highly anomalous response patterns. Removing these cases resulted in a large increase in the fit of the unidimensional model and a substantial reduction in spurious multidimensionality.

Diagnosing molecular subtypes of breast cancer by means of Raman spectroscopy.

OBJECTIVES: Raman spectroscopy has been used to discriminate human breast cancer and its different tumor molecular subtypes (luminal A, luminal B, HER2, and triple-negative) from normal tissue in surgical specimens. MATERIALS AND METHODS: Breast cancer and normal tissue samples from 31 patients were obtained by surgical resection and submitted for histopathology. Before anatomopathological processing, the samples had been submitted to Raman spectroscopy (830 nm, 25 mW excitation laser parameters). In total, 424 Raman spectra were obtained. Principal component analysis (PCA) was used in an exploratory analysis to unveil the compositional differences between the tumors and normal tissues. Discriminant models were developed to distinguish the different cancer subtypes by means of partial least squares (PLS) regression. RESULTS: PCA vectors showed spectral features referred to the biochemical constitution of breast tissues, such as lipids, proteins, amino acids, and carotenoids, where lipids were decreased and proteins were increased in breast tumors. Despite the small spectral differences between the different subtypes of tumor and normal tissues, the discriminant model based on PLS was able to discriminate the spectra of the breast tumors from normal tissues with an accuracy of 97.3%, between luminal and nonluminal subtypes with an accuracy of 89.9%, between nontriple-negative and triple-negative with an accuracy of 94.7%, and each molecular subtype with an accuracy of 73.0%. CONCLUSION: PCA could reveal the compositional difference between tumors and normal tissues, and PLS could discriminate the Raman spectra of breast tissues regarding the molecular subtypes of cancer, being a useful tool for cancer diagnosis.

Wording Effects in Assessment: Missing the Trees for the Forest.

This article examines wording effects when positive and negative worded items are included in psychological assessment. Wordings effects have been analyzed in the literature using statistical approaches based on population homogeneity assumptions (i.e. CFA, SEM), commonly adopting the bifactor model to separate trait variance and wording effects. This article presents an alternative approach by explicitly modeling population heterogeneity through a latent profile model, based on the idea that a subset of individuals exhibits wording effects. This kind of mixture model allows simultaneously to classify respondents, substantively characterize the differences in their response profiles, and report respondents' results in a comparable manner. Using the Rosenberg's self-esteem scale data from the LISS Panel (N = 6,762) in three studies, we identify a subgroup of participants who respond differentially according to item-wording and examine the impact of its responses in the estimation of the RSES measurement model, in terms of global and individual fit, under one-factor and bifactor models.The results of these analyses support the interpretation of wording effects in terms of a theoretically-proposed differential pattern of response to positively and negatively worded items, introducing a valuable tool for examining the artifactual or substantive interpretations of such wording effects.

Psychotropic drugs intake in people aging with intellectual disability: Prevalence and predictors.

BACKGROUND: Psychotropic medication is frequently administered to people with intellectual disability with mental health and/or behavioural problems, instead of other non-pharmacological interventions. This study describes the mental health and behavioural problems of people aging with intellectual disability, their psychotropic medication intake, and the factors contributing to a greater medication intake. METHOD: The sample consisted of 991 people with intellectual disability over 45 years. Descriptive statistics and multinominal logistic regression were carried out. RESULTS: Antipsychotics were the most used psychotropic drug. Older people with mild intellectual disability living in institutions and affected by mental health and behavioural problems were more likely to take larger amounts of psychotropic medication. CONCLUSIONS: Antipsychotics continue to be widely used by people with intellectual disability and mental and behavioural health problems, especially those in institutionalised settings. Future research should consider if medication intake could be reduced providing better supports in the community and non-pharmacological interventions.

A little garbage in, lots of garbage out: Assessing the impact of careless responding in personality survey data.

In self-report surveys, it is common that some individuals do not pay enough attention and effort to give valid responses. Our aim was to investigate the extent to which careless and insufficient effort responding contributes to the biasing of data. We performed analyses of dimensionality, internal structure, and data reliability of four personality scales (extroversion, conscientiousness, stability, and dispositional optimism) in two independent samples. In order to identify careless/insufficient effort (C/IE) respondents, we used a factor mixture model (FMM) designed to detect inconsistencies of response to items with different semantic polarity. The FMM identified between 4.4% and 10% of C/IE cases, depending on the scale and the sample examined. In the complete samples, all the theoretical models obtained an unacceptable fit, forcing the rejection of the starting hypothesis and making additional wording factors necessary. In the clean samples, all the theoretical models fitted satisfactorily, and the wording factors practically disappeared. Trait estimates in the clean samples were between 4.5% and 11.8% more accurate than in the complete samples. These results show that a limited amount of C/IE data can lead to a drastic deterioration in the fit of the theoretical model, produce large amounts of spurious variance, raise serious doubts about the dimensionality and internal structure of the data, and reduce the reliability with which the trait scores of all surveyed are estimated. Identifying and filtering C/IE responses is necessary to ensure the validity of research results.

A new scale for measuring quality of life in acquired brain injury.

PURPOSE: A common and frequent consequence of an acquired brain injury (ABI) is the diminished quality of life (QoL) of affected people. Because the majority of existing QoL instruments assess health-related domains, new instruments that allow for the evaluation of the QoL from an integral perspective that considers the context and personal factors of the individual are warranted. Hence, the purpose of this study is to develop and validate an instrument with these characteristics. METHODS: The CAVIDACE scale is a new 64-item specific instrument to assess QoL in people with ABI based on a third-person perspective. The validation sample comprises 421 adults with ABI, with ages ranging from 17 to 90 years (M = 53.12; SD = 14.87). The scale was completed by 97 professionals and 58 family members. Validity evidence based on the internal structure of the scale was provided through confirmatory factor analyses. Reliability was analyzed in terms of internal consistency and inter-rater reliability. RESULTS: The results supported the internal structure of the scale, based on the theoretical and assessment framework in which QoL is composed of eight intercorrelated first-order domains (CFI = 0.890, RMSEA = 0.065, SRMR = 0.071). The internal consistency was good or excellent for the eight domains (ordinal alpha ranging from 0.77 to 0.93). The inter-rater reliability was very high (0.97). CONCLUSIONS: The CAVIDACE scale is found to be a specific instrument with excellent psychometric properties that is helpful for the assessment of QoL in people with ABI, both in clinical practice and for research purposes.

Invariance of parent ratings of attention deficit hyperactivity disorder symptoms for children with and without intellectual disability.

BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) is considered a valid diagnosis for children with intellectual disability, no studies have evaluated the invariance of ADHD symptom ratings across children with and without intellectual disability. METHOD: Parents completed ratings on the ADHD symptoms for 189 children with intellectual disability and for 474 children without intellectual disability. Differential item functioning analysis was used to determine the equivalence of the ADHD symptoms across the two groups. RESULTS: The symptoms loses things, talks too much, and blurts out answers showed significant bias against children with intellectual disability. The prevalence of ADHD in children with intellectual disability was 18% (according to the symptom criterion), and 7.4% when the academic and/or social impairment criterion was also considered. CONCLUSIONS: Most of the ADHD symptoms can be valid for the assessment of ADHD in children with mild and moderate intellectual disability. ADHD symptoms may be used in further studies to establish base rates of the disorder in the intellectual disability population.

Examining measurement invariance and differences across groups in the support needs of children with and without intellectual disability.

BACKGROUND: The purposes of this study were to empirically determine whether the support needs construct is generalizable across children with and without intellectual disability and to conduct cross-group comparisons to explore how extraordinary and non-extraordinary support needs differ in children. METHOD: One thousand thirty-six children (814 with intellectual disability 222 without intellectual disability) were assessed using the SIS-C. RESULTS: The SIS-C achieved scalar invariance between children with and without intellectual disability. Cross-group comparisons revealed differences in variances, in correlations between factors and significant latent mean differences for all factors. CONCLUSION: Results show that the support needs construct is generalizable to children with and without intellectual disability and that there are no qualitative differences in how they show their support needs, so typically developing children can be used as a reference group to explore differences between extraordinary and non-extraordinary support needs. Conceptual and practical implications are discussed, and future lines of research are provided.

Enterococci as a key parameter for water quality index: Purires River, Costa Rica.

This study used the Canadian Water Quality Index (CWI) to characterize water sampled at three points within the Purires River micro basin, Costa Rica. The first sampling point is located in a high zone with domestic agricultural activities, the second point around the mid-point of the flow of the river, and the third point at the lowest zone with extensive agricultural activities mainly centered on the production of fresh vegetables. Eleven physicochemical parameters (As, Cd, Cr, biochemical oxygen demand (BOD), chemical oxygen demand (COD), NH4 +, NO3 -, Pb, pH, percent saturation of dissolved oxygen (PSO), and total suspended solids (TSS)) and two microbiological parameters (fecal coliforms and enterococci) were evaluated. We evaluated three different Canadian Water Quality Indexes (CWIs): CWI-1 included only physicochemical parameters, CWI-2 included CWI-1 parameters plus fecal coliforms, and CWI-3 included CWI-2 in addition to enterococci. Statistical analysis of individual parameters showed significant differences between sampling sites. CWI-1 was unable to discriminate between the three sampling points, and characterized the water quality as 'fair'. CWI-2 was only able to discriminate when the water contained high levels of chemical and microbiological contaminants, while CWI-3 adequately discriminated water quality at each of the sampling points. The evaluation of enterococci together with more traditional water quality parameters enabled better categorization of surface water quality.

The use of mesenchymal stem cells in bladder augmentation.

PURPOSE: To compare integration of bladder acellular matrix (BAM) with the bladder when seeded with mesenchymal stem cells (MSC) and when MSC are injected intravenously (IV). METHODS: MSCs were isolated from bone marrow of EPM-1 Wistar male rats. Female rats were distributed into: Group A-BAM augmentation; Group B-BAM augmentation and MSCs IV administered; Group C-BAM-MSC seeded augmentation. Animals were killed on postoperative days 7, 14 and 28. Morphological analyses were performed using hematoxylin and eosin and Masson's trichrome, in addition to immunohistochemical staining with α-SMA and neurofilament for assessment of tissue repair. RNAm expression of the SRY gene was used to mark MSCs in the rats killed on postoperative day 28. RESULTS: The muscle layer was best repaired in Groups B and C. No difference in the repair of the urothelium in the animals in any of the three groups was found. Group B presented the smallest inflammatory reaction and the best neural repair on postoperative day 28. None of the animals examined had MSCs in their bladder graft. CONCLUSION: The MSCs were able to improve repair of the muscle layer and when injected intravenously, they were noted to initiate the neuronal regeneration process.

Improving Quality of Life and Reducing Behavioral Problems of People With Intellectual and Developmental Disabilities Through Deinstitutionalization.

ANTECEDENTS: People with intellectual and developmental disability (IDD) with extensive support needs are more likely to live in segregated and highly institutionalized environments. The aim of this study was to analyze changes in functioning and quality of life for people with IDD and extensive support needs after transitioning to ordinary homes in the community. METHOD: The sample included 54 adults with IDD and extensive support needs, who were assessed at three time points: before transition, six months later, and one year after transition. The Resident Choice Scale, San Martin Quality of Life Scale, Active Support Participation Measure, and the Behavior Problem section of the Inventory for Client and Agency Planning were administered. Partial least squares-structural equation modeling (PLS-SEM) and t-tests for repeated measures were carried out. RESULTS: There were significant improvements in decision-making, participation and independence in daily activities and quality of life, as well as a reduction in the presence and intensity of behavioral problems. CONCLUSIONS: The benefits found in this study support transformation processes towards more inclusive services and professional practices that foster people's rights and feeling of belonging to the community.

Q-Herilearn: Assessing heritage learning in digital environments. A mixed approach with factor and IRT models.

The assessment of heritage learning in digital environments lacks instruments that measure it with sufficient guarantees of accuracy, validity, and reliability. This study attempts to fill this gap by developing an instrument that has shown solid metric qualities. The process of design and calibration of a scale applied to 1,454 participants between 19 and 63 years of age is presented in this article. Exploratory factor analysis (Exploratory Structural Equation Modeling ESEM) and Item Response Theory models (Graded Response Model GRM) were used. Sufficient evidence of both reliability and validity based on content and internal structure was obtained. Invariance of scores as a function of gender and age of participants has also been demonstrated. The discrimination parameters of the items have been found to be high, and the test information curves have shown that the subscales measure with sufficient precision wide ranges of the respective latent variables. The instrument presents wide possibilities of application to various areas of Heritage Education (e.g., design of programs in HE, definition and planning of teaching objectives, evaluation of programs, etc., in virtual environments).

Construction and Validation of a Scale to Assess Social Judgments Toward Sex Work from the Stereotype Content Model.

Sex workers (SW) are subject to social judgment and the associated attitudes, ranging from admiration to contempt. The presence of stereotypical attitudes toward SW is common and can be analyzed using the Stereotype Content Model (SCM), where the concepts of warmth and competence play a central role. The interweaving of both dimensions allows the identification of four emotions and corresponding political positions toward SW: admiration (non-interventionism), pity (abolitionism), contempt (prohibitionism), and fear (regulationism). From the SCM framework, this study offers the construction, validation and performance of a 25-item scale with a snowball sample of 1,543 participants residing in Spanish-speaking countries. The four-factor hypothesized model yielded adequate values. Internal consistency was sufficient on all factors, as was model-based reliability and convergent validity. The scale also showed measurement invariance between gender and age groups, suggesting that the measure is interpreted in a conceptually similar manner by respondents representing different genders or ages. Further analysis revealed that male participants scored significantly higher on admiration. Baby boomers showed less pity and contempt while Millennials showed more fear and less admiration. SW and those who know or work with SW showed less fear and pity and more admiration. The SCM and the process of developing social judgments offer us a way to understand the differences that underlie irreconcilable policy positions. Overcoming these differences requires mutual understanding from scientific frameworks instead of from ideological perspectives.

Cardiac metastasis of melanoma presenting as acute aortic occlusion.

Cardiac diseases are the most common cause of acute arterial emboli, however, cardiac tumors are not as frequent. Cardiac metastases from melanoma are usually silent, and rarely cause symptoms. Only a few reports are found in the literature of metastatic melanoma, causing arterial emboli. Here, we report a case of a cardiac metastasis of melanoma cancer that presented preoperative as arterial emboli. The gross appearance of the emboli already suggested the presence of a cardiac tumor. In selected patients who have a solitary intracardiac melanoma, surgical resection can provide relief from clinical symptoms and minimize potential cardiac sequelae of the tumor.

Integration of collagen matrices into the urethra when implanted as onlay graft.

OBJECTIVE: To assess the integration of decellularized heterologous collagen matrices into the urethra, when implanted with no cells or when seeded with autologous smooth muscle cells. MATERIALS AND METHODS: Eighteen New Zealand rabbits were randomly assigned to two groups: Group I (n = 9) - animals undergoing urethral segment resection with interposition of a patch of heterologous collagen matrix seeded with autologous smooth muscle cells; Group II (n = 9) - animals undergoing resection of a urethral segment with interposition of a decellularized heterologous collagen matrix patch. Two animals from each group were sacrificed on postoperative days seven, fourteen and twenty-eight; three animals from each group were sacrificed at the end of three postoperative months. At the end of the third month one animal from each group underwent urethroscopy for urethral integrity assessment and one animal from each group had its microcirculation image captured by a SDF device (Side-stream Dark Field - Microscan Analysis Software). One animal from each group in each euthanasia period underwent cystourethrography so as the urethra could be viewed at flow time. The matrices integration was assessed through histological examination using hematoxylin and eosin (H & E), Masson trichrome (MT), Picrosirius red and Von Willebrand staining. In a blind study with two pathologists all the slides were studied. RESULTS: The matrices whether seeded or not with autologous muscle cells were able to restore the architecture of the urethra, but were eliminated from the first week on, before incorporation. Microcirculation of the neourethra, at the end of the third month, showed the same characteristics as a normal urethra in both groups of animals. CONCLUSION: Natural heterologous matrices implanted in the urethra as onlay graft were not incorporated into its walls but were able to fully restore the cell architecture of the organ, regardless of being seeded or not with autologous muscle cells.

The ephemeral nature of wording effects.

This article explores the analysis and interpretation of wording effects associated with using direct and reverse items in psychological assessment. Previous research using bifactor models has suggested a substantive nature of this effect. The present study uses mixture modeling to systematically examine an alternative hypothesis and surpass recognized limitations in the bifactor modeling approach. In preliminary supplemental Studies S1 and S2, we examined the presence of participants who exhibited wording effects and evaluated their impact on the dimensionality of Rosenberg's Self-Esteem and the Revised Life Orientation Test, confirming the ubiquity of wording effects in scales containing direct and reverse items. Then, after analyzing the data for both scales (n = 5,953), we found that, despite a significant association between wording factors (Study 1), a low proportion of participants simultaneously exhibited asymmetric responses in both scales (Study 2). Similarly, despite finding both longitudinal invariance and temporal stability of this effect in three waves (n = 3,712, Study 3), a small proportion of participants was identified with asymmetric responses over time (Study 4), reflected in lower transition parameters compared to the other patterns of profiles examined. In both cases, we illustrate how bifactor models capitalize on the responses of individuals who do not even exhibit wording effects, yielding spurious correlations suggesting a substantive nature of the wording effect. These findings support the notion of an ephemeral nature underlying wording effects. The discussion focuses on alternative hypotheses to understand these findings and emphasizes the utility of including reverse items in psychological assessment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A community living experience: Views of people with intellectual disability with extensive support needs, families, and professionals.

BACKGROUND: Despite the benefits of community living for people with intellectual disabilities (ID) and extensive support needs, they remain highly institutionalized. AIMS: To qualitatively analyze the perceptions of people with ID, including those with extensive support needs, professionals, and family members six months after the implementation of 11 community homes for 47 people in different regions of Spain METHODS: Thematic analysis of 77 individual interviews conducted with 13 people with ID, 30 professionals and 34 family members was performed using Nvivo12. RESULTS: Seven themes were found: (1) "the room as I like it", (2) "sometimes I don't obey", (3) "here I do a bit of everything", (4) "lots of people love me here", (5) "all thanks to them, who have helped me" (6) "I miss my mom", and (7) "I'm happy here". IMPLICATIONS: Transitioning into the community has shown a clear positive change in emotional well-being, opportunities to participate in activities or exercise control over one's life. Nevertheless, certain restrictions were still present in people's lives, which significantly limit their right to independent living. While many of these restrictions may disappear, professional practices typical of a medical model can be recreated in services located in the community.

An oncolytic adenovirus coding for a variant interleukin 2 cytokine improves response to chemotherapy through enhancement of effector lymphocyte cytotoxicity, fibroblast compartment modulation and mitotic slippage.

Pancreatic ductal adenocarcinoma (PDAC) is a highly treatment-resistant cancer. Currently, the only curative treatment for PDAC is surgery, but most patients are diagnosed with metastatic disease and thus outside the scope of surgery. The majority of metastatic patients receive chemotherapy, but responses are limited. New therapeutics are thus urgently needed for PDAC. One major limitation in treating PDAC has been the highly immunosuppressive tumor microenvironment (TME) which inhibits anti-cancer immune responses. We have constructed an oncolytic adenovirus coding for a variant the interleukin 2 molecule, Ad5/3-E2F-d24-vIL2 (also known as TILT-452, and "vIL-2 virus"), with preferential binding to IL-2 receptors on the surface of effector lymphocytes over T regulatory cells (T regs). In the present study this virus was evaluated in combination with nab-paclitaxel and gemcitabine chemotherapy in Panc02 mouse model. Ad5/3-E2F-d24-vIL2 showed marked PDAC cell killing in vitro, alongside induction of mitotic slippage and immunogenic cell death in PDAC cell lines, when combined with chemotherapy. Increased survival was seen in vivo with 80% of animals surviving long term, when compared to chemotherapy alone. Moreover, combination therapy mediated enhanced tumor growth control, without observable toxicities in internal organs or external features. Survival and tumor control benefits were associated with activation of tumor infiltrating immune cells, downregulation of inhibitory signals, change in fibroblast populations in the tumors and changes in intratumoral cytokines, with increased chemokine amounts (CCL2, CCL3, CCL4) and anti-tumor cytokines (IFN-γ and TNFα). Furthermore, vIL-2 virus in combination with chemotherapy efficiently induced tumor protection upon rechallenge, that was extended to a previously non-encountered cancer cell line. In conclusion, Ad5/3-E2F-d24-vIL2 is a promising immunotherapy candidate when combined with nab-paclitaxel and gemcitabine.

Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.

Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated in vitro. When TILT-321 was combined with allogeneic T cells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased T cell activity and its binding to MUC1 and CD3. In vivo, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral T cell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific T cell engager delivery for solid tumor treatment.