An Immunomodulatory Gallotanin-Rich Fraction From Caesalpinia spinosa Enhances the Therapeutic Effect of Anti-PD-L1 in Melanoma.

PD-1/PD-L1 pathway plays a role in inhibiting immune response. Therapeutic antibodies aimed at blocking the PD-1/PD-L1 interaction have entered clinical development and have been approved for a variety of cancers. However, the clinical benefits are reduced to a group of patients. The research in combined therapies, which allow for a greater response, is strongly encouraging. We previously characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) with antitumor activity in both melanoma and breast carcinoma, as well as immunomodulatory activity. We hypothesize that the combined treatment with P2Et and anti-PD-L1 can improve the antitumor response through an additive antitumor effect. We investigated the antitumor and immunomodulatory activity of P2Et and anti-PD-L1 combined therapy in B16-F10 melanoma and 4T1 breast carcinoma. We analyzed tumor growth, hematologic parameters, T cell counts, cytokine expression, and T cell cytotoxicity. In the melanoma model, combined P2Et and anti-PD-L1 therapy has the following effects: decrease in tumor size; increase in the number of activated CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells; decrease in the number of suppressor myeloid cells; increase in PD-L1 expression; decrease in the frequency of CD8 <sup>+</sup> T cell expressing PD-1; improvement in the cytotoxic activity of T cells; and increase in the IFN γ secretion. In the breast cancer model, P2Et and PD-L1 alone or in combination show antitumor effect with no clear additive effect. This study shows that combined therapy of P2Et and anti-PD-L1 can improve antitumor response in a melanoma model by activating the immune response and neutralizing immunosuppressive mechanisms

Immune-system-dependent anti-tumor activity of a plant-derived polyphenol rich fraction in a melanoma mouse model.

Recent findings suggest that part of the anti-tumor effects of several chemotherapeutic agents require an intact immune system. This is in part due to the induction of immunogenic cell death. We have identified a gallotannin-rich fraction, obtained from Caesalpinia spinosa (P2Et) as an anti-tumor agent in both breast carcinoma and melanoma. Here, we report that P2Et treatment results in activation of caspase 3 and 9, mobilization of cytochrome c and externalization of annexin V in tumor cells, thus suggesting the induction of apoptosis. This was preceded by the onset of autophagy and the expression of immunogenic cell death markers. We further demonstrate that P2Et-treated tumor cells are highly immunogenic in vaccinated mice and induce immune system activation, clearly shown by the generation of interferon gamma (IFN-γ) producing tyrosine-related protein 2 antigen-specific CD8+ T cells. Moreover, the tumor protective effects of P2Et treatment were abolished in immunodeficient mice, and partially lost after CD4 and CD8 depletion, indicating that P2Et's anti-tumor activity is highly dependent on immune system and at least in part of T cells. Altogether, these results support the hypothesis that the gallotannin-rich fraction P2Et's anti-tumor effects are mediated to a great extent by the endogenous immune response following to the exposure to immunogenic dying tumor cells

Failure propagation in GMPLS optical rings: CTMC model and performance analysis

Network reliability and resilience has become a key design parameter for network operators and Internet service providers. These often seek ways to have their networks fully operational for at least 99.999% of the time, regardless of the number and type of failures that may occur in their networks. This article presents a continuous-time Markov chain model to characterise the propagation of failures in optical GMPLS rings. Two types of failures are considered depending on whether they affect only the control plane, or both the control and data planes of the node. Additionally, it is assumed that control failures propagate along the ring infecting neighbouring nodes, as stated by the Susceptible-Infected-Disabled (SID) propagation model taken from epidemic-based propagation models. A few numerical examples are performed to demonstrate that the CTMC model provides a set of guidelines for selecting the appropriate repair rates in order to attain specific availability requirements, both in the control plane and the data plane.This work is partially supported by the Spanish Ministry of Science and Innovation project TEC 2009-10724 and by the Generalitat de Catalunya research support programme (SGR-1202). Additionally, the authors would like to thank the support of the T2C2 Spanish project (under code TIN2008-06739-C04-01) and the CAM-UC3M Greencom research grant (under code CCG10-UC3M/TIC-5624) in the development of this work.Publicad

Mpox vaccination willingness, determinants, and communication needs in gay, bisexual, and other men who have sex with men, in the context of limited vaccine availability in the Netherlands (Dutch Mpox-survey)

IntroductionIn the 2022 multicountry mpox (formerly named monkeypox) outbreak, several countries offered primary preventive vaccination (PPV) to people at higher risk for infection. We study vaccine acceptance and its determinants, to target and tailor public health (communication-) strategies in the context of limited vaccine supply in the Netherlands. MethodsOnline survey in a convenience sample of gay, bisexual and other men who have sex with men, including transgender persons (22/07-05/09/2022, the Netherlands). We assessed determinants for being (un)willing to accept vaccination. We used multivariable multinominal regression and logistic regression analyses, calculating adjusted odds ratios (aOR) and 95 percent confidence-intervals. An open question asked for campaigning and procedural recommendations. ResultsOf respondents, 81.5% (n = 1,512/1,856) were willing to accept vaccination; this was 85.2% (799/938) in vaccination-eligible people and 77.7% (713/918) in those non-eligible. Determinants for non-acceptance included: urbanization (rural: aOR:2.2;1.2-3.7; low-urban: aOR:2.4;1.4-3.9; vs. high-urban), not knowing mpox-vaccinated persons (aOR:2.4;1.6-3.4), and lack of connection to gay/queer-community (aOR:2.0;1.5-2.7). Beliefs associated with acceptance were: perception of higher risk/severity of mpox, higher protection motivation, positive outcome expectations post vaccination, and perceived positive social norms regarding vaccination. Respondents recommended better accessible communication, delivered regularly and stigma-free, with facts on mpox, vaccination and procedures, and other preventive options. Also, they recommended, "vaccine provision also at non-clinic settings, discrete/anonymous options, self-registration" to be vaccinated and other inclusive vaccine-offers (e.g., also accessible to people not in existing patient-registries). ConclusionIn the public health response to the mpox outbreak, key is a broad and equitable access to information, and to low-threshold vaccination options for those at highest risk. Communication should be uniform and transparent and tailored to beliefs, and include other preventive options. Mpox vaccine willingness was high. Public health efforts may be strengthened in less urbanized areas and reach out to those who lack relevant (community) social network influences

A gallotannin-rich fraction from Caesalpinia spinosa (Molina) Kuntze displays cytotoxic activity and raises sensitivity to doxorubicin in a leukemia cell line

<p>Abstract</p> <p>Background</p> <p>Enhancement of tumor cell sensitivity may help facilitate a reduction in drug dosage using conventional chemotherapies. Consequently, it is worthwhile to search for adjuvants with the potential of increasing chemotherapeutic drug effectiveness and improving patient quality of life. Natural products are a very good source of such adjuvants.</p> <p>Methods</p> <p>The biological activity of a fraction enriched in hydrolysable polyphenols (P2Et) obtained from <it>Caesalpinia spinosa </it>was evaluated using the hematopoietic cell line K562. This fraction was tested alone or in combination with the conventional chemotherapeutic drugs doxorubicin, vincristine, etoposide, camptothecin and taxol. The parameters evaluated were mitochondrial depolarization, caspase 3 activation, chromatin condensation and clonogenic activity.</p> <p>Results</p> <p>We found that the P2Et fraction induced mitochondrial depolarization, activated caspase 3, induced chromatin condensation and decreased the clonogenic capacity of the K562 cell line. When the P2Et fraction was used in combination with chemotherapeutic drugs at sub-lethal concentrations, a fourfold reduction in doxorubicin inhibitory concentration 50 (IC₅₀) was seen in the K562 cell line. This finding suggested that P2Et fraction activity is specific for the molecular target of doxorubicin.</p> <p>Conclusions</p> <p>Our results suggest that a natural fraction extracted from <it>Caesalpinia spinosa </it>in combination with conventional chemotherapy in combination with natural products on leukemia cells may increase therapeutic effectiveness in relation to leukemia.</p

Microbiota intestinal y alergia a las proteínas de la leche de vaca en la infancia. ¿Tenemos novedades?

Trabajo presentado en el XLVI Congreso de la Sociedad Española de Inmunología Clínica, Alergología y Asma Pediátrica, celebrado en Oviedo (España), del 5 al 7 de mayo de 2022Objetivo / Caso Clínico: Introducción: Se ha demostrado la existencia de relaciones entre la microbiota y alergias alimentarias durante los dos primeros años de vida, siendo la alergia a proteínas de la leche de vaca (APLV) la más frecuente. Nuestro objetivo fue analizar características clínico-epidemiológicas y la microbiota intestinal según el mecanismo inmunológico tratando de buscar asociaciones que faciliten el manejo en APLV. Material y Métodos / Caso Clínico: Descripción del caso: Estudio descriptivo, multicéntrico con una cohorte de APLV menores de un año reclutados al diagnóstico a lo largo de un año en tres hospitales. Grupo control de lactantes sanos de 6 meses reclutados en centros de atención primaria. Criterios de exclusión: alergias alimentarias/enteropatía, antibiótico/ corticoide/probiótico el mes previo, gastroenteritis, síndrome de enterocolitis inducida por proteínas. Resultados / Caso Clínico: Comentarios: 47 participantes: 14 IgE, 8 no IgE y 25 controles. No diferencias significativas en sexo, parto, somatometría o tipo de lactancia, pero sí en la media de edad; siendo en IgE 6.45 meses y 3.38 en no IgE. Los síntomas más frecuentes fueron los cutáneos en IgE (78.6%) y el reflujo gastroesofágico en no IgE (75%). En IgE mediados, el 71, 4% fue positivo a seroproteínas frente a un 57, 1% a caseína. Se observaron diferencias significativas en la composición de la microbiota en la abundancia relativa del filo Bacteroidetes (17% en IgE, 6.9% en no IgE y 9.6% en controles). El filo Actinobacterias se encontró en mayor proporción en controles (60.9%) frente a casos. Conclusiones: Además de evaluar las características clínico-epidemiológicas de menores de 1 año con diagnóstico de APLV en nuestra región, se ha realizado un estudio comparativo de la microbiota intestinal con controles sanos, encontrándose diferencias entre las poblaciones microbianas en función de la fisiopatología de la APLV que refuerzan la interacción entre alergia alimentaria y microbiota intestinal en lactantes y nos permitirán mejorar el abordaje clínico y la intervención en los distintos casos de APL

Effectiveness of an mHealth intervention combining a smartphone app and smart band on body composition in an overweight and obese population: Randomized controlled trial (EVIDENT 3 study)

Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect

Strategies to reengage patients lost to follow up in HIV care in high income countries, a scoping review

Background: Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90-90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact. Methods: A scoping review was done following Arksey & O'Malley's methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles. Results: Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures. Conclusions: This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied