Oleanolic acid controls allergic and inflammatory responses in experimental allergic conjunctivitis

Producción CientíficaPollen is the most common aeroallergen to cause seasonal conjunctivitis. The result of allergen exposure is a strong Th2- mediated response along with conjunctival mast cell degranulation and eosinophilic infiltration. Oleanolic acid (OA) is natural a triterpene that displays strong anti-inflammatory and immunomodulatory properties being an active anti-allergic molecule on hypersensitivity reaction models. However, its effect on inflammatory ocular disorders including conjunctivits, has not yet been addressed. Hence, using a Ragweed pollen (RWP)-specific allergic conjunctivitis (EAC) mouse model we study here whether OA could modify responses associated to allergic processes. We found that OA treatment restricted mast cell degranulation and infiltration of eosinophils in conjunctival tissue and decreased allergen-specific Igs levels in EAC mice. Th2-type cytokines, secreted phospholipase A2 type-IIA (sPLA2-IIA), and chemokines levels were also significantly diminished in the conjunctiva and serum of OA-treated EAC mice. Moreover, OA treatment also suppressed RWP-specific Tcell proliferation. In vitro studies, on relevant cells of the allergic process, revealed that OA reduced the proliferative and migratory response, as well as the synthesis of proinflammatory mediators on EoL-1 eosinophils and RBL-2H3 mast cells exposed to allergic and/or crucial inflammatory stimuli such as RWP, sPLA2-IIA or eotaxin. Taken together, these findings demonstrate the beneficial activity of OA in ocular allergic processes and may provide a new intervention strategy and potential therapy for allergic diseases

Progress in 3D Bioprinting Technology for Osteochondral Regeneration

Osteochondral injuries can lead to osteoarthritis (OA). OA is characterized by the progressive degradation of the cartilage tissue together with bone tissue turnover. Consequently, joint pain, inflammation, and stiffness are common, with joint immobility and dysfunction being the most severe symptoms. The increase in the age of the population, along with the increase in risk factors such as obesity, has led OA to the forefront of disabling diseases. In addition, it not only has an increasing prevalence, but is also an economic burden for health systems. Current treatments are focused on relieving pain and inflammation, but they become ineffective as the disease progresses. Therefore, new therapeutic approaches, such as tissue engineering and 3D bioprinting, have emerged. In this review, the advantages of using 3D bioprinting techniques for osteochondral regeneration are described. Furthermore, the biomaterials, cell types, and active molecules that are commonly used for these purposes are indicated. Finally, the most recent promising results for the regeneration of cartilage, bone, and/or the osteochondral unit through 3D bioprinting technologies are considered, as this could be a feasible therapeutic approach to the treatment of OA.This research was funded by the BASQUE COUNTRY GOVERNMENT/EUSKO JAURLARITZA (Department of Education, University and Research, Consolidated Groups IT907- 16). Author S.R.-A. thank the BASQUE COUNTRY GOVERNMENT for the granted fellowship (PRE_2021_2_0153)

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 factors and prognostic communication preferences in advanced cancer: multicentre study

Objectives: Communication regarding prognosis to patients with advanced cancer is fundamental for informed medical decision making. Our objective was to analyse (1) the proportion of subjects with advanced cancer who prefer to know their prognosis, (2) the characteristics associated with patients’ preference for prognostic information, (3) the psychological factors that impact the preference to know prognosis and 4) the concordance between preference for prognostic information perceived among physicians and patients. Methods: A prospective, cross-sectional design was adopted. Data were collected from 748 participants with advanced cancer at 15 tertiary hospitals in Spain. Participants completed the following questionnaires: Mental Adjustment to Cancer; Trust in the Physician; Uncertainty in Illness Scale Patient’s Prognostic Preferences. Results: Fifty-two per cent of advanced cancer sufferers preferred to know the prognosis of their disease. Compared with participants who preferred not to know, those who did reported more uncertainty, greater satisfaction with their physician and higher scores on positive attitude (all p=0.001). Thirty-seven per cent of the physicians believed that patients want to know their prognosis, indicating that they underestimate the number of such patients. No significant differences were found regarding preference to know prognosis as a function of sociodemographic and clinical variables. Conclusions: A substantial proportion of individuals with advanced cancer prefer to know the prognosis of their disease. It appears that knowing their prognosis was mainly motivated by a need to maintain a positive attitude, lessen uncertainty and by satisfaction with the physician. It is important to explore patients’ preferences for information to offer more personalised communication

Sphingolipid extracts enhance gene delivery of cationic lipid vesicles into retina and brain

[EN]The aim was to evaluate relevant biophysic processes related to the physicochemical features and gene transfection mechanism when sphingolipids are incorporated into a cationic niosome formulation for non-viral gene delivery to central nervous system. For that, two formulations named niosphingosomes and niosomes devoid of sphingolipid extracts, as control, were developed by the oil-in water emulsion technique. Both formulations and the corresponding complexes, obtained upon the addition of the reporter EGFP plasmid, were physicochemically and biologically characterized and evaluated. Compared to niosomes, niosphingosomes, and the corresponding complexes decreased particle size and increased superficial charge. Although there were not significant differences in the cellular uptake, cell viability and transfection efficiency increased when human retinal pigment epithelial (ARPE-19) cells were exposed to niosphingoplexes. Endocytosis via caveolae decreased in the case of niosphingoplexes, which showed higher co-localization with lysosomal compartment, and endosomal escape properties. Moreover, niosphingoplexes transfected not only primary central nervous system cells, but also different cells in mouse retina, depending on the administration route, and brain cortex. These preliminary results suggest that niosphingosomes represent a promising non-viral vector formulation purposed for the treatment of both retinal and brain diseases by gene therapy approach.This work was supported by the Basque Country Government (Department of Education, University and Research, Consolidated Groups IT907-16) . Additional funding was provided by the CIBER of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , an initiative of the Carlos III Health Institute (ISCIII) . I.V.B. and M.S.R. thank the University of the Basque Country (UPV/EHU) for the granted postdoctoral fellowship (ESPDOC19/47) and the granted pre-doctoral fellowship (PIF17/79) , respectively. Authors wish to thank the intel-lectual and technical assistance from the ICTS "NANBIOSIS," more specifically by the Drug Formulation Unit (U10) of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the University of Basque Country (UPV/EHU) . Technical and human sup-port provided by SGIKER (UPV/EHU) is also gratefully acknowledged

Prediction of unplanned hospitalizations in older patients treated with chemotherapy

Purpose: To determine the incidence of unplanned hospitalization (UH) and to identify risk factors for UH in elderly patients with cancer who start chemotherapy. Methods: In all, 493 patients over 70 years starting new chemotherapy regimens were prospectively included. A pre-chemotherapy geriatric assessment was performed, and tumor and treatment variables were collected. The association between these factors and UH was examined by using multivariable logistic regression. Score points were assigned to each risk factor. Results: During the first 6 months of treatment, 37% of patients had at least one episode of UH. Risk factors were the use of combination chemotherapy at standard doses, a MAX2 index ≥1, a Charlson comorbidity score ≥2, albumin level <3.5 g/dL, falls in the past 6 months ≥1, and weight loss >5%. Three risk groups for UH were established according to the score in all patients: 0–1: 17.5%; 2: 34%; and 3–7: 57% (p < 0.001). The area under receiver operation characteristic (ROC) curve was 0.72 (95% CI: 0.67–0.77). Conclusion: This simple tool can help to reduce the incidence of UH in elderly patients with cancer who are scheduled to initiate chemotherapy treatmen

Prediction of Chemotoxicity, Unplanned Hospitalizations and Early Death in Older Patients with Colorectal Cancer Treated with Chemotherapy

Simple Summary Chemotoxicity, unplanned hospitalizations (Uhs) and early death (ED) are common among older patients with cancer who receive chemotherapy. Our objective was to determine factors predicting these complications. A predictive score for these three complications based on geriatric, tumor and laboratory variables was developed in a series of 215 older patients with colorectal carcinoma receiving chemotherapy. The use of this score may reliably identify patients at risk to have excessive toxicity with chemotherapy, UH or ED, thus helping to plan treatment, implement adaptive measures, and intensify follow-up. Purpose: To identify risk factors for toxicity, unplanned hospitalization (UH) and early death (ED) in older patients with colorectal carcinoma (CRC) initiating chemotherapy. Methods: 215 patients over 70 years were prospectively included. Geriatric assessment was performed before treatment, and tumor and treatment variables were collected. The association between these factors and grade 3-5 toxicity, UH and ED (<6 months) was examined by using multivariable logistic regression. Score points were assigned to each risk factor. Results: During the first 6 months of treatment, 33% of patients developed grade 3-5 toxicity, 31% had UH and 23% died. Risk factors were, for toxicity, instrumental activities of daily living, creatinine clearance, weight loss and MAX2 index; for UH, Charlson Comorbidity Score, creatinine clearance, weight loss, serum albumin, and metastatic disease; and for ED, basic activities in daily living, weight loss, metastatic disease, and hemoglobin levels. Predictive scores were built with these variables. The areas under receiver operation characteristic (ROC) curves for toxicity, UH and ED were 0.70 (95% CI: 0.64-0.766), 0.726 (95% IC: 0.661-0.799) and 0.74 (95% IC: 0.678-0.809), respectively. Conclusion: Simple scores based on geriatric, tumor and laboratory characteristics predict severe toxicity, UH and ED, and may help in treatment planning

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma

Dissemination; Paediatric cancer; Solid tumoursDiseminación; Cáncer pediátrico; Tumores sólidosDisseminació; Càncer pediàtric; Tumors sòlidsThe majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.This research was supported by grants from: Institut Català d’Oncologia (ICO); Instituto de Salud Carlos III (PI18/00398 and FI18/00178); ACCIÓ (COMRDI15-1-0014); Fundació la Marató de TV3; Fundació A. BOSCH; Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst e.V. and others from Barcelona and province; Eric Abidal Foundation; Del Hospital a la catedral Initiative by Xavi Vallès; and Mi compañero de viaje Association

Synthetic conjugates of ursodeoxycholic acid inhibit cystogenesis in experimental models of polycystic liver disease

Background and aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and results: here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: these UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs

Development and Validation of an Early Mortality Risk Score for Older Patients Treated with Chemotherapy for Cancer

Background: Estimation of life expectancy in older patients is relevant to select the best treatment strategy. We aimed to develop and validate a score to predict early mortality in older patients with cancer. Patients and Methods: A total of 749 patients over 70 years starting new chemotherapy regimens were prospectively included. A prechemotherapy assessment that included sociodemographic variables, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and early death was examined using multivariable logistic regression. Score points were assigned to each risk factor. External validation was performed on an independent cohort. Results: In the training cohort, the independent predictors of 6-month mortality were metastatic stage (OR 4.8, 95% CI [2.4-9.6]), ECOG-PS 2 (OR 2.3, 95% CI [1.1-5.2]), ADL ≤ 5 (OR 1.7, 95% CI [1.1-3.5]), serum albumin levels ≤ 3.5 g/dL (OR 3.4, 95% CI [1.7-6.6]), BMI < 23 kg/m2 (OR 2.5, 95% CI [1.3-4.9]), and hemoglobin levels < 11 g/dL (OR 2.4, 95% CI (1.2-4.7)). With these results, we built a prognostic score. The area under the ROC curve was 0.78 (95% CI, 0.73 to 0.84), and in the validation set, it was 0.73 (95% CI: 0.67-0.79). Conclusions: This simple and highly accurate tool can help physicians making decisions in elderly patients with cancer who are planned to initiate chemotherapy treatment