Comprehensive analysis of human tissues reveals unique expression and localization patterns of HSF1 and HSF2.

Heat shock factors (HSFs) are the main transcriptional regulators of the evolutionarily conserved heat shock response. Beyond cell stress, several studies have demonstrated that HSFs also contribute to a vast variety of human pathologies, ranging from metabolic diseases to cancer and neurodegeneration. Despite their evident role in mitigating cellular perturbations, the functions of HSF1 and HSF2 in physiological proteostasis have remained inconclusive. Here, we analyzed a comprehensive selection of paraffin-embedded human tissue samples with immunohistochemistry. We demonstrate that both HSF1 and HSF2 display distinct expression and subcellular localization patterns in benign tissues. HSF1 localizes to the nucleus in all epithelial cell types, whereas nuclear expression of HSF2 was limited to only a few cell types, especially the spermatogonia and the urothelial umbrella cells. We observed a consistent and robust cytoplasmic expression of HSF2 across all studied smooth muscle and endothelial cells, including the smooth muscle cells surrounding the vasculature and the high endothelial venules in lymph nodes. Outstandingly, HSF2 localized specifically at cell-cell adhesion sites in a broad selection of tissue types, such as the cardiac muscle, liver, and epididymis. To the best of our knowledge, this is the first study to systematically describe the expression and localization patterns of HSF1 and HSF2 in benign human tissues. Thus, our work expands the biological landscape of these factors and creates the foundation for the identification of specific roles of HSF1 and HSF2 in normal physiological processes.

DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a neuron-like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine-related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 decreases proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype, and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a driver of t-NEPC progression.

Assessing Guidelines on the Need for Colonoscopy After Initial Flexible Sigmoidoscopy in Young Patients With Outlet-Type Rectal Bleeding.

BACKGROUND: Although young-age-of-onset colorectal cancer is increasing in incidence, lack of screening leads to symptomatic presentation, often with rectal bleeding. Because most cancers in patients younger than 50 years are left-sided, flexible sigmoidoscopy is a reasonable way of investigating bleeding in these patients. OBJECTIVE: To predict which patients undergoing flexible sigmoidoscopy for outlet-type rectal bleeding need a full colonoscopy. DESIGN: Findings at colonoscopy were compared with published indications for colonoscopy after flexible sigmoidoscopy, which were as follows: 1) any number of advanced adenomas defined as a tubular adenoma of >9 mm diameter, a tubulovillous or villous adenoma of any size, or any adenoma with high-grade dysplasia; 2) 3 or more tubular adenomas of any size or histology; 3) any sessile serrated lesion; and 4) 20 or more hyperplastic polyps. SETTING: Charity Hospital with volunteer specialists. PATIENTS: Patients were included if they were younger than 57 years, had outlet-type rectal bleeding, and underwent flexible sigmoidoscopy at least to the descending colon followed by colonoscopy with biopsy of all resected lesions. INTERVENTIONS: Flexible sigmoidoscopy and colonoscopy with excision of all removable lesions. MAIN OUTCOME MEASURES: Findings at colonoscopy. RESULTS: There were 66 patients who had a colonoscopy between 5 and 811 days after sigmoidoscopy and also had complete data. There were 43 men and 23 women with a mean age of 39.5 years. Analysis of flexible sigmoidoscopy criteria for finding proximal high-risk lesions on colonoscopy showed a sensitivity of 76.9%, a specificity of 67.9%, a positive predictive value of 37%, a negative predictive value of 92.3%, and an accuracy of 69.7%. LIMITATIONS: A large number of exclusions for inadequate colonoscopy or inadequate data resulted in a reduced patient number in the study. CONCLUSIONS: Our criteria for follow-up colonoscopy based on the findings at initial flexible sigmoidoscopy in young patients with outlet-type rectal bleeding are reliable enough to be used in routine clinical practice, provided this is audited. See Video Abstract. GUA DE EVALUACIN PARA LA NECESIDAD DE COLONOSCOPIA DESPUS DE UNA SIGMOIDOSCOPIA FLEXIBLE INICIAL EN PACIENTES JVENES CON RECTORRAGIA: ANTECEDENTES:Si bien la edad de aparición temprana del cáncer colorrectal está aumentando en incidencia, la falta de pruebas de detección conduce a una presentación sintomática, a menudo con sangrado rectal. Debido a que la mayoría de los cánceres en pacientes menores de 50 años son del lado izquierdo, la sigmoidoscopia flexible es una forma razonable de investigar el sangrado en estos pacientes.OBJETIVO:Predecir qué pacientes sometidos a sigmoidoscopia flexible por rectorragia necesitan una colonoscopia completa.DISEÑO:Los resultados de la colonoscopia se compararon con las indicaciones publicadas para la colonoscopia después de una sigmoidoscopia flexible. Estos fueron: 1. Cualquier número de adenomas avanzados, definidos como un adenoma tubular > 9 mm, un adenoma tubulovelloso o velloso de cualquier tamaño, o cualquier adenoma con displasia de alto grado. 2. Tres o más adenomas tubulares de cualquier tamaño o histología. 3. Cualquier lesión serrada sésil. 4. Veinte o más pólipos hiperplásicos.ENTORNO CLINICO:Hospital de Caridad con especialistas voluntarios.PACIENTES:Menores de 57 años, con rectorragia, sometidos a sigmoidoscopia flexible al menos hasta el colon descendente, seguida de colonoscopia con biopsia de todas las lesiones resecadas.INTERVENCIONES:sigmoidoscopia flexible y colonoscopia con escisión de todas las lesiones removibles.PRINCIPALES MEDIDAS DE VALORACIÓN:Hallazgos en la colonoscopia.RESULTADOS:66 casos a los que se les realizó una colonoscopia entre 5 y 811 días después de la sigmoidoscopia, que también tenían datos completos. 43 hombres y 23 mujeres con una edad media de 39,5 años. El análisis de los criterios de sigmoidoscopia flexible para encontrar lesiones proximales de alto riesgo en la colonoscopia mostró una sensibilidad del 76,9 %, una especificidad del 67,9 %, un valor predictivo positivo del 37 %, un valor predictivo negativo del 92,3 % y una precisión del 69,7 %.LIMITACIONES:Gran número de exclusiones por colonoscopia inadecuada o datos inadecuados que causan un número reducido de pacientes en el estudio.CONCLUSIÓN:Nuestros criterios para la colonoscopia de seguimiento basados en los hallazgos de la sigmoidoscopia flexible inicial en pacientes jóvenes con rectorragia son lo suficientemente confiables para ser utilizados en la práctica clínica habitual, siempre que se audite. (Traducción- Dr. Ingrid Melo ).

Unresponsive Low Mixed Venous Oxygen Saturation During Early Intensive Care Unit Stay is Associated With Increased Risk of Organ Dysfunction After Cardiac Surgery: A Single-Center Retrospective Study.

OBJECTIVES: The aim of the study was to determine if unresponsive mixed venous oxygen saturation (SvO2) values during early postoperative hours are associated with postoperative organ dysfunction. DESIGN: A single-center retrospective observational study. SETTING: A university hospital. PARTICIPANTS: A total of 6,282 adult patients requiring cardiac surgery who underwent surgery in a University Hospital from 2007 to 2020. INTERVENTIONS: A pulmonary artery catheter was used to gather SvO2 samples after surgery at admission to the intensive care unit (ICU) and 4 hours later. For the analysis, patients were divided into 4 groups according to their SvO2 values. The rate of organ dysfunctions categorized according to the SOFA score was then studied among these subgroups. MEASUREMENTS AND MAIN RESULTS: The crude mortality rate for the cohort at 1 year was 4.3%. Multiple organ dysfunction syndrome (MODS) was present in 33.0% of patients in the early postoperative phase. During the 4-hour initial treatment period, 43% of the 931 patients with low SvO2 on admission responded to goal-directed therapy to increase SvO2 >60%; whereas, in 57% of the 931 patients, the low SvO2 was sustained. According to the adjusted logistic regression analyses, the odds ratio for MODS (4.23 [95% CI 3.41-5.25]), renal- replacement therapy (4.97 [95% CI 3.28-7.52]), time on a ventilator (2.34 [95% CI 2.17-2.52]), and vasoactive-inotropic score >30 (3.62 [95% CI 2.96-4.43]) were the highest in the group with sustained low SvO2. CONCLUSIONS: Patients with SvO2 <60% at ICU admission and 4 hours later had the greatest risk of postoperative MODS. Responsiveness to a goal-directed therapy protocol targeting maintaining or increasing SvO2 ≥60% at and after ICU admission may be beneficial.

Online health information-seeking behaviour and mental well-being among Finnish higher education students during COVID-19.

Online health information-seeking behaviour has increased since the World Health Organization declared COVID-19 a global pandemic in March 2020. This study examined whether health-related information on COVID-19 searched on the internet was associated with mental well-being among higher education students. A cross-sectional internet survey was conducted among 18- to 34-year-old students in Finland (N = 2976; mean age 24.61 years and median 24) in the spring of 2020. The data were analysed using descriptive statistics, Pearson's chi-square tests, Kruskal-Wallis nonparametric H tests, and a two-way ANOVA. The results indicated that most students (86% of females, 82% of males) used the internet to search for information on COVID-19. Students' self-perceived abilities to determine the relevance of online information on COVID-19 were associated with mental well-being.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

BACKGROUND: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. AIM: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. METHODS: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. RESULTS: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. CONCLUSION: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).

Towards Tobacco-Free Generation: implementation of preventive tobacco policies in the Nordic countries.

AIMS: Europe's Beating Cancer Plan set a goal of creating a Tobacco-Free Generation in Europe by 2040. Prevention is important for achieving this goal. We compare the Nordic countries' preventive tobacco policies, discuss the possible determinants for similarities and differences in policy implementation, and provide strategies for strengthening tobacco prevention. METHODS: We used the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) to identify the key policies for this narrative review. We focused on Articles 6, 8, 9, 11, 13 and 16 of the WHO FCTC, and assessed the status of the required (core) and recommended (advanced) policies and their application to novel tobacco and nicotine products. Information on the implementation of strategies, acts and regulations were searched from global and national tobacco control databases, websites and scientific articles via PubMed and MEDLINE. RESULTS: The WHO FCTC and European regulations have ensured that the core policies are mostly in place, but also contributed to the shared deficiencies that are seen especially in the regulations on smokeless tobacco and novel products. Strong national tobacco control actors have facilitated countries to implement some advanced policies - even as the first countries in the world: point-of-sale display bans (Iceland), outdoor smoking bans (Sweden), flavour bans on electronic cigarettes (Finland), plain packaging (Norway), and plain packaging on electronic cigarettes (Denmark). CONCLUSIONS: Collaboration and participation in reinforcing the European regulations, resources for national networking between tobacco control actors, and national regulations to provide protection from the tobacco industry's interference are needed to strengthen comprehensive implementation of tobacco policies in the Nordic countries.

Expression profiles of small non-coding RNAs in breast cancer tumors characterize clinicopathological features and show prognostic and predictive potential.

Precision medicine approaches are required for more effective therapies for cancer. As small non-coding RNAs (sncRNAs) have recently been suggested as intriguing candidates for cancer biomarkers and have shown potential also as novel therapeutic targets, we aimed at profiling the non-miRNA sncRNAs in a large sample set to evaluate their role in invasive breast cancer (BC). We used small RNA sequencing and 195 fresh-frozen invasive BC and 22 benign breast tissue samples to identify significant associations of small nucleolar RNAs, small nuclear RNAs, and miscellaneous RNAs with the clinicopathological features and patient outcome of BC. Ninety-six and five sncRNAs significantly distinguished (Padj < 0.01) invasive local BC from benign breast tissue and metastasized BC from invasive local BC, respectively. Furthermore, 69 sncRNAs significantly associated (Padj < 0.01) with the tumor grade, hormone receptor status, subtype, and/or tumor histology. Additionally, 42 sncRNAs were observed as candidates for prognostic markers and 29 for predictive markers for radiotherapy and/or tamoxifen response (P < 0.05). We discovered the clinical relevance of sncRNAs from each studied RNA type. By introducing new sncRNA biomarker candidates for invasive BC and validating the potential of previously described ones, we have guided the way for further research that is warranted for providing novel insights into BC biology.

Association of low mixed venous oxygen saturations during early ICU stay with increased 30-day and 1-year mortality after cardiac surgery: a single-center retrospective study.

BACKGROUND: Low postoperative mixed venous oxygen saturation (SvO2) values have been linked to poor outcomes after cardiac surgery. The present study was designed to assess whether SvO2 values of < 60% at intensive care unit (ICU) admission and 4 h after admission are associated with increased mortality after cardiac surgery. METHODS: During the years 2007-2020, 7046 patients (74.4% male; median age, 68 years [interquartile range, 60-74]) underwent cardiac surgery at an academic medical center in Finland. All patients were monitored with a pulmonary artery catheter. SvO2 values were obtained at ICU admission and 4 h later. Patients were divided into four groups for analyses: SvO2 ≥ 60% at ICU admission and 4 h later; SvO2 ≥ 60% at admission but < 60% at 4 h; SvO2 < 60% at admission but ≥ 60% at 4 h; and SvO2 < 60% at both ICU admission and 4 h later. Kaplan-Meier survival curves, Cox regression models, and receiver operating characteristic curve analysis were used to assess differences among groups in 30-day and 1-year mortality. RESULTS: In the overall cohort, 52.9% underwent coronary artery bypass grafting (CABG), 29.1% valvular surgery, 12.1% combined CABG and valvular procedures, 3.5% surgery of the ascending aorta or aortic dissection, and 2.4% other cardiac surgery. The 1-year crude mortality was 4.3%. The best outcomes were associated with SvO2 ≥ 60% at both ICU admission and 4 h later. Hazard ratios for 1-year mortality were highest among patients with SvO2 < 60% at both ICU admission and 4 h later, regardless of surgical subgroup. CONCLUSION: SvO2 values < 60% at ICU admission and 4 h after admission are associated with increased 30-day and 1-year mortality after cardiac surgery. Goal-directed therapy protocols targeting SvO2 ≥ 60% may be beneficial. Prospective studies are needed to confirm these observational findings.

Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease.

BACKGROUND: Epidemiological studies have indicated that exposure of the heart to doses of ionizing radiation as low as 0.5 Gy increases the risk of cardiac morbidity and mortality with a latency period of decades. The damaging effects of radiation to myocardial and endothelial structures and functions have been confirmed radiobiologically at high dose, but much less are known at low dose. Integration of radiation biology and epidemiology data is a recommended approach to improve the radiation risk assessment process. The adverse outcome pathway (AOP) framework offers a comprehensive tool to compile and translate mechanistic information into pathological endpoints which may be relevant for risk assessment at the different levels of a biological system. Omics technologies enable the generation of large volumes of biological data at various levels of complexity, from molecular pathways to functional organisms. Given the quality and quantity of available data across levels of biology, omics data can be attractive sources of information for use within the AOP framework. It is anticipated that radiation omics studies could improve our understanding of the molecular mechanisms behind the adverse effects of radiation on the cardiovascular system. In this review, we explored the available omics studies on radiation-induced cardiovascular disease (CVD) and their applicability to the proposed AOP for CVD. RESULTS: The results of 80 omics studies published on radiation-induced CVD over the past 20 years have been discussed in the context of the AOP of CVD proposed by Chauhan et al. Most of the available omics data on radiation-induced CVD are from proteomics, transcriptomics, and metabolomics, whereas few datasets were available from epigenomics and multi-omics. The omics data presented here show great promise in providing information for several key events (KEs) of the proposed AOP of CVD, particularly oxidative stress, alterations of energy metabolism, extracellular matrix (ECM), and vascular remodeling. CONCLUSIONS: The omics data presented here shows promise to inform the various levels of the proposed AOP of CVD. However, the data highlight the urgent need of designing omics studies to address the knowledge gap concerning different radiation scenarios, time after exposure, and experimental models. This review presents the evidence to build a qualitative omics-informed AOP and provides views on the potential benefits and challenges in using omics data to assess risk-related outcomes.

MCF10CA Breast Cancer Cells Utilize Hyaluronan-Coated EV-Rich Trails for Coordinated Migration.

Invasion of tumor cells through the stroma is coordinated in response to migratory cues provided by the extracellular environment. One of the most abundant molecules in the tumor microenvironment is hyaluronan, a glycosaminoglycan known to promote many hallmarks of tumor progression, including the migratory potential of tumor cells. Strikingly, hyaluronan is also often found to coat extracellular vesicles (EVs) that originate from plasma membrane tentacles of tumor cells crucial for migration, such as filopodia, and are abundant in tumor niches. Thus, it is possible that hyaluronan and hyaluronan-coated EVs have a cooperative role in promoting migration. In this work, we compared the hyaluronan synthesis, EV secretion and migratory behavior of normal and aggressive breast cell lines from MCF10 series. Single live cell confocal imaging, electron microscopy and correlative light and electron microscopy experiments revealed that migrating tumor cells form EV-rich and hyaluronan -coated trails. These trails promote the pathfinding behavior of follower cells, which is dependent on hyaluronan. Specifically, we demonstrated that plasma membrane protrusions and EVs left behind by tumor cells during migration are strongly positive for CD9. Single cell tracking demonstrated a leader-follower behavior, which was significantly decreased upon removal of pericellular hyaluronan, indicating that hyaluronan promotes the pathfinding behavior of follower cells. Chick chorioallantoic membrane assays in ovo suggest that tumor cells behave similarly in 3D conditions. This study strengthens the important role of extracellular matrix production and architecture in coordinated tumor cell movements and validates the role of EVs as important components and regulators of tumor matrix. The results suggest that tumor cells can modify the extracellular niche by forming trails, which they subsequently follow coordinatively. Future studies will clarify in more detail the orchestrated role of hyaluronan, EVs and other extracellular cues in coordinated migration and pathfinding behavior of follower cells.

M1 Macrophages Induce Protumor Inflammation in Melanoma Cells through TNFR-NF-κB Signaling.

The tumor microenvironment, with distinctive cell types and a complex extracellular matrix has a tremendous impact on cancer progression. In this study, we investigated the effects of proinflammatory (M1) and immunosuppressive (M2) macrophages on hyaluronan (HA) matrix formation and inflammatory response in melanoma cells. Proinflammatory factors secreted from M1 macrophages stimulated the formation of a thick pericellular HA matrix in melanoma cells due to upregulation of HA synthase 2 (HAS2). HAS2 silencing reversed the effect of M1 conditioned medium on pericellular HA coat formation, and interestingly, it also partly downregulated the M1 conditioned medium‒induced upregulation of inflammation-related genes (IL1ß, IL6), as did the inhibitors for TNFR and IKKγ. Gene set enrichment analysis revealed that genes related to inflammatory responses and TNF-α signaling via NF-κB are enriched in the M1 conditioned medium‒treated melanoma cells. Moreover, the expression of matrix metalloproteinase 9 and three-dimensional cell invasion were induced in these cells, whereas M2 macrophages had no effect on HA synthesis, inflammatory response, or invasion. Our results indicate that the activation of TNFR-NF-κB signaling in M1 conditioned medium‒treated cells leads to HAS2 upregulation, which associates with a protumor inflammatory and invasive phenotype of melanoma cells.

Circulating Cell-Free DNA Reflects the Clonal Evolution of Breast Cancer Tumors.

Liquid biopsy of cell-free DNA (cfDNA) is proposed as a potential method for the early detection of breast cancer (BC) metastases and following the clonal evolution of BC. Though the use of liquid biopsy is a widely discussed topic in the field, only a few studies have demonstrated such usage so far. We sequenced the DNA of matched primary tumor and metastatic sites together with the matched cfDNA samples from 18 Eastern Finnish BC patients and investigated how well cfDNA reflected the clonal evolution of BC interpreted from tumor DNA. On average, liquid biopsy detected 56.2 ± 7.2% of the somatic variants that were present either in the matched primary tumor or metastatic sites. Despite the high discordance observed between matched samples, liquid biopsy was found to reflect the clonal evolution of BC and identify novel driver variants and therapeutic targets absent from the tumor DNA. Tumor-specific somatic variants were detected in cfDNA at the time of diagnosis and 8.4 ± 2.4 months prior to detection of locoregional recurrence or distant metastases. Our results demonstrate that the sequencing of cfDNA may be used for the early detection of locoregional and distant BC metastases. Observed discordance between tumor DNA sequencing and liquid biopsy supports the parallel sequencing of cfDNA and tumor DNA to yield the most comprehensive overview for the genetic landscape of BC.

Adolescents' Perceptions of Harmfulness of Tobacco and Tobacco-like Products in Finland.

During the recent years, new tobacco and tobacco-like products, e.g., e-cigarettes, have emerged on the market. Adolescents often underestimate health risks in general, including those concerning tobacco. Little is known of adolescents' perceptions of health risks of the newer products. Our paper compares adolescents' perceptions of harmfulness of cigarettes, e-cigarettes, snus, water pipes, and nicotine in Finland, a country with a long history of strict tobacco control policy. Online surveys to nationally representative samples of 12-18-year-olds were conducted in 2017 and 2019, with 7578 answering the surveys. Only 3% of boys and 2% of girls did not agree that cigarettes are harmful to health. The percentages were slightly higher for snus (6% and 3%, respectively) and nicotine (12%, 8%) but much higher for e-cigarettes (30%, 22%) and water pipes (36%, 38%). Those who used the product, whose parents were smokers or had lower education, and whose school performance was lower, less often agreed with the harmful health effects of the products. Our results showed that adolescents understood the harmfulness of older tobacco products better than the harmfulness of the newer ones. Our results also showed the need to strengthen health education and fix adolescents' misperceptions of the health effects of the newer products.

Single, Dual, and Triple Use of Cigarettes, e-Cigarettes, and Snus among Adolescents in the Nordic Countries.

New tobacco and nicotine products have emerged on the market in recent years. Most research has concerned only one product at a time, usually e-cigarettes, while little is known about the multiple use of tobacco and nicotine products among adolescents. We examined single, dual, and triple use of cigarettes, e-cigarettes, and snus among Nordic adolescents, using data of 15-16-year-olds (n = 16,125) from the European School Survey Project on Alcohol and other Drugs (ESPAD) collected in 2015 and 2019 from Denmark, Finland, Iceland, Norway, Sweden, and the Faroe Islands. Country-specific lifetime use of any of these products ranged between 40% and 50%, and current use between 17% and 31%. Cigarettes were the most common product in all countries except for Iceland, where e-cigarettes were remarkably more common. The proportion of dual and triple users was unexpectedly high among both experimental (24%-49%) and current users (31-42%). Triple use was less common than dual use. The users' patterns varied somewhat between the countries, and Iceland differed substantially from the other countries, with a high proportion of single e-cigarette users. More knowledge on the patterns of multiple use of tobacco and nicotine products and on the potential risk and protective factors is needed for targeted intervention and prevention efforts.

The role of health literacy in the association between academic performance and substance use.

BACKGROUND: To address social inequalities in adolescent substance use and consequent disparities in health, it is important to identify the mechanisms of the association between substance use and academic performance. We study the role of health literacy (HL) in the association between academic performance and weekly smoking, monthly alcohol use and cannabis ever-use among adolescents in Europe. METHODS: SILNE-R school survey data, which was collected in 2016-17 with paper-and-pencil-method from Hanover (GE), Amersfoort (NL) and Tampere (FI), were used (N = 5088, age 13-19). Health Literacy for School-aged Children instrument was used to assess students' HL. Logistic regression analyzed the association of substance use with academic performance and HL, separately and in the same model. Linear and multinomial logistic regression analyzed the association between academic performance and HL. RESULTS: Poor academic performance compared with high was associated with smoking [odds ratio (OR) 3.94, 95% confidence interval (CI) 2.83-5.49], alcohol use (OR: 2.94, 95% CI: 2.34-3.68) and cannabis use (OR: 2.56, 95% CI: 1.89-3.48). Poor HL was also associated with each substance use (with ORs of 2.32, 1.85 and 1.29). HL was positively associated with academic performance (ß = 1.04, 95% CI: 0.89-1.20). The associations between academic performance and substance use were only slightly attenuated after controlling for HL. CONCLUSIONS: Academic performance and HL were both determinants of substance use, confirming their role in tackling the disparities in substance use. However, HL did not demonstrably mediate the association between academic performance and substance use. A wider set of factors needs to be tackled to address emerging social inequalities in adolescent substance use.

Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes.

IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

The Way of Distance Teaching Is Related to Adolescent Students' Health and Loneliness during the School Closure in Finland.

The COVID-19 pandemic enforced countries to close schools and rapidly transfer to distance teaching without preparation. Little is known about how different distance teaching practices influenced students' wellbeing. We studied this during the period of school closures in Finland. Wellbeing was measured by health complaints and perceived loneliness, and distance learning was measured in terms of structure and dialogue of teaching, functioning of internet and digital equipment, difficulty of given tasks, and support for studies. All lower secondary schools were invited, and 29,898 students from 340 schools (grades 7-9) participated. A digital survey was distributed through schools just when these were reopened in May 2020. The main results were that the distance learning practices were related to adolescent health complaints and loneliness, so that less structure and dialogue in teaching, more problems with digital devices and internet, more difficult tasks and less support for studies were associated with higher health complaints and loneliness. From the point of view of students' wellbeing, it matters how the distance learning is organised, how digital communication works, and if enough support for studies is available. These results of our research on distance learning practices during the present pandemic may guide schools in future crises and pandemic situations when distance learning is needed.

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.