Pollution with complex mixtures of contaminants including micro- and nano-plastics (MNPs) and organic pollutants like polycyclic aromatic hydrocarbons (PAH) poses a major threat to coastal marine ...ecosystems. Toxic mechanisms of contaminant mixtures are not well understood in marine organisms. We studied the effects of single and combined exposures to polycyclic aromatic hydrocarbon phenanthrene (Phe) and MNPs mixture with sizes of 70 nm, 5 μm and 100 μm on the immune health and oxidative stress parameters in the thick-shell mussel Mytilus coruscus. Immune cells (hemocytes) were more sensitive to the pollutant-induced oxidative stress than the gills. In hemocytes of co-exposed mussels, elevated mortality, lower lysosomal content, high production of reactive oxygen species (ROS) and decrease mitochondrial were found. Disparate responses of antioxidant enzymes in the hemolymph (e.g. increased superoxide dismutase (SOD) activity without a corresponding increase in catalase (CAT) in Phe exposures and an increase in CAT without a change in SOD in MNPs exposures) suggests misbalance of the antioxidant defense in the pollutant-exposed mussels. Gill lacked pronounced oxidative stress response showing a decline in ROS and antioxidant levels. Tissue-specific single and combined effects of Phe and MNPs suggest variation in bioavailability and/or different sensitivity to these pollutants in the studied tissues. Notably, the combined effects of MNPs and Phe were additive or antagonistic, showing that MNPs do not enhance and occasionally mitigate the toxic effects of Phe on the hemocytes and the gills of the mussels. Overall, our study sheds light on the impact of long-term exposure to MNPs and Phe mixtures on mussels, showing high sensitivity of the immune system and modulation of the Phe toxicity by MNPs co-exposure. These findings that may have implications for understanding the impacts of combined PAH and MNPs pollution on the health of mussel populations from polluted coastal habitats.
To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC).
...Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status (ClinicalTrials.gov identifier: NCT02866383). The primary end point was the clinical benefit rate (CBR), defined as the percentage of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary end points included safety, response rate, duration of response, progression-free survival, and overall survival. Exploratory analyses included biomarkers related to the benefits.
Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (8.0 to 30.6) for patients receiving SBRT/nivolumab and 37.2% (24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient receiving SBRT/nivolumab and lasted for 4.6 months. Six patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months (4.2 to not reached). Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) and 13 (30.2%) patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively. Programmed cell death ligand-1 expression by tumor proportion score or combined positivity score of ≥ 1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better overall survival.
Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with SBRT/nivolumab/ipilimumab in patients with refractory mPC. However, the contribution from SBRT is unknown. Further studies are warranted.
According to current evidence, the best treatment for fit patients with non-resectable pancreatic cancer (PC) is combination chemotherapy, whereas frail patients are recommended gemcitabine (Gem) ...monotherapy. Randomized controlled trials in colorectal cancer and a post-hoc analysis of gemcitabine and nab-paclitaxel (GemNab) in PC suggest, however, that reduced dose of combination chemotherapy may be feasible and more efficient compared to monotherapy in frail patients. The aim of this study is to investigate whether reduced dose GemNab is superior to full dose Gem in patients with resectable PC, who are not candidates for full dose combination chemotherapy in first line.
The Danish Pancreas Cancer Group (DPCG)-01 trial is a national multicenter prospective randomized phase II trial. A total of 100 patients in ECOG performance status 0-2 with non-resectable PC, not candidate for full dose combination chemotherapy in first line, but eligible for full dose Gem, will be included. Patients are randomized 1:1 to either full dose Gem or GemNab in 80% of recommended dose. The primary endpoint is progression-free survival. Secondary endpoints are overall survival, overall response rate, quality of life, toxicity and rate of hospitalizations during treatment. The correlation between blood inflammatory markers, including YKL-40 and IL-6, circulating tumor DNA, and tissue biomarkers of resistance to chemotherapy and outcome will be explored. Finally, the study will include measures of frailty (G8, modified G8, and chair-stand-test) to assess whether scoring would enable a personalized allocation to different treatments or indicates a possibility for interventions.
Single-drug treatment with Gem has for frail patients with non-resectable PC been the main treatment option for more than thirty years, but the impact on outcome is modest. If improved results and sustained tolerability with reduced dose combination chemotherapy can be shown, this could change the future practice for this increasing group of patients.
ClinicalTrials.gov Identifier: NCT05841420. Secondary Identifying No: N-20210068. EudraCT No: 2021-005067-52.
1.5, 16-MAY-2023.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nano‑titanium dioxide (nTiO2) is a widely used nanomaterial posing potential ecological risk for marine ecosystems that might be enhanced by elevated temperatures such as expected during climate ...change. nTiO2 may affect benthic filter feeders like mussels through waterborne exposures and via food chain due to the adsorption on/in algae. Mussel byssus are proteinaceous fibers secreted by byssal glands of the mussels for attachment. Byssus production and mechanical properties are sensitive to environmental stressors but the combined effects of warming and nTiO2 on byssus performance of mussels are unclear hampering our understanding of the predation and dislodgement risk of mussels under the multiple stressor scenarios. We explored the effects of a short-term (14-day) single and combined exposures to warming (28 °C) and 100 μg L−1 nTiO2 (including food co-exposure) on the byssus performance of the thick shell mussel Mytilus coruscus. The mechanical strength (measured as the breaking force) of the byssal threads was impaired by warming and nTiO2 (including food co-exposure), but the number and length of the byssal threads were increased. The mRNA expression levels of mussel foot proteins (mfp-3, mfp-5) and pre-collagens (preCOL-D, preCOL-P, preCOL-NG) were up-regulated to varying degrees, with the strongest effects induced by warming. This indicates that the physiological and molecular mechanisms of byssus secretion are plastic. However, downregulation of the mRNA expression of preCOL-D and preCOL-P under the combined warming and nTiO2 exposures indicate the limits of these plasticity mechanisms and suggest that the attachment ability and survival of the mussels may be impaired if the pollution or temperature conditions further deteriorate.
Display omitted
•Warming and nTiO2 independently reduced byssus performance of mussels.•Under warming×nTiO2, the expressions of some mussel foot proteins were down-regulated (<1).•nTiO2 via food chain further reduced the pre-collagens of byssal strength in mussels.
In the tumor microenvironment, the extracellular matrix (ECM) has been recognized as an important part of cancer development. The dominant ECM proteins are the 28 types of collagens, each with a ...unique function in tissue architecture. Type XX collagen, however, is poorly characterized, and little is known about its involvement in cancer. We developed an ELISA quantifying type XX collagen, named PRO-C20, using a monoclonal antibody raised against the C-terminus. PRO-C20 and PRO-C1, an ELISA targeting the N-terminal pro-peptide of type I collagen, was measured in sera of 219 patients with various solid cancer types and compared to sera levels of 33 healthy controls. PRO-C20 was subsequently measured in a separate cohort comprising 36 patients with pancreatic ductal adenocarcinoma (PDAC) and compared to 20 healthy controls and 11 patients with chronic pancreatitis. PRO-C20 was significantly elevated in all cancers tested: bladder, breast, colorectal, head and neck, kidney, lung, melanoma, ovarian, pancreatic, prostate, and stomach cancer (p < 0.01−p < 0.0001). PRO-C1 was only elevated in patients with ovarian cancer. PRO-C20 could discriminate between patients and healthy controls with AUROC values ranging from 0.76 to 0.92. Elevated levels were confirmed in a separate cohort of patients with PDAC (p < 0.0001). High PRO-C20 levels (above 2.57 nM) were predictive of poor survival after adjusting for the presence of metastasis, age, and sex (HR: 4.25, 95% CI: 1.52−11.9, p-value: 0.006). Circulating type XX collagen is elevated in sera of patients with various types of cancer and has prognostic value in PDAC. If validated, PRO-C20 may be a novel biomarker for patients with solid tumors and can help understand the ECM biology of cancer.
The objective of this study was to evaluate the diagnostic and prognostic potential of soluble CD163 (sCD163) in patients with pancreatic ductal adenocarcinoma (PDAC). Preoperative serum samples from ...255 patients with PDAC were analyzed for sCD163 using a commercially available enzyme-linked immunosorbent assay. The diagnostic value of sCD163 was evaluated using receiver operating characteristic (ROC) curves. The prognostic significance of sCD163 was evaluated by Cox regression analysis and Kaplan-Meier survival curves. sCD163 was significantly increased in patients with PDAC, across all stages, compared to healthy subjects (stage 1:
value = 0.033; stage 2-4:
value ≤ 0.0001). ROC curves showed that sCD163 combined with CA 19-9 had the highest diagnostic potential compared to sCD163 and CA 19-9 alone both in patients with local PDAC and patients with advanced PDAC. Univariate and multivariate analysis showed no association between sCD163 and overall survival. This study found elevated levels of circulating sCD163 in patients with PDAC, regardless of stage, compared to healthy subjects. This suggests that sCD163 may have a clinical value as a novel diagnostic biomarker in PDAC.
Hyaluronan (HA) and collagen are highly expressed in pancreatic cancer (PC) stroma. HA and collagen accumulation increase tumor interstitial fluid pressure, compromising blood flow and drug ...penetration. The aim of this biomarker study was to determine the clinical utility of serum HA and the propeptide of type III collagen (PRO‐C3) in patients with PC. A cohort from the Danish BIOPAC study (NCT03311776) including patients with histologically confirmed pancreatic ductal adenocarcinoma (n = 809), ampullary carcinoma (n = 44), distal biliary tract cancer (n = 31), chronic pancreatitis (n = 15), intraductal papillary mucinous neoplasm (n = 41), duodenal adenoma (n = 7) and no cancer (n = 25). Healthy controls were available for serum HA (n = 141) and PRO‐C3 (n = 8). The main outcome was overall survival (OS) of patients with PC in relation to pretreatment serum HA and PRO‐C3 levels. Patients with PC had higher baseline serum HA and PRO‐C3 than healthy subjects and patients with benign conditions. Pretreatment serum baseline HA and PRO‐C3 in patients with PC were associated with poorer survival and PRO‐C3 remained prognostic also after adjusting for age, performance status, stage, the presence of liver and peritoneum metastasis, and CA19‐9. Detection of HA and PRO‐C3 may be useful in differentiating between malignant and benign pancreatic conditions. Serum HA and PRO‐C3 were prognostic for OS in patients with PC.
What's new?
Hyaluronan (HA) and collagen are highly expressed in pancreatic cancer (PC) stroma. HA and collagen accumulation increase tumor interstitial fluid pressure, compromising blood flow and drug penetration. In this biomarker study, high levels of serum HA and type III collagen propeptide (PRO‐C3) were associated with short overall survival. Serum HA and PRO‐C3 levels were higher in PC patients than in patients with benign conditions. The findings warrant further exploration to help clarify links between HA, collagen type III, and PC. Moreover, they point to serum PRO‐C3 as a potential prognostic marker in patients with PC.
Background
YKL-40, also known as chitinase-3-like protein 1 (CHI3L1), is a secreted glycoprotein produced by various cell types including stromal, immune, and cancer cells. It contributes to cancer ...progression through tumor-promoting inflammation and has been shown to inhibit the cytotoxicity of T and NK lymphocytes.
In vivo
studies have demonstrated synergistic anti-cancer effects of blocking YKL-40 in combination with immune checkpoint inhibitors (ICIs). Biomarkers for the prediction of the response to ICIs are highly needed. We investigated the association between plasma YKL-40 and clinical benefit and survival in patients with metastatic pancreatic cancer (mPC) receiving ICIs and stereotactic body radiotherapy (SBRT).
Methods
Blood samples were collected from 84 patients with mPC who participated in the randomized phase II CheckPAC study, in which patients received nivolumab with or without ipilimumab combined with a single fraction of SBRT. Plasma YKL-40 was measured using a commercial ELISA kit.
Results
Elevated baseline plasma YKL-40 was an independent predictor of shorter overall survival (OS) (HR 2.19, 95% CI 1.21–3.95). A ≥ 40% decrease in plasma YKL-40 during treatment was associated with longer progression-free survival (
p
= 0.009) and OS (
p
= 0.0028). There was no correlation between plasma YKL-40 and the tumor burden marker CA19-9 at baseline or during treatment.
Conclusion
This study contributes new knowledge regarding YKL-40 as a predictor of clinical benefit from ICIs and radiotherapy. These exploratory results warrant further investigation of YKL-40 as a biomarker for patients treated with immunotherapies.
Clinical trial registration
Clinicaltrials.gov
, identifier NCT02866383.
Pancreatic cancer is one of the deadliest cancer types with poor treatment options. Better detection of early symptoms and relevant disease correlations could improve pancreatic cancer prognosis. In ...this retrospective study, we used symptom and disease codes (ICD-10) from the Danish National Patient Registry (NPR) encompassing 6.9 million patients from 1994 to 2018,, of whom 23,592 were diagnosed with pancreatic cancer. The Danish cancer registry included 18,523 of these patients. To complement and compare the registry diagnosis codes with deeper clinical data, we used a text mining approach to extract symptoms from free text clinical notes in electronic health records (3078 pancreatic cancer patients and 30,780 controls). We used both data sources to generate and compare symptom disease trajectories to uncover temporal patterns of symptoms prior to pancreatic cancer diagnosis for the same patients. We show that the text mining of the clinical notes was able to complement the registry-based symptoms by capturing more symptoms prior to pancreatic cancer diagnosis. For example, 'Blood pressure reading without diagnosis', 'Abnormalities of heartbeat', and 'Intestinal obstruction' were not found for the registry-based analysis. Chaining symptoms together in trajectories identified two groups of patients with lower median survival (<90 days) following the trajectories 'Cough→Jaundice→Intestinal obstruction' and 'Pain→Jaundice→Abnormal results of function studies'. These results provide a comprehensive comparison of the two types of pancreatic cancer symptom trajectories, which in combination can leverage the full potential of the health data and ultimately provide a fuller picture for detection of early risk factors for pancreatic cancer.
Type XI collagen has been associated with tumor fibrosis and aggressiveness in patients with pancreatic ductal adenocarcinoma (PDAC). The propeptide on Type XI collagen is released into the ...circulation after proteolytic processing at either amino acid 253 or 511. This allows for a noninvasive biomarker approach to quantify Type XI collagen production. We developed two ELISA‐based biomarkers, targeting the two enzymatic cleavage sites (PRO‐C11‐253 and PRO‐C11‐511). In a discovery cohort including serum from patients with PDAC (n = 39, Stages 1‐4), chronic pancreatitis (CP, n = 12) and healthy controls (n = 20), PRO‐C11‐511, but not PRO‐C11‐253, was significantly upregulated in patients with PDAC and CP compared to healthy controls. Furthermore, PRO‐C11‐511 levels >75th percentile were associated with poor overall survival (OS) (HR, 95% CI: 3.40, 1.48‐7.83). The PRO‐C11‐511 biomarker potential was validated in serum from 686 patients with PDAC. Again, high levels of PRO‐C11‐511 (>75th percentile) were associated with poor OS (HR, 95% CI: 1.68, 1.40‐2.02). Furthermore, PRO‐C11‐511 remained significant after adjusting for clinical risk factors (HR, 95% CI: 1.50, 1.22‐1.86). In conclusion, quantifying serum levels of Type XI collagen with PRO‐C11‐511 predicts poor OS in patients with PDAC. This supports that Type XI collagen is important for PDAC biology and that PRO‐C11‐511 has prognostic noninvasive biomarker potential for patients with PDAC.
What's new?
Desmoplasia, characterized by increased collagen turnover, plays an important role in pancreatic ductal adenocarcinoma (PDAC), potentially influencing cancer progression and limiting drug uptake. Poor therapeutic response in particular appears to be associated with type XI collagen, which enters the circulation following proteolytic processing. Here, assays were developed to detect either of two type XI collagen proteolytic products, PRO‐C11‐253 or PRO‐C11‐511, in PDAC patient serum. The assays show that PRO‐C11‐511 type XI collagen is significantly upregulated in PDAC patients and is associated with poor overall survival. The findings identify a potential role for collagen products as predictive markers in PDAC.