The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.

BACKGROUND: Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP. METHODS: By mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa. RESULTS: A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARα1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa. CONCLUSIONS: The possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.

Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities.

BACKGROUND: Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted glycoprotein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis. RESULTS: We show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV-MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231. CONCLUSIONS: As to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites and metastatic tumor nodules. These results increase our understanding on the role of lactadherin in sEVs as promoter of metastatic capacities which can be used as a therapeutic option for BC and other malignancies.

Helicobacter pylori outer membrane vesicles induce astrocyte reactivity through nuclear factor-κappa B activation and cause neuronal damage in vivo in a murine model.

BACKGROUND: Helicobacter pylori (Hp) infects the stomach of 50% of the world's population. Importantly, chronic infection by this bacterium correlates with the appearance of several extra-gastric pathologies, including neurodegenerative diseases. In such conditions, brain astrocytes become reactive and neurotoxic. However, it is still unclear whether this highly prevalent bacterium or the nanosized outer membrane vesicles (OMVs) they produce, can reach the brain, thus affecting neurons/astrocytes. Here, we evaluated the effects of Hp OMVs on astrocytes and neurons in vivo and in vitro. METHODS: Purified OMVs were characterized by mass spectrometry (MS/MS). Labeled OMVs were administered orally or injected into the mouse tail vein to study OMV-brain distribution. By immunofluorescence of tissue samples, we evaluated: GFAP (astrocytes), ßIII tubulin (neurons), and urease (OMVs). The in vitro effect of OMVs in astrocytes was assessed by monitoring NF-κB activation, expression of reactivity markers, cytokines in astrocyte-conditioned medium (ACM), and neuronal cell viability. RESULTS: Urease and GroEL were prominent proteins in OMVs. Urease (OMVs) was present in the mouse brain and its detection coincided with astrocyte reactivity and neuronal damage. In vitro, OMVs induced astrocyte reactivity by increasing the intermediate filament proteins GFAP and vimentin, the plasma membrane αVß3 integrin, and the hemichannel connexin 43. OMVs also produced neurotoxic factors and promoted the release of IFNγ in a manner dependent on the activation of the transcription factor NF-κB. Surface antigens on reactive astrocytes, as well as secreted factors in response to OMVs, were shown to inhibit neurite outgrowth and damage neurons. CONCLUSIONS: OMVs administered orally or injected into the mouse bloodstream reach the brain, altering astrocyte function and promoting neuronal damage in vivo. The effects of OMVs on astrocytes were confirmed in vitro and shown to be NF-κB-dependent. These findings suggest that Hp could trigger systemic effects by releasing nanosized vesicles that cross epithelial barriers and access the CNS, thus altering brain cells.

Oncological outcomes among young women with non-epithelial ovarian cancer: the YOC-Care study (Young Ovarian Cancer - Care).

OBJECTIVE: To determine oncological outcomes and associated prognostic factors in women younger than 45 years diagnosed with non-epithelial ovarian cancer. METHODS: A retrospective, multicenter Spanish study was performed including women with non-epithelial ovarian cancer younger than 45 years between January 2010 and December 2019. All types of treatments and stages at diagnosis with at least 12 months of follow-up were collected. Women with missing data, epithelial cancers, borderline or Krukenberg tumors, and benign histology, as well as patients with previous or concomitant cancer, were excluded. RESULTS: A total of 150 patients were included in this study. The mean±SD age was 31.45±7.45 years. Histology subtypes were divided into germ cell (n=104, 69.3%), sex-cord (n=41, 27.3%), and other stromal tumors (n=5, 3.3%). Median follow-up time was 58.6 (range: 31.10-81.91) months. Nineteen (12.6%) patients presented with recurrent disease with a median time to recurrence of 19 (range: 6-76) months. Progression-free survival and overall survival did not significantly differ among histology subtypes (p=0.09 and 0.26, respectively) and International Federation of Gynecology and Obstetrics (FIGO) stage (I-II vs III-IV) with p=0.08 and p=0.67, respectively. Univariate analysis identified sex-cord histology with the lowest progression-free survival. Multivariate analysis showed that body mass index (BMI) (HR=1.01; 95% CI 1.00 to 1.01) and sex-cord histology (HR=3.6; 95% CI 1.17 to 10.9) remained important independent prognostic factors for progression-free survival. Independent prognostic factors for overall survival were BMI (HR=1.01; 95% CI 1.00 to 1.01) and residual disease (HR=7.16; 95% CI 1.39 to 36.97). CONCLUSIONS: Our study showed that BMI, residual disease, and sex-cord histology were prognostic factors associated with worse oncological outcomes in women younger than 45 years diagnosed with non-epithelial ovarian cancers. Even though the identification of prognostic factors is relevant to identify high-risk patients and guide adjuvant treatment, larger studies with international collaboration are essential to clarify oncological risk factors in this rare disease.

Core competencies in applied infectious disease epidemiology: a framework for countries in Europe.

In 2009, the European Centre for Disease Prevention and Control (ECDC) developed a competency framework to support European Union countries and the European Commission in ensuring a competent public health workforce for Europe. The coronavirus disease (COVID-19) pandemic emphasised the importance of harmonised public health strategies and competencies across international boundaries, specifically for infectious diseases. This perspective presents the process to update the competency framework for applied infectious disease epidemiology, highlighting ECDC's efforts to support countries with using the framework. ECDC commissioned the Association of Schools of Public Health in the European Region (ASPHER) to update the framework through publication and dissemination of a technical report and a self-assessment tool linked to training resources. A mixed methods approach to gather input from experts in relevant specialities included qualitative interviews with 42 experts, workshops with ECDC Technical Advisory Group and an online survey of 212 public health professionals across Europe and beyond. Modifications resulted in 157 core competencies in 23 domains, each mapping to one of six subject areas of importance in applied infectious disease epidemiology. The framework serves as a basis to update the curriculum of the ECDC Fellowship programme with two alternative paths: intervention epidemiology or public health microbiology.

Hyperandrogenism Protects Against High Blood Pressure by Nongenomic Mechanisms and Obesity Causes Hypertension in Females with Polycystic Ovary Syndrome.

BACKGROUND: Androgens induce vasorelaxation and reduce blood pressure in different mammals, including humans. Most women with polycystic ovary syndrome (PCOS), with hyperandrogenism, are obese and exhibit hypertension; thus, the fact that androgens increase blood pressure (BP) is controversial. Our aim was to determine whether hypertension is produced by androgen excess and/or obesity. METHODS: Experiments were performed in dehydroepiandrosterone; (DHEA, s.c)-induced PCOS model. BP from nonobese and obese rats with PCOS (fed a normal or high-fat diet, respectively) was evaluated weekly for 10 weeks by plethysmography and compared between them. We determined whether androgen receptors are responsible for androgen action on BP in rats with PCOS; a group of DHEA-treated rats was implanted with pellets of an antiandrogen and was compared with nonobese rats with PCOS. Isometric tension from aortas of nonobese and obese rats was recorded and compared to explore the integrity of the vascular endothelium when acetylcholine-induced endothelium-dependent vascular relaxation on phenylephrine contraction. Additionally, BP was obtained from 30 women diagnosed with PCOS: nonobese (BMI ≤25) and obese women (BMI ≥35) and compared with healthy counterparts; 15 obese and 15 nonobese women. RESULTS: Nonobese rats and women with PCOS showed hypotension, while obese rats and women with PCOS displayed hypertension. Healthy obese women were hypertensive and nonobese women remained normotensive. Antiandrogen did not modify the BP values in nonobese rats with PCOS, and obese rats with PCOS revealed marked endothelial dysfunction. CONCLUSIONS: Our findings show that obesity is responsible for hypertension in PCOS and partial endothelial damage was observed, which may contribute to elevated BP. Remarkably, hyperandrogenism is capable of regulating BP to low values that are androgen receptor-independent.

Feature Extraction of a Non-Stationary Seismic-Acoustic Signal Using a High-Resolution Dyadic Spectrogram.

Using a novel mathematical tool called the Te-gram, researchers analyzed the energy distribution of frequency components in the scale-frequency plane. Through this analysis, a frequency band of approximately 12 Hz is identified, which can be isolated without distorting its constituent frequencies. This band, along with others, remained inseparable through conventional time-frequency analysis methods. The Te-gram successfully addresses this knowledge gap, providing multi-sensitivity in the frequency domain and effectively attenuating cross-term energy. The Daubechies 45 wavelet function was employed due to its exceptional 150 dB attenuation in the rejection band. The validation process encompassed three stages: pre-, during-, and post-seismic activity. The utilized signal corresponds to the 19 September 2017 earthquake, occurring between the states of Morelos and Puebla, Mexico. The results showcased the impressive ability of the Te-gram to surpass expectations in terms of sensitivity and energy distribution within the frequency domain. The Te-gram outperformed the procedures documented in the existing literature. On the other hand, the results show a frequency band between 0.7 Hz and 1.75 Hz, which is named the planet Earth noise.

EV-miRNA-Mediated Intercellular Communication in the Breast Tumor Microenvironment.

Cancer research has prioritized the study of the tumor microenvironment (TME) as a crucial area of investigation. Understanding the communication between tumor cells and the various cell types within the TME has become a focal point. Bidirectional communication processes between these cells support cellular transformation, as well as the survival, invasion, and metastatic dissemination of tumor cells. Extracellular vesicles are lipid bilayer structures secreted by cells that emerge as important mediators of this cell-to-cell communication. EVs transfer their molecular cargo, including proteins and nucleic acids, and particularly microRNAs, which play critical roles in intercellular communication. Tumor-derived EVs, for example, can promote angiogenesis and enhance endothelial permeability by delivering specific miRNAs. Moreover, adipocytes, a significant component of the breast stroma, exhibit high EV secretory activity, which can then modulate metabolic processes, promoting the growth, proliferation, and migration of tumor cells. Comprehensive studies investigating the involvement of EVs and their miRNA cargo in the TME, as well as their underlying mechanisms driving tumoral capacities, are necessary for a deeper understanding of these complex interactions. Such knowledge holds promise for the development of novel diagnostic and therapeutic strategies in cancer treatment.

Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models.

Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag-/- immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.

Annona cherimola Seed Extracts Trigger an Early Apoptosis Response and Selective Anticlonogenic Activity against the Human Gastric Carcinoma Cell Line SNU-1.

The aim of this study was to evaluate, for the first time, the antiproliferative, apoptotic and diminishing effects of the anchored growth-independent capacity of an ethanol macerate extract from the Annona cherimola seed (EMCHS) in the human gastric cancer cell line SNU-1. The cells treated with EMCHS (20 µg/mL) significantly reduced the capacity to form clones of the tumor cell. Moreover, 50 µg/mL of EMCHS extract induced apoptosis, as was shown by the Annexin-V assay. UHPLC-MS/MS analysis detected two acetogenins (Annonacinone and Annonacin) in the EMCHS, which could be largely responsible for its selective antiproliferative effect. The identification of fatty acids by GC-FID showed the presence of eight fatty acids, among which was, oleic acid, which has recognized activity as an adjuvant in antitumor treatments. Taken together, our results indicate that the EMCHS seems promising for use as a natural therapy against gastric cancer disease.

Risk Factors Associated with COVID-19 Lethality: A Machine Learning Approach Using Mexico Database.

Identifying risk factors associated with COVID-19 lethality is crucial in combating the ongoing pandemic. In this study, we developed lethality predictive models for each epidemiological wave and for the overall dataset using the Extreme Gradient Boosting technique and analyzed them using Shapley values to determine the contribution levels of various features, including demographics, comorbidities, medical units, and recent medical information from confirmed COVID-19 cases in Mexico between February 23, 2020, and April 15, 2022. The results showed that pneumonia and advanced age were the most important factors predicting patient death in all cohorts. Additionally, the medical unit where the patient received care acted as a risk or protective factor. IMSS medical units were identified as high-risk factors in all cohorts, except in wave four, while SSA medical units generally were moderate protective factors. We also found that intubation was a high-risk factor in the first epidemiological wave and a moderate-risk factor in the following waves. Female gender was a protective factor of moderate-high importance in all cohorts, while being between 18 and 29 years old was a moderate protective factor and being between 50 and 59 years old was a moderate risk factor. Additionally, diabetes (all cohorts), obesity (third wave), and hypertension (fourth wave) were identified as moderate risk factors. Finally, residing in municipalities with the lowest Human Development Index level represented a moderate risk factor. In conclusion, this study identified several significant risk factors associated with COVID-19 lethality in Mexico, which could aid policymakers in developing targeted interventions to reduce mortality rates.

Relationship Between DDT Concentrations with Multiparity and Breastfeeding History.

Organochlorine pesticides are persistent organic pollutants (POPs) that can enter the body through environmental exposure and food consumption. The aim of this study was to investigate the influence of parity and breast milk consumption on dichlorodiphenyltrichloroethane (DDT) concentrations in women from Southern Mexico. Gas chromatography was used to detect o,p'-DDT, p,p'-DDT, and p,p'-dichlorodiphenyldichloroethylene (DDE) in milk samples. The frequency of detection of the compounds was above 78%, finding low median concentrations of o,p'-DDT (0.010 mg/kg) and p,p'-DDT (0.043 mg/kg) compared to p,p'-DDE (0.672 mg/kg). The median DDE/DDT ratio was 14.7. The concentrations of o,p'-DDT and p,p'-DDE were significantly higher in primiparous women (0.010 mg/kg and 0.868 mg/kg) compared to multiparous women (0.005 mg/kg and 0.583 mg/kg) (p < 0.05). Breastfed donors had similar levels of o,p'-DDT, p,p'-DDE, and Σ-DDT compared to those who were not breastfed.

A Cross-Sectional Study of Distress Levels in Patients with Newly Diagnosed Breast Cancer: The Impact of Race, Ethnicity, and Language Preference.

PURPOSE: Our objective was to assess distress levels in female breast cancer patients as a function of race, ethnicity, and preferred language. We hypothesized minority patients and non-English screen-takers would report higher distress levels compared to English screen-takers and non-Hispanic whites. METHODS: We conducted a retrospective observational study of female breast cancer patients at an NCI designated cancer center from 2009 to 2016 who were administered a validated biopsychosocial distress screening questionnaire. Self-reported data on race and ethnicity was collected. RESULTS: A total of 3,156 patients were included in the analysis; mean age of 56.3 (SD 12.25) years. The racial/ethnic cohort distribution included 54% non-Hispanic white (NHW), 19% Hispanic, 16% Asian, 7% Black/African American, and 4% other. On multivariable analysis only Hispanic patients were significantly more likely to report overall distress compared to NHW (OR [1.39; CI [1.03-1.87; p=0.03). Asians were significantly less likely to report distress in the functional domain (OR 0.71, CI [0.58-0.88]; p=0.002), while Black patients were significantly more likely to report highest distress levels in the physical (OR 1.53, CI [1.11-2.12]; p=0.01) domain. Hispanic Spanish screen-takers reported significantly more distress compared to Hispanic English screen-takers across all four domains of distress (p<0.05 for all). CONCLUSIONS: Top sources of distress in female breast cancer patients vary as a function of race, ethnicity, and preferred language. Future studies should focus on identifying effective, culturally appropriate targeted interventions to mitigate emotional distress levels in ethnic and racial minorities as well as non-English speaking patients with breast cancer.

The 2020 Pandemics: Lessons Learned in Academic Surgery and Beyond.

2020 was a significant year because of the occurrence of two simultaneous public health crises: the coronavirus pandemic and the public health crisis of racism brought into the spotlight by the murder of George Floyd. The coronavirus pandemic has affected all aspects of health care, particularly the delivery of surgical care, surgical education, and academic productivity. The concomitant public health crisis of racism and health inequality during the viral pandemic highlighted opportunities for action to address gaps in surgical care and the delivery of public health services. At the 2021 Academic Surgical Congress Hot Topics session on flexibility and leadership, we also explored how our military surgeon colleagues can provide guidance in leadership during times of crisis. The following is a summary of the issues discussed during the session and reflections on the important lessons learned in academic surgery over the past year.

Burden of chemotherapy-induced myelosuppression among patients with ES-SCLC in US community oncology settings.

Aim: To describe the burden of chemotherapy-induced myelosuppression among chemotherapy-treated patients with extensive-stage small-cell lung cancer (ES-SCLC). Materials & methods: Occurrence of grade ≥3 myelosuppressive hematological adverse events (HAEs), treatment patterns and healthcare resource utilization (HCRU) after chemotherapy initiation were evaluated using data from The US Oncology Network and Non-network clinics (1/1/2015-12/31/2020). Results: Among patients with laboratory values (Network: N = 1,374/1,574; Non-network: N = 661/959), over half-experienced grade ≥3 HAEs after chemotherapy initiation (Network = 56.6%; Non-network = 64.1%), and approximately one-third had grade ≥3 HAEs in at least two lineages (Network = 33.0%; Non-network = 31.3%). Patients with grade ≥3 HAEs had greater dose reductions, treatment delays and HCRU than those without. Conclusion: Myelosuppression is a burden to patients with ES-SCLC treated with chemotherapy and the healthcare system.

Our objective was to describe the burden of myelosuppression, a side effect of chemotherapy that results from damage to blood-forming cells in the bone marrow, among patients with extensive-stage small-cell lung cancer (ES-SCLC). We evaluated the prevalence of myelosuppression, chemotherapy treatment patterns and outpatient healthcare use and costs after chemotherapy initiation using data from The US Oncology Network and Non-network clinics between 1 January 2015 and 31 December 2020. Among patients with laboratory values, which were required to identify myelosuppression events, over half of patients experienced severe myelosuppression-related adverse events in one or more lineages after chemotherapy initiation, and approximately one-third experienced severe myelosuppression-related adverse events in at least two blood cell lineages. Patients with severe myelosuppression-related adverse events had greater dose reductions, treatment delays, and healthcare use and costs than those without. Myelosuppression is a burden to patients with ES-SCLC treated with chemotherapy and the healthcare system. Reduction of chemotherapy-induced myelosuppression has the potential to reduce burden on patients and healthcare organizations.

Volviéndonos mejores: necesidad de acción inmediata ante el reto de la obesidad. Una postura de profesionales de la salud.

La creciente epidemia de obesidad ha sido uno de los retos más importantes de salud pública en México durante los últimos años. Con apoyo de la Federación Mundial de Obesidad, en 2021 formamos un grupo de profesionales para identificar y resumir las acciones prioritarias en las que puede enfocarse nuestro país para hacer frente a esta epidemia. Al proceso de desarrollo y discusión de este grupo se sumaron más de 1 000 profesionales de la salud para retomar recomendaciones de documentos y guías de alto nivel previamente publicados. En conmemoración del Día Mundial de la Obesidad, en este 2022 se presenta esta postura como insumo para el desarrollo de acciones en el ámbito profesional y de los diferentes sectores, en la que se incluyen 10 recomendaciones de acción, desde la perspectiva poblacional hasta la atención individualizada, y se enfatiza en la importancia de la participación social, de las intervenciones integrales con visión centrada en la persona y de la sostenibilidad planetaria, además de mejorar la educación y las campañas de difusión, propiciar un ambiente promotor de entornos activos y blindar de conflictos de interés los esfuerzos de prevención y control. La postura hace un llamado para abordar la obesidad de manera seria, con base en la evidencia científica, oportuna e integral, con enfoque de curso de vida, de forma ética y sensible, y sin perpetuar las barreras del estigma de peso en la sociedad.

Lactadherin: From a Well-Known Breast Tumor Marker to a Possible Player in Extracellular Vesicle-Mediated Cancer Progression.

Lactadherin is a secreted glycoprotein associated with the milk fat globule membrane, which is highly present in the blood and in the mammary tissue of lactating women. Several biological functions have been associated with this protein, mainly attributable to its immunomodulatory role promoting phagocyte-mediated clearance of apoptotic cells. It has been shown that lactadherin also plays important roles in cell adhesion, the promotion of angiogenesis, and tissue regeneration. On the other hand, this protein has been used as a marker of breast cancer and tumor progression. Recently, high levels of lactadherin has been associated with poor prognosis and decreased survival, not only in breast cancer, but also in melanoma, ovarian, colorectal, and other types of cancer. Although the mechanisms responsible for the tumor-promoting effects attributed to lactadherin have not been fully elucidated, a growing body of literature indicates that lactadherin could be a promising therapeutic target and/or biomarker for breast and other tumors. Moreover, recent studies have shown its presence in extracellular vesicles derived from cancer cell lines and cancer patients, which was associated with cancer aggressiveness and worse prognosis. Thus, this review will focus on the link between lactadherin and cancer development and progression, its possible use as a cancer biomarker and/or therapeutic target, concluding with a possible role of this protein in cellular communication mediated by extracellular vesicles.

Socioeconomic determinants of health and COVID-19 in Mexico.

INTRODUCTION: The population living in conditions of poorness has a heavier pathological burden than social strata with better economic possibilities. OBJECTIVE: To determine the influence of socioeconomic and demographic factors on COVID-19 morbidity, mortality and lethality in municipalities and states of Mexico. METHODS: Morbidity, mortality and lethality associated with COVID-19 were analyzed according to the human development index and its indicators, and type of population. Descriptive statistical analyses, correlations between developmental variables and morbidity, mortality and lethality, association tests and hierarchical groupings were carried out. RESULTS: Positive correlations were observed between morbidity and mortality and the human development index; COVID-19 fatality increased as the values of said index decreased. There was a significantly higher risk of elevated mortality in localities with moderate and low development, and in those with less than 49,999 inhabitants. The main factors associated with fatality were lack of access to health services, income vulnerability and social deprivation. CONCLUSIONS: The evidence generated should lead to decisions aimed at improving the quality of life of the population with social deprivations and vulnerabilities, which needs to be protected against the consequences of current COVID-19 pandemic.

INTRODUCCIÓN: La población en situación de pobreza presenta una carga patológica mayor que los estratos sociales con mejores posibilidades económicas. OBJETIVO: Determinar la influencia de los factores socioeconómicos y demográficos en la morbilidad, mortalidad y letalidad de COVID-19 en municipios y estados de México. MÉTODOS: Se analizó la morbilidad, mortalidad y letalidad asociadas a COVID-19 conforme el índice de desarrollo humano y sus indicadores, así como el tipo de población. Se realizaron análisis estadísticos descriptivos, de correlación entre variables de desarrollo versus morbilidad, mortalidad y letalidad, pruebas de asociación y agrupaciones jerárquicas. RESULTADOS: Se observaron correlaciones positivas entre la morbilidad y mortalidad y el índice de desarrollo humano; la letalidad por COVID-19 aumentó conforme disminuyó dicho índice. Existió riesgo significativamente superior de alta letalidad en las localidades con moderado y bajo desarrollo, así como en aquellas con menos de 49 999 habitantes. Los principales factores asociados a la letalidad fueron la falta de acceso a los servicios de salud, la vulnerabilidad por ingreso y la carencia social. CONCLUSIONES: La evidencia generada debe llevar a decisiones tendentes al mejoramiento de la calidad de vida de la población con carencias y vulnerabilidades sociales, que necesita ser protegida contra las consecuencias de la actual pandemia de COVID-19.

Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice.

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by the progressive and irreversible loss of vision. We previously found that intraperitoneal administration of Adalimumab, a monoclonal anti-TNFα antibody, slowed down retinal degeneration in the murine model of RP, the rd10 mice. The aims of this study were to improve its neuroprotective effect and to deepen understanding of the molecular mechanisms involved in this effect. We analyzed (i) the in vitro effect of Adalimumab on the TNFα-mediated cell death in retinal cells; (ii) the effect of a single intravitreal injection of Adalimumab on retinal degeneration in rd10 mice at postnatal day (P) 23. In vitro studies showed that TNFα induced caspase and poly ADP ribose polymerase (PARP) activation, downregulation of (kinase receptor-interacting protein 1) RIPK1 and upregulation of RIPK3 in retinal cells. Adalimumab reduced cell death probably through the inhibition of caspase 3 activation. In vivo studies suggested that PARP and NLRP3 inflammasome are mainly activated and to a lesser extent caspase-dependent mechanisms in rd10 retinas at P23. Necroptosis seems to be inhibited by the downregulation of RIPK1. Adalimumab prevented from retinal degeneration without affecting caspase -dependent mechanisms but decreasing PARP activation, microglia activation as well as NLRP3 inflammasome.

Covid-19 y el índice de desarrollo humano en México.

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