Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance

Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within sustainable health systems. Recent studies have demonstrated the role of Substance P (SP) and its preferred receptor, Neurokinin 1 Receptor (NK-1R), in human cancer and the potential antitumor activity of NK-1R antagonists as an anticancer treatment. In this review, we outline the relevant studies published to date regarding the SP/NK-1R complex as a key player in human cancer and also evaluate if the repurposing of already marketed NK-1R antagonists may be useful in the development of new treatment strategies to overcome cancer resistanceThe researcher Marilina García-Aranda is the benefactor of a postdoctoral contract financed by the European Social Fund—Operational Program of Andalusia 2014–2020 for the “Incorporation of Research Personnel with a PhD degree in the field of Health Sciences and Technologies in R&D and Innovation Centers of the Public Health System of Andalusia” (RH-0055-2020). This work was partially supported by grant from the University of Malaga—Consejería de Transformación Económica, Industria, Conocimiento y Universidades—Junta de Andalucia (UMA20-FEDERJA-161). Partial funding for open access charge: Universidad de Málag

Calcium Homeostasis in the Development of Resistant Breast Tumors.

Cancer is one of the main health problems worldwide. Only in 2020, this disease caused more than 19 million new cases and almost 10 million deaths, with breast cancer being the most diagnosed worldwide. Today, despite recent advances in breast cancer treatment, a significant percentage of patients will either not respond to therapy or will eventually experience lethal progressive disease. Recent studies highlighted the involvement of calcium in the proliferation or evasion of apoptosis in breast carcinoma cells. In this review, we provide an overview of intracellular calcium signaling and breast cancer biology. We also discuss the existing knowledge on how altered calcium homeostasis is implicated in breast cancer development, highlighting the potential utility of Ca2+ as a predictive and prognostic biomarker, as well as its potential for the development of new pharmacological treatments to treat the disease.Partial funding for open access charge: Universidad de Málaga

Cambios emocionales y alteraciones en la Inmunoglobulina A (IgA) tras el tratamiento psicológico en mujeres víctimas de violencia doméstica

El objetivo de este estudio ha sido determinar, en mujeres víctimas de maltrato, los beneficios de un tratamiento psicológico y evaluar su impacto en la salud psicológica y en el sistema inmune. Las participantes fueron 60 mujeres usuarias del Área de Igualdad del Ayuntamiento de Málaga. Se constituyeron 2 grupos en función de si acudieron o no a la terapia psicológica. Se evaluaron antes y después del tratamiento las variables psicológicas Autoestima, Depresión y Ansiedad, así como el nivel de Inmunoglobulina A en saliva. Los resultados muestran diferencias en las mujeres que recibieron el tratamiento antes y después de éste en todas las variables, mejorando en todos los indicadores. Estas diferencias no se observan en las mujeres que no acudieron a las sesiones de terapia, y en alguna variable, como depresión e Inmunoglobulina A, incluso existe un empeoramiento. Entre ambos grupos existen diferencias en todas las variables después del tratamiento, así, las mujeres que lo recibieron muestran menos indicadores de alteración psicológica y mayor nivel de Inmunoglobulina A; en el pretratmiento en cambio, estas diferencias no se encontraron. Se hace patente la importancia del tratamiento psicológico en esta población, tanto para su salud psicológica como física.Proyecto de Investigación Personalidad, Estrés crónico y Salud subvencionado por el Ministerio de Ciencia y Tecnología (España) y cuya referencia es BSO2002-00910

Anticlusterin treatment of breast cancer cells increases the sensitivities of chemotherapy and tamoxifen and counteracts the inhibitory action of dexamethasone on chemotherapy-induced cytotoxicity

Introduction: Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. We describe the use of clusterin-specific antisense oligonucleotides and antibodies to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy. Methods: MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these. Results: Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival. Conclusion: These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses

Validation and comparison of instruments to identify frail patientes in primary care settings: Study protocol

Background: In the last few years several indices and tools, aimed at identifying frail subjects in various care settings have been developed. However, to date none of them has been incorporated into usual practice in the primary care setting. The purposes of this study are: 1) to evaluate the predictive capacity of the Tilburg Frailty Indicator (TFI), the Gérontopôle Frailty Screening Tool (GFST) and the KoS model together with two biomarker levels (SOX2 and p16INK4a) for adverse events related to frailty; 2) to determine differences in the use of healthcare services according to frailty. Methods/design: Prospective multicentre cohort study with a 2-year follow-up. The study will be performed in primary care centres of Gipuzkoa and Costa del Sol, both located in Spain. Autonomous, non-institutionalized individuals aged 70 and over that agree to participate in this study will constitute the study population. A total of 900 individuals will be randomly selected from the healthcare administrative data bases of the participating health services. Data will be collected at baseline and at 1 and 2 years. The main independent variables assessed at baseline will be TFI outcomes, GFST and the KoS model, together with the expression of SOX2 and p16INK4a levels. During follow-up, loss of autonomy, the occurrence of death and consumption of healthcare resources will be assessed. Discussion: The main focus of this work is the identification and evaluation of several instruments constructed under different rationales to identify frail subjects in primary care settings. The resulting outcomes have potential for direct application to the primary care practice. Early identification of the onset of functional impairment of elderly is an essential, still unresolved aspect in the prevention of dependence in the scope of primary care

Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus

Neurogenesis persists in certain regions of the adult brain including the subgranular zone of the hippocampal dentate gyrus wherein its regulation is essential, particularly in relation to learning, stress and modulation of mood. Lysophosphatidic acid (LPA) is an extracellular signaling phospholipid with important neural regulatory properties mediated by specific G protein-coupled receptors, LPA1–5. LPA1 is highly expressed in the developing neurogenic ventricular zone wherein it is required for normal embryonic neurogenesis, and, by extension may play a role in adult neurogenesis as well. By means of the analyses of a variant of the original LPA1-null mutant mouse, termed the Malaga variant or “maLPA1-null,” which has recently been reported to have defective neurogenesis within the embryonic cerebral cortex, we report here a role for LPA1 in adult hippocampal neurogenesis. Proliferation, differentiation and survival of newly formed neurons are defective in the absence of LPA1 under normal conditions and following exposure to enriched environment and voluntary exercise. Furthermore, analysis of trophic factors in maLPA1-null mice demonstrated alterations in brain-derived neurotrophic factor and insulin growth factor 1 levels after enrichment and exercise. Morphological analyses of doublecortin positive cells revealed the anomalous prevalence of bipolar cells in the subgranular zone, supporting the operation of LPA1 signaling pathways in normal proliferation, maturation and differentiation of neuronal precursors

Influence of depression on survival of colorectal cancer patients drawn from a large prospective cohort

Objective The prevalence of depressive symptoms immediately after the diagnosis of colorectal cancer (CRC) is high and has important implications both psychologically and on the course of the disease. The aim of this study is to analyse the association between depressive symptoms and CRC survival at 5 years after diagnosis. Methods This multicentre, prospective, observational cohort study was conducted on a sample of 2602 patients with CRC who completed the Hospital Anxiety and Depression Scale (HADS-D) at 5 years of follow-up. Survival was analysed using the Kaplan–Meier method and Cox regression models. Results According to our analysis, the prevalence of depressive symptoms after a CRC diagnosis was 23.8%. The Cox regression analysis identified depression as an independent risk factor for survival (HR = 1.47; 95% CI: 1.21–1.8), a finding which persisted after adjusting for sex (female: HR = 0.63; 95% CI: 0.51–0.76), age (>70 years: HR = 3.78; 95% CI: 1.94–7.36), need for help (yes: HR = 1.43; 95% CI: 1.17–1.74), provision of social assistance (yes: HR = 1.46; 95% CI: 1.16–1.82), tumour size (T3–T4: HR = 1.56; 95% CI: 1.22–1.99), nodule staging (N1–N2: HR = 2.46; 95% CI: 2.04–2.96), and diagnosis during a screening test (yes: HR = 0.71; 95% CI: 0.55–0.91). Conclusions There is a high prevalence of depressive symptoms in patients diagnosed with CRC. These symptoms were negatively associated with the survival rate independently of other clinical variables. Therefore, patients diagnosed with CRC should be screened for depressive symptoms to ensure appropriate treatment can be provided.Funding for open Access charge: Universidad de Málaga / CBUA. This study was supported by public grant from Instituto de Salud Carlos III (PI09/90397, PS09/00314, PS09/00746, PI09/90460, PI/0990490, PI13/01692, PI13/00013, PI18/01181, Pi18/01589) and was co-funded by the European Regional Development fund

The Crucial Role of Inflammation and the Immune System in Colorectal Cancer Carcinogenesis: A Comprehensive Perspective

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively ‘cloaking’ themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer

Factors Associated with Prolonged Patient-Attributable Delay in the Diagnosis of Colorectal Cancer

Purpose The delayed diagnosis of colorectal cancer (CRC) may be attributable to sociodemographic characteristics, to aspects of tumour histopathology or to the functioning of the health system. We seek to determine which of these factors most influences prolonged patient-attributable delay (PPAD) in the diagnosis and treatment of CRC. Materials and Methods A prospective, multicentre observational study was conducted in 22 Spanish hospitals. In total, 1,785 patients were recruited to the study between 2010 and 2012 and underwent elective or urgent surgery. PPAD is considered to occur when the time elapsed between a patient presenting the symptom and him/her seeking attention from the primary care physician or hospital emergency department exceeds 180 days. A bivariate analysis was performed to assess differences in variables segmented by tumour location and patient delay. Multivariate logistic regression analysis was performed on the outcome variable, PPAD. Results The rate of PPAD among this population was 12.1%. PPAD was significantly associated with altered bowel rhythm (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.02 to 1.83) and with adenocarcinoma histology, in comparison with mucinous adenocarcinoma (OR, 2.03; 95% CI, 1.11 to 3.71). Other sociocultural factors and clinicopathological features were not independent predictors of PPAD. Conclusion Many patients do not consider altered bowel rhythm an alarming symptom, warranting a visit to the doctor. PPAD could be reduced by improving health education, raising awareness of CRC-related symptoms. Key words Delay, Patients, Diagnosis, Colorectal neoplas