Occupational exposures among women beedi workers in Mysore District, India: A mixed-methods study protocol.

Beedi is the most common smoking form of tobacco used in India. The rolling of beedis is performed primarily by women in settings that lack occupational safeguards. The aims of this protocol are to establish methods for the study of occupational exposures among women beedi workers and their experiences and challenges working with unburnt tobacco. This protocol employs a convergent parallel mixed-methods approach. Qualitatively, we plan to explore the experiences and challenges faced by women beedi workers using photovoice, a community based participatory method. Occupational exposures to pesticides will be assessed through the use of silicone wristbands worn for seven days by workers, and exposure to toxic metals and metalloids will be assessed in dust samples collected in the homes of workers. The outcomes will be analyzed to form policy recommendations to improve the occupational health of women beedi workers.

Tailoring a cellulolytic enzyme cocktail for efficient hydrolysis of mildly pretreated lignocellulosic biomass.

Commercially available cellulase cocktails frequently demonstrate high efficiency in hydrolyzing easily digestible pretreated biomass, which often lacks hemicellulose and/or lignin fractions. However, the challenge arises with enzymatic hydrolysis of mildly pretreated lignocellulosic biomasses, which contain cellulose, hemicellulose and lignin in high proportions. This study aimed to address this question by evaluating the supplementation of a commercial cellulolytic cocktail with accessory hemicellulases and two additives (H2O2 and Tween® 80). Statistical optimization methods were employed to enhance the release of glucose and xylose from mildly pretreated sugarcane bagasse. The optimized supplement composition resulted in the production of 304 and 124 mg g-1 DM of glucose and xylose, respectively, significantly increasing glucose release by 84% and xylose release by 94% compared to using only the cellulolytic cocktail. This enhancement might be attributed to a coordinated hemicellulases action degrading hemicellulose, creating more space for cellulase activity, potentially boosted by the presence of H2O2 and Tween® 80. However, the addition of different concentrations of H2O2 in combination with hemicellulase and Tween® 80 did not result a significant difference on sugar release, which could be attributed to the limited range of concentrations studied (5 to 65 µM). The results obtained in this study using the mix of three supplements were also compared to the addition of only hemicellulase and only Tween® 80 to the cellulolytic cocktail. A significant increase in glucose release of 39% and 41%, respectively, was observed when using the optimized combination. For xylose, the increase was 38% and 41%, respectively. This study underscores the substantial potential in optimizing enzyme cocktails for the hydrolysis of mildly pretreated lignocellulosic biomass by using enzymes and additive combinations tailored to the specific biomass composition.

Software BreastAnalyser for the semi-automatic analysis of breast cancer immunohistochemical images.

Breast cancer is the most diagnosed cancer worldwide and represents the fifth cause of cancer mortality globally. It is a highly heterogeneous disease, that comprises various molecular subtypes, often diagnosed by immunohistochemistry. This technique is widely employed in basic, translational and pathological anatomy research, where it can support the oncological diagnosis, therapeutic decisions and biomarker discovery. Nevertheless, its evaluation is often qualitative, raising the need for accurate quantitation methodologies. We present the software BreastAnalyser, a valuable and reliable tool to automatically measure the area of 3,3'-diaminobenzidine tetrahydrocholoride (DAB)-brown-stained proteins detected by immunohistochemistry. BreastAnalyser also automatically counts cell nuclei and classifies them according to their DAB-brown-staining level. This is performed using sophisticated segmentation algorithms that consider intrinsic image variability and save image normalization time. BreastAnalyser has a clean, friendly and intuitive interface that allows to supervise the quantitations performed by the user, to annotate images and to unify the experts' criteria. BreastAnalyser was validated in representative human breast cancer immunohistochemistry images detecting various antigens. According to the automatic processing, the DAB-brown area was almost perfectly recognized, being the average difference between true and computer DAB-brown percentage lower than 0.7 points for all sets. The detection of nuclei allowed proper cell density relativization of the brown signal for comparison purposes between the different patients. BreastAnalyser obtained a score of 85.5 using the system usability scale questionnaire, which means that the tool is perceived as excellent by the experts. In the biomedical context, the connexin43 (Cx43) protein was found to be significantly downregulated in human core needle invasive breast cancer samples when compared to normal breast, with a trend to decrease as the subtype malignancy increased. Higher Cx43 protein levels were significantly associated to lower cancer recurrence risk in Oncotype DX-tested luminal B HER2- breast cancer tissues. BreastAnalyser and the annotated images are publically available https://citius.usc.es/transferencia/software/breastanalyser for research purposes.

Hear my voice: understanding how community health workers in the Peruvian Amazon expanded their roles to mitigate the impact of the COVID-19 pandemic through community-based participatory research.

INTRODUCTION: The COVID-19 pandemic led to the collapse of the Peruvian health system, disrupting healthcare access for indigenous communities in the Amazon. Our study analysed how community health workers (CHWs) from indigenous communities in the Peruvian Amazon expanded their roles to mitigate the effects of the COVID-19 pandemic. METHODS: Fourteen CHWs from Loreto, Peru, participated in a community-based participatory research project using Photovoice, a technique encouraging vulnerable groups to take photos and develop stories illustrating their lived experiences. Participants were recruited from Mamás del Río, a local university-based programme, through purposive sampling. CHWs were asked to photograph how the pandemic affected their lives and work. Participants met four times over 5 months to share photos and develop action items. Data were organised into key themes using thematic analysis. CHWs shared photo galleries with policy-makers in Loreto and Lima. RESULTS: CHWs produced 36 photos with 33 texts highlighting their roles during COVID-19. Three core themes emerged: the (1) collapse of health infrastructure, (2) use of medicinal plants versus pharmaceuticals and (3) community adaptations and struggles. The leadership of CHWs emerged as a cross-cutting theme as CHWs supported COVID-19 efforts without government training or resources. CHWs asked policy-makers for formal integration into the health system, standardisation of training and management of community pharmacies. CONCLUSION: CHWs demonstrated their leadership and expanded their roles during the pandemic with little to no training from the government. Global investment in robust CHW programmes can fortify healthcare delivery.

TACkling Cancer by Targeting Selective Protein Degradation.

Targeted protein degradation has emerged as an alternative therapy against cancer, offering several advantages over traditional inhibitors. The new degrader drugs provide different therapeutic strategies: they could cross the phospholipid bilayer membrane by the addition of specific moieties to extracellular proteins. On the other hand, they could efficiently improve the degradation process by the generation of a ternary complex structure of an E3 ligase. Herein, we review the current trends in the use of TAC-based technologies (TACnologies), such as PROteolysis TArgeting Chimeras (PROTAC), PHOtochemically TArgeting Chimeras (PHOTAC), CLIck-formed Proteolysis TArgeting Chimeras (CLIPTAC), AUtophagy TArgeting Chimeras (AUTAC), AuTophagosome TEthering Compounds (ATTEC), LYsosome-TArgeting Chimeras (LYTAC), and DeUBiquitinase TArgeting Chimeras (DUBTAC), in experimental development and their progress towards clinical applications.

Addressing knowledge gaps: the key role of community health workers and healthcare providers in human papillomavirus prevention and vaccine uptake in a border community.

The Human Papillomavirus (HPV) is the most common sexually transmitted infection and nearly every person who is sexually active will get HPV at some point in their lifetime without having the HPV vaccine. Healthcare Providers (HCPs) and Community Health Workers (CHWs) play an essential role in promoting the HPV vaccine and providing education about HPV in communities. Three focus groups with CHWs (n = 17) and HCPs (n = 7) were conducted and led by trained facilitators. In addition to participating in the focus group, CHWs and HCPs completed a brief questionnaire. Focus groups were voice recorded and transcribed for qualitative analysis. Independent coders conducted content analysis to identify the salient themes of the focus groups. Several important findings emerged from this study highlighting the barriers to HPV knowledge, gaps in the self-perceived role of HPV cancer prevention, and opportunities to action. Financial, knowledge, patriarchy, behaviors, attitudes, and fears were identified as the perceived patient-related barriers to promoting HPV cancer prevention. Both CHWs and HCPs explained that their female patients are often discouraged by their husbands from seeking out sexual health-related healthcare. Finding suggest the need for community tailored education on HPV and "best practice" trainings for HPV prevention that is applicable to both CHWs and HCPs.

Human Papillomavirus Vaccine Acceptance (HPV-VA) and Vaccine Uptake (HPV-VU): assessing the impact of theory, culture, and trusted sources of information in a Hispanic community.

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection and is associated with many types of cancers that disproportionately impact Hispanics. An HPV vaccine is available for individuals ages 9-45 that can prevent up to 90% of HPV-associated cancers. The current study investigates factors associated with accepting the HPV vaccine in a predominately Hispanic community. METHODS: A cross-sectional study design with an online questionnaire was used to collect data from a community sample of adults between the ages 18-65 residing in a U.S./Mexico border city, El Paso, Texas. Theory-based factors (e.g., the Health Belief Model), culture-based factors (e.g., familism), and trusted sources of information were examined as predictors of HPV-vaccine acceptance (HPV-VA) and HPV-vaccine uptake (HPV-VU). RESULTS: Community members (N = 602, Mage = 34.65, SD = 9.79) who were predominately Hispanic (89.4%) and female (79.6%) participated in the study. Linear regression models revealed that HPV-VA was associated with household size, primary language, engagement in organizational activities, health-related community stigma, government trust, and the HBM theory-based factors: perceived benefits, perceived harm, and perceived severity. Logistic regression analyses revealed that HPV-VU was associated with household size, engagement in non-organizational activities, HPV trusted sources of information, and perceived safety. CONCLUSIONS: Adequate HPV vaccination uptake among all vaccine-eligible Hispanics is an important step to lessen the HPV-attributed cancer burden. Our hypothesis that theory-based factors would be associated with HPV-VA and HPV-VU was supported. Our findings have implications for designing trusted, theory-based, and culturally sensitive health communications and interventions to promote vaccines in minority underrepresented communities.

Adaptation and validation of the PAC-19QoL-specific quality of life questionnaire for the Spanish population with long COVID.

INTRODUCTION: The post-acute (long) COVID-19 Quality of Life instrument is the only specific instrument designed to assess the quality of life in long COVID patients. The present study aims to make a transcultural adaptation and validation into Spanish of the disease-specific (long COVID) quality of life instrument, post-acute (long) COVID-19 Quality of Life, to have a tool for objective measurement of quality of life in this population. METHODS: A descriptive cross-sectional study was divided into two phases. In phase one, the translation and cultural adaptation of the questionnaire was performed, while in phase two, the questionnaire was validated. The Spanish version of the questionnaire was used with a sample of 206 people, 40 males (19.4%) and 166 females (80.6%), with an age range between 21 and 70 years old. Participants completed the questionnaire through an online platform. Internal consistency, construct validity, convergent validity, test-retest reliability, and ceiling and floor effects of the Spanish version were analyzed. RESULTS: The Spanish version of the post-acute (long) COVID-19 Quality of Life instrument showed high internal consistency, with Cronbach's alpha= 0.922 and an intraclass correlation coefficient of 0.936. Mean scores obtained in the PAC-19QoL and SF-12 questionnaires showed that those who had a worse quality of life in the SF-12 tool also a had worse quality of life in the PAC-19QoL tool. CONCLUSIONS: This study shows that the Spanish version of the post-acute (long) COVID-19 Quality of Life instrument is an appropriate and valid tool for assessing the quality of life of long COVID patients.

Enzymatic hydrolysis cocktail optimization for the intensification of sugar extraction from sugarcane bagasse.

Lignocellulosic biomasses have a very important role as a raw material to produce biofuels and biochemicals. However, a sustainable, efficient, and economically competitive process for the release of sugars from such materials has still not been achieved. In this work, the optimization of the enzymatic hydrolysis cocktail was evaluated as an approach to maximize sugar extraction from mildly pretreated sugarcane bagasse. Different additives and enzymes, including hydrogen peroxide (H2O2), laccase, hemicellulase and the surfactants Tween 80 and PEG4000 were added to a cellulolytic cocktail with the aim of improving biomass hydrolysis. An increase of 39 % and 46 % of glucose and xylose concentrations, respectively, compared to the control (when only the cellulolytic cocktail (20 or 35 FPU g-1 dry mass), was obtained when H2O2 (0.24 mM) was added at the beginning of the hydrolysis. On the other hand, the addition of hemicellulase (81-162 µL g-1 DM) increased the production of glucose up to 38 % and xylose up to 50 %. The findings of this study reveal that it is possible to increase the extraction of sugars from mildly pretreated lignocellulosic biomass by using an appropriate enzymatic cocktail supplemented with additives. This opens up new opportunities for the development of a more sustainable, efficient, and economically competitive process for biomass fractionation.

What incentives encourage local communities to collect and upload mosquito sound data by using smartphones? A mixed methods study in Tanzania.

BACKGROUND: To detect and identify mosquitoes using their characteristic high-pitched sound, we have developed a smartphone application, known as the 'HumBug sensor', that records the acoustic signature of this sound, along with the time and location. This data is then sent remotely to a server where algorithms identify the species according to their distinctive acoustic signature. Whilst this system works well, a key question that remains is what mechanisms will lead to effective uptake and use of this mosquito survey tool? We addressed this question by working with local communities in rural Tanzania and providing three alternative incentives: money only, short message service (SMS) reminders and money, and SMS reminders only. We also had a control group with no incentive. METHODS: A multi-site, quantitative empirical study was conducted in four villages in Tanzania from April to August 2021. Consenting participants (n = 148) were recruited and placed into one of the three intervention arms: monetary incentives only; SMS reminders with monetary incentives; and SMS reminders only. There was also a control group (no intervention). To test effectiveness of the mechanisms, the number of audio uploads to the server of the four trial groups on their specific dates were compared. Qualitative focus group discussions and feedback surveys were also conducted to explore participants' perspectives on their participation in the study and to capture their experiences of using the HumBug sensor. RESULTS: Qualitative data analysis revealed that for many participants (37 out of 81), the main motivation expressed was to learn more about the types of mosquitoes present in their houses. Results from the quantitative empirical study indicate that the participants in the 'control' group switched on their HumBug sensors more over the 14-week period (8 out of 14 weeks) when compared to those belonging to the 'SMS reminders and monetary incentives' trial group. These findings are statistically significant (p < 0.05 or p > 0.95 under a two-sided z-test), revealing that the provision of monetary incentives and sending SMS reminders did not appear to encourage greater number of audio uploads when compared to the control. CONCLUSIONS: Knowledge on the presence of harmful mosquitoes was the strongest motive for local communities to collect and upload mosquito sound data via the HumBug sensor in rural Tanzania. This finding suggests that most efforts should be made to improve flow of real-time information back to the communities on types and risks associated with mosquitoes present in their houses.

Hispanic Survivors and Caregivers of Human Papillomavirus-Associated Cancers: Lived Experiences in a U.S.-Mexico Border Community.

Although human papillomavirus (HPV)-associated cancers are preventable and treatable at early stages, health disparities in HPV-associated cancer outcomes continue to exist among Hispanic populations. Hispanics residing along the U.S.-Mexico border face barriers distinct from other geographically dispersed populations within the United States. The current research aimed to explore perspectives and lived experiences of survivors and caregivers of HPV-associated cancers in El Paso, Texas, to inform intervention development and health practices to increase preventive services among populations residing on the U.S.-Mexico border region. A mixed-method approach was employed using a semi-structured interview guide with Quality of Life (QOL) scales with (N = 29) survivors and caregivers of HPV-associated cancers. Content analysis was used to extract themes and descriptive statistics were reported for quality of life. Five major themes were identified: (1) barriers to preventive services and treatment; (2) role of health care providers in diagnosis and care; (3) treatment challenges, support systems, and challenges associated with caregiving; and (4) HPV prevention and health recommendations from survivors and caregivers. Finally, given the context of the COVID-19 pandemic, an additional theme was explored on accessibility to health and human services. QOL scales suggested better overall physical health and spiritual well-being in survivors and fear of reoccurrence among caregivers and survivors. The current research highlights the role of health care providers and human service professionals in the promotion of health practices of at-risk populations by increasing health literacy among cancer patients and caregivers, and exploring experiences, challenges, and messages caregivers and survivors had regarding HPV prevention.

Food and housing security at a US Hispanic-Serving Institution: An examination before and during the COVID-19 pandemic.

University students occupy a socially marginal position and therefore are often underserved by academic and service institutions. This article analyzes food and housing security among students at The University of Texas at El Paso, a Hispanic-Serving Institution located in the U.S.-Mexico Border region. Findings of a sample of n = 7,633 university students are presented in the first cross-sectional, two-year food and housing security study on campus administered via platform Campus Labs Baseline. The first sample in 2019 consisted of n = 2,615 students representing 10.4% of student enrollment (25,177 total 2019 enrollment), and the second sample in 2020 was n = 5,018 representing 20.2% of student enrollment (24,879 total 2020 enrollment). To measure food security, the six-item short form of the U.S. Department of Agriculture (USDA) Household Food Security Survey Module was used. To document housing security, we created questions informed by student input. In this study, survey results are reported, and tests are conducted to assess the relationships between various student characteristics and food and housing security. Student characteristics significantly impacting food and housing security are probed further using data visualizations and subpopulation analysis with a focus on analyzing factors impacted by the COVID-19 pandemic. Results indicate that employment status, consistent employment status, hours per week, academic level, number of dependents, and gender are all factors associated with food security during the pandemic but not prior to the pandemic. Other factors, including, college affiliation, ethnicity/race, having any dependents and being head of household, living alone, mode of campus transportation and mode of the transportation, household income, and age, all were associated with food security in both academic years. Using these results, a critical analysis of past interventions addressing food and housing security is presented with a focus on changes made during the pandemic. Recommendations are made for further data-driven interventions and future steps.

The Use of Photovoice Methodology to Assess Health Needs and Identify Opportunities Among Migrant Transgender Women in the U.S.-Mexico Border.

Psychosocial, social and structural conditions have rarely been studied among transgender women in the U.S.-Mexico Border. This study used Photovoice methodology to empower migrant transgender women of color (TWC) to reflect on realities from their own perspectives and experiences and promote critical dialogue, knowledge, and community action. Sixteen participants documented their daily experiences through photography, engaged in photo-discussions to assess needs and identify opportunities, and developed a community-informed Call to Action. Four major themes emerged from the participants' photographs, discussions, and engagement: (1) mental health, (2) migration experiences and challenges, (3) stigma, discrimination, and resiliency, and (4) impact of the COVID-19 pandemic. Through active community engagement, a Call to Action was developed. A binational advisory committee of decision makers and scholars reviewed a set of recommendations to better respond to the needs of TWC in the U.S.-Mexico Border. Photovoice served as an empowerment tool for TWC to assess the myriad of syndemic conditions, including mental health, stigma, discrimination and COVID-19, affecting them daily and identify initiatives for change.

Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.

Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08-2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17-2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.

Analysis of Cancer Knowledge, Attitudes, and Practices in Adolescents and Young Adults in Two Texas Rural Communities.

The Youth and Young Adults Cancer Knowledge Attitudes and Practices (C-KAP) exploratory study in 2 rural underserved areas in a border community. C-KAP is an interdisciplinary research pilot project led by university scholars in psychology and social work in partnership with community partners. The exploratory cross-sectional mix-method study recruited 141 (n=141) youth and young adults (ages 18-39). This study was informed on empirical research and a bilingual online questionnaire was field-tested, and data was collected via QuestionPro Software. Quantitative analysis was conducted using SPSS version 27. Descriptive statistics and frequency analysis were used for demographics and basic statistics. Chi square tests and Fisher's exact tests between variables were ran to find statistically significant associations. For the qualitative data, independent coders conducted recurrent content analysis to identify themes. Salient themes include knowledge about cancer types; access to health care; prevention; and the perceived impact of COVID-19 pandemic. Findings highlight a lack of knowledge and orientation on cancer in youth and young adults suggesting the need for community tailored education and screening interventions. Other findings reflect gender differences in knowledge and practices, which indicates that a gender-specific lens is needed when delivering education.

Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis.

BACKGROUND: Identification of membrane proteins differentially expressed on tumor cells is a key step in drug development. The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein belonging to the immunoglobulin superfamily. Here, we explore the prognostic role CEACAM6 expression on patient outcome in cancer. METHODS: A systematic search for studies evaluating the association between tumor expression of CEACAM6 and overall survival (OS) and disease-free survival (DFS) was performed. Hazard ratios (HR) were pooled in a meta-analysis using generic inverse variance and random effect modeling. Subgroup analyses were conducted based on tumor type and method of HR extraction. RESULTS: Sixteen studies met the inclusion criteria. CEACAM6 expression was associated with worse OS [HR = 1.96, 95% confidence interval (CI) = 1.51-2.53], and DFS (HR = 2.49, 95% CI = 2.01-3.07) with subgroup analysis showing no significant differences between disease site subgroups. CONCLUSIONS: High expression of CEACAM6 is associated with worse OS and DFS in different malignancies. CEACAM6 is a target for the future development of novel therapeutics.

COVID-19 Imperils Access to Health and Human Services in El Paso, Texas and New York City: Perspectives from Hispanic Parents.

Low-income Hispanic communities are disproportionately impacted by the COVID-19 pandemic through exacerbated financial vulnerabilities and health challenges. The aim of this study is to assess and compare the self-reported impact and challenges caused by COVID-19 in Mexican-origin parents in New York City (NYC), NY and El Paso, TX. Data is based on routine follow-up calls used to assess uptake of the HPV vaccine and COVID-19 concerns conducted between March and August 2020. Three salient themes emerged: (1) financial insecurities; (2) emotional distress associated with COVID-19; and (3) limited access to health and human services. This study revealed increased financial insecurities and emotional distress, and disruptions to health and human services to low-income Mexican-born parents during the pandemic.

The Impact of Restrictive Policies on Mexican Immigrant Parents and Their Children's Access to Health Care.

Background: This study assessed whether policies that limit Mexican immigrants' access to care affects their children's access to a regular source of care, health insurance, and timely preventive health visits. Method: This was a cross-sectional study among Mexican immigrant parents who attended a health promotion program in Texas, Nevada, New York, and Illinois. A sociodemographic survey, including parental and child variables, was administered. Results: Children of parents without health insurance were almost four times more likely to be uninsured and eight times more likely to lack a regular source of care. Children of parents without a regular source of care were less than half as likely to have their own regular source of care than children whose parents had a regular source of care. Discussion: Findings suggest when parents are uninsured/lack a regular source of care, a child's health disparity is created. Reducing disparities in health care coverage, affecting foreign-born parents, positively impacts their children's access to care. Clinical Trial Registration number: NCT03209713.

Characterization of Permeability Barrier Dysfunction in a Murine Model of Cutaneous Field Cancerization Following Chronic UV-B Irradiation: Implications for the Pathogenesis of Skin Cancer.

Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.

Genomic Correlates of DNA Damage in Breast Cancer Subtypes.

Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer.