For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular ...understanding of these distinct disease manifestations can critically inform patient management. Using genetically engineered mouse models, we show that heterozygous mutation of Dpc4/Smad4 attenuates the metastatic potential of KrasG12D/+;Trp53R172H/+ pancreatic ductal adenocarcinomas while increasing their proliferation. Subsequent loss of heterozygosity of Dpc4 restores metastatic competency while further unleashing proliferation, creating a highly lethal combination. Expression levels of Runx3 respond to and combine with Dpc4 status to coordinately regulate the balance between cancer cell division and dissemination. Thus, Runx3 serves as both a tumor suppressor and promoter in slowing proliferation while orchestrating a metastatic program to stimulate cell migration, invasion, and secretion of proteins that favor distant colonization. These findings suggest a model to anticipate likely disease behaviors in patients and tailor treatment strategies accordingly.
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•DPC4 dosage regulates RUNX3 levels in a biphasic manner•RUNX3 controls the balance between local growth and dissemination in PDA•RUNX3 functions as both tumor suppressor and tumor promoter in PDA•DPC4 and RUNX3 levels can jointly inform clinical decision making
RUNX3 regulates the balance between proliferation and dissemination of pancreas cancer cells in response to gene dosage of DPC4/SMAD4. Evaluating the levels of DPC4 and RUNX3 can help predict patterns of relapse and response to therapies in patients, informing clinical disease management.
Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship ...between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). We confirmed LCAMhi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAMhi lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.
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•scRNA-seq of immune cells in 35 NSCLCs reveals activation module (LCAM)•CITE-seq validates and extends scRNA-seq-based cell annotations•LCAM is associated with tumor mutational burden, ectopic antigens, and driver mutations•LCAM confers prognostic benefit in anti-PD-L1 treatment but not chemotherapy
Leader et al. provide the largest NSCLC cohort analyzed by scRNA-seq and CITE-seq, demonstrating shared and variable elements of the treatment-naive immune response and identifying independent immune-modifying effects of tumor mutational burden and TP53 mutation, resulting in a refined model of how neoantigens, driver mutations, and immune state combine to drive immunotherapeutic response.
Long-term exposure to particulate matter (PM) air pollution may increase blood pressure and the risk of hypertension. However, epidemiological evidence is scarce and inconsistent.
We investigated the ...associations between long-term exposure to PM with an aerodynamic diameter <2.5μm (PM
), blood pressure, and incident hypertension in a large Taiwanese cohort.
We studied 361,560 adults ≥18y old from a large cohort who participated in a standard medical examination program during 2001 to 2014. Among this group, 125,913 nonhypertensive participants were followed up. A satellite-based spatiotemporal model was used to estimate the 2-y average PM
concentrations at each participant's address. Multivariable linear regression was used in the cross-sectional data analysis with the 361,560 participants to investigate the associations between PM
and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), and Cox proportional hazard regression was used in the cohort data analysis with the 125,913 participants to investigate the associations between PM
and incident hypertension.
Each 10-μg/m
increment in the 2-y average PM
concentration was associated with increases of 0.45 mmHg 95% confidence interval (CI): 0.40, 0.50, 0.07 mmHg (95% CI: 0.04, 0.11), and 0.38 mmHg (95% CI: 0.33, 0.42) in SBP, DBP, and PP, respectively, after adjusting for a wide range of covariates and possible confounders. Each 10-μg/m
increment in the 2-y average PM
concentration was associated with an increase of 3% in the risk of developing hypertension hazard ratio=1.03 (95% CI: 1.01, 1.05). Stratified and sensitivity analyses yielded similar results.
Long-term exposure to PM
air pollution is associated with higher blood pressure and an increased risk of hypertension. These findings reinforce the importance of air pollution mitigation strategies to reduce the risk of cardiovascular disease. https://doi.org/10.1289/EHP2466.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant “window of opportunity” study of metformin ...in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13–40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (−0.5 kg/m
2
,
p
< 0.0001), weight (−1.2 kg,
p
< 0.0001), and HOMA (−0.21,
p
= 0.047) decreased significantly while non-significant decreases were seen in insulin (−4.7 pmol/L,
p
= 0.07), leptin (−1.3 ng/mL,
p
= 0.15) and CRP (−0.2 mg/L,
p
= 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %,
p
= 0.016) and TUNEL staining increased (from 0.56 to 1.05,
p
= 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.
Advances in digital image analysis have the potential to transform the practice of breast pathology. In the near future, a move to a digital workflow offers improvements in efficiency. Coupled with ...artificial intelligence (AI), digital pathology can assist pathologist interpretation, automate time‐consuming tasks, and discover novel morphologic patterns. Opportunities for digital enhancements abound in breast pathology, from increasing reproducibility in grading and biomarker interpretation, to discovering features that correlate with patient outcome and treatment. Our objective is to review the most recent developments in digital pathology with clear impact to breast pathology practice. Although breast pathologists currently undertake limited adoption of digital methods, the field is rapidly evolving. Care is needed to validate emerging technologies for effective patient care.
There is limited information on the relationship between risk of cardiovascular disease and the joint effects of sleep quality and sleep duration, especially from large, prospective, cohort studies. ...This study is to prospectively investigate the joint effects of sleep quality and sleep duration on the development of coronary heart disease.
This study examined 60,586 adults aged 40 years or older. A self-administered questionnaire was used to collect information on sleep quality and sleep duration as well as a wide range of potential confounders. Events of coronary heart disease were self-reported in subsequent medical examinations. Two types of Sleep Score (multiplicative and additive) were constructed to reflect the participants' sleep profiles, considering both sleep quality and sleep duration. The Cox regression model was used to estimate the hazard ratio (HR) and the 95% confidence interval (CI).
A total of 2,740 participants (4.5%) reported new events of coronary heart disease at follow-up. For sleep duration, participants in the group of < 6 h/d was significantly associated with an increased risk of coronary heart disease (HR: 1.13, 95% CI: 1.04-1.23). However, the association in the participants with long sleep duration (> 8 h/d) did not reach statistical significance (HR: 1.11, 95% CI: 0.98-1.26). For sleep quality, both dreamy sleep (HR: 1.21, 95% CI: 1.10-1.32) and difficult to fall asleep/use of sleeping pills or drugs (HR: 1.40, 95% CI: 1.25-1.56) were associated with an increased risk of the disease. Participants in the lowest quartile of multiplicative Sleep Score (HR: 1.31, 95% CI: 1.16-1.47) and of additive sleep score (HR: 1.31, 95% CI: 1.16-1.47) were associated with increased risk of coronary heart disease compared with those in the highest quartile.
Both short sleep duration and poor sleep quality are associated with the risk of coronary heart disease. The association for long sleep duration does not reach statistical significance. Lower Sleep Score (poorer sleep profile) increases the risk of coronary heart disease, suggesting the importance of considering sleep duration and sleep quality together when developing strategies to improve sleep for cardiovascular disease prevention.
•This is a large cohort study consisting of 385,650 adults aged ≥18 years in Taiwan.•PM2.5 was associated with higher risk of gastrointestinal cancer mortality.•PM2.5 was associated with higher risk ...of liver and colorectal cancers mortality.
Information on the association between long-term exposure to PM2.5 and gastrointestinal cancer mortality is scarce.
This study investigated the association between long-term exposure to PM2.5 and deaths from gastrointestinal cancer and its subtypes in adults in Taiwan.
A total of 385,650 Taiwanese adults (≥18 years old) jointed a standard medical examination program between 2001 and 2014 and were followed up until 2016. Their vital data were obtained from the National Death Registry maintained by the Ministry of Health and Welfare in Taiwan. We estimated the ambient PM2.5 concentration at individual’s address utilising a satellite-based spatiotemporal model at a resolution of 1 km2. Cox proportional hazard regression model was used to investigate the associations between ambient PM2.5 and deaths from gastrointestinal, stomach, colorectal and liver cancers.
We found that each 10 µg/m3 increase in PM2.5 was associated with an increased hazard risk (HR) of 1.09 (95% confidence interval (CI): 1.03–1.16) and 1.13 (95%CI: 1.02–1.24) in deaths from gastrointestinal and liver cancers, respectively. The association between PM2.5 and death from colorectal cancer was marginally statistically significant HR: 1.13 (95%CI: 1.00–1.26). We did not find significant associations between PM2.5 and mortality from stomach cancer.
Long-term exposure to ambient PM2.5 was associated with an increased risk of deaths from gastrointestinal cancers, liver cancer and also potentially colorectal cancer. Air pollution control strategies are necessary to reduce the burden of gastrointestinal cancer.
To describe the clinical features and outcomes of estrogen receptor negative (ER-) and progesterone receptor positive (PgR+) breast cancer.
We retrospectively reviewed a well-characterized database ...of sequential patients diagnosed with early stage invasive breast carcinoma. Outcomes of interest were time to relapse (TTR) and overall survival (OS). Multivariable Cox proportional hazards analysis was conducted to assess the association of ER-/PgR+ with TTR and OS in comparison to ER+ and to ER- and PgR negative (ER-/PgR-) tumors irrespective of HER2 status. ER and PgR expression was conservatively defined as 10% or greater staining of cancer cells.
815 patients were followed for a median of 40.5 months; 56 patients (7%) had ER-/PgR+, 624 (77%) had ER+ and 136 (17%) had ER-/PgR- phenotypes. Compared with ER+ tumors, ER-/PgR+ tumors were associated with younger age (50 versus 59 years, p=0.03), high grade (50% versus 24%, p<0.001) and more frequent HER2 overexpression/amplification (43% versus 14%, p<0.001). TTR for ER-/PgR+ was intermediate between ER+ and ER-/PgR- tumors, but was not significantly different from ER+ tumors. Recurrences in the ER-/PgR+ and ER-/PgR- groups occurred early in follow-up while in ER+ tumors recurrences continued to occur over the duration of follow-up. OS of ER-/PgR+ was similar to ER+ tumors and better than that of ER-/PgR- tumors.
The ER-/PgR+ phenotype is associated with higher grade with HER2 overexpression/amplification and occurs more commonly in younger women. Risk of relapse and death more closely resembles ER+ than ER-/PgR- tumors suggesting this phenotype represents a group of more aggressive hormone receptor positive tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A novel family of soluble conjugated dendritic oligothiophenes (DOTs) as monodisperse 3D macromolecular architectures was characterized with respect to optical and redox properties in solution and in ...solid films. Band gaps of 2.5–2.2 eV, typical for organic semiconductors, were determined as well as HOMO/LUMO energy levels ideal for efficient electron transfer to acceptors such as 6,6‐phenyl‐C61‐butyric acid methyl ester (PCBM) identifying them as suitable materials for solar cell applications. Solution‐processed bulk‐heterojunction solar cells using DOTs as electron donor and PCBM as acceptor were prepared and investigated. High open‐circuit voltages VOC of 1.0 V and power‐conversion efficiencies up to 1.72% were obtained for the DOT‐based devices. The higher generations DOTs provide the highest efficiencies. Based on the monodispersity of the DOTs, an analysis of the molar ratio between donor and acceptor in the blended film was possible leading to an optimal value of five to six thiophene units per PCBM.
Solution‐processed bulk‐heterojunction solar cells using novel monodisperse dendritic oligothiophenes (DOTs) as the donor and a fullerene derivative (PCBM) as the acceptor are prepared and investigated. Devices show high open‐circuit voltages of 1.0 V and reach power‐conversion efficiencies up to 1.7%. Based on the monodispersity of the DOTs, an analysis of the molar ratio between donor and acceptor in the blended film is performed leading to an optimal value of five to six thiophene units per PCBM.
Validated biomarkers are needed to improve risk assessment and treatment decision-making for women with ductal carcinoma in situ (DCIS) of the breast. The Onco
type
DX
®
DCIS Score (DS) was shown to ...predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 C
p
units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS,
N
= 44; invasive,
N
= 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26;
P
< 0.001) and in all patients regardless of ER status (HR 2.15;
P
< 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68;
P
= 0.02). DCIS was associated with invasive LR (HR 1.78;
P
= 0.04) and DCIS LR (HR 2.43;
P
= 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone.
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