Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine ...methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.
High-grade liver laceration is a common injury with bleeding as the main cause of death. Timely resuscitation and hemostasis are keys to the successful management. The impact of in-hospital trauma ...system on the quality of resuscitation and management in patients with traumatic high-grade liver laceration, however, was rarely reported. We retrospectively reviewed the impact of team-based approach on the quality and outcomes of high-grade traumatic liver laceration in our hospital. Patients with traumatic liver laceration between 2002 and 2020 were enrolled in this retrospective study. Inverse probability of treatment weighting (IPTW)-adjusted analysis using the propensity score were performed. Outcomes before the trauma team establishment (PTTE) and after the trauma team establishment (TTE) were compared. A total of 270 patients with liver trauma were included. After IPTW adjustment, interval between emergency department arrival and managements was shortened in the TTE group with a median of 11 min (p < 0.001) and 28 min (p < 0.001) in blood test reports and duration to CT scan, respectively. Duration to hemostatic treatments in the TTE group was also shorter by a median of 94 min in patients receiving embolization (p = 0.012) and 50 min in those undergoing surgery (p = 0.021). The TTE group had longer ICU-free days to day 28 (0.0 vs. 19.0 days, p = 0.010). In our study, trauma team approach had a survival benefit for traumatic high-grade liver injury patients with 65% reduction of risk of death within 72 h (Odds ratio (OR) = 0.35, 95% CI = 0.14-0.86) and 55% reduction of risk of in-hospital mortality (OR = 0.45, 95% CI = 0.23-0.87). A team-based approach might contribute to the survival benefit in patients with traumatic high-grade liver laceration by facilitating patient transfer from outside the hospital, through the diagnostic examination, and to the definitive hemostatic procedures.
The objective of this study was to evaluate the efficacy and safety of induction chemotherapy (ICT), GOFL (gemcitabine, oxaliplatin plus fluorouracil (5-FU)/leucovorin) versus modified FOLFIRINOX ...(irinotecan, oxaliplatin plus 5-FU/leucovorin), followed by concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic adenocarcinoma (LAPC).
Chemo-naive patients with measurable LAPC were eligible and randomly assigned to receive biweekly ICT with either mFOLFIRINOX or GOFL for 3 months. Patients without systemic progression would have 5-FU- or gemcitabine-based CCRT (5040 cGy/28 fractions) and were then subjected to surgery or continuation of chemotherapy until treatment failure. The primary endpoint was 9-month progression-free survival (PFS) rate.
Between July 2013 and January 2019, 55 patients were enrolled. After ICT, 21 (77.8%) of 27 patients who received mFOLFIRINOX and 17 (60.7%) of 28 patients who received GOFL completed CCRT. Of them, one and five had per-protocol R0/R1 resection. On intent-to-treat analysis, the 9-month PFS rate, median PFS and overall survival in mFOLFIRINOX and GOFL arms were 30.5% versus 35.9%, 6.6 (95% confidence interval: 5.9-12.5) versus 7.6 months (3.9-12.3) and 19.6 (13.4-22.9) versus 17.9 months (13.4-23.9), respectively. Grade 3-4 neutropenia and diarrhoea during induction mFOLFIRINOX and GOFL were 37.0% versus 21.4% and 14.8% versus 3.6%, respectively.
Induction GOFL and mFOLFIRINOX followed by CCRT provided similar clinical outcomes in LAPC patients.
NCT01867892.
Osteopontin (OPN) can recruit macrophages to the site of inflammation and promote tumorigenesis. M2 tumor-associated macrophages (M2-TAMs) also play an important role in cancer progression. This ...study aimed to clarify the role of OPN and M2-TAMs co-existence in gastric cancer.
The levels of OPN and M2-TAMs were evaluated by immunohistochemical staining in 170 resected gastric cancer specimens that were collected from 1998 to 2012. M2-TAMs were identified by staining for an M2 marker, CD204. The prognostic significance and correlation between OPN and CD204 expression were analyzed. A co-culture system of OPN+-AGS and U937 cells was designed to study the effect of OPN on the skewing of macrophages toward M2-TAMs for gastric cancer progression in vitro and in vivo.
Patients with high expression (>50%) of OPN or CD204 exhibited poor 5-year overall survival rates (48.61%, p = 0.0055, and 52.14%, p = 0.0498, respectively). A positive correlation was observed between OPN and CD204 expression and high co-expression of OPN and CD204 demonstrated poor 5-year overall survival rates (48.90%, p = 0.0131). In the co-culture study, OPN was able to attract U937 cells and skew them toward M2-TAMs through paracrine action. The M2-TAMs could increase the invasiveness of OPN+-AGS cells and the growth rate of xenograft of a mixture of co-cultured OPN+-AGS and U937 cells.
OPN can skew macrophages toward M2-TAMs during gastric cancer progression. The co-existence of OPN and infiltrating M2-TAMs correlates with disease progression and poor survival and thus can serve as a prognostic marker in gastric cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The search of alternative approaches to epithelial cell adhesion molecule (EpCAM), for the isolation of circulating tumor cells (CTC), is on the rise. This work attempts at evaluating the feasibility ...of using a new glycosaminoglycan, SCH45, as a probe to isolate CTCs from the peripheral blood of 65 advanced/metastatic cholangiocarcinoma (CCA) patients. The positive enrichment of CTCs from 1 mL of blood using SCH45‐bound magnetic beads and subsequent staining on an integrated microfluidic platform is demonstrated. Results detailing CTC concentrations averaging ≥1 CTCs mL−1 of blood are shown, and a conventional protein biomarker, EpCAM, has been used to corroborate the finding that 100% of the patients possess CTCs in their blood. Studies detailing the use of CTCs in the prognostic monitoring and treatment effectiveness of advanced/metastatic CCA are scarce, and the isolation of CTCs from all CCA patients tested has not been reported yet. A strong correlation between CTC counts and disease progression at the time of and/or in advance of radiographic imaging in patients receiving chemotherapy is also reported. This study is one of its kind with the new probe and reduced sample volume and has potential for use in CCA diagnosis and prognosis in the near future.
Isolation of circulating tumor cells (CTCs) from 1 mL of cholangiocarcinoma (CCA) patient's blood in about 1 h is demonstrated. A novel glycosaminoglycan is used as a probe on a magnetic bead based integrated microfluidic platform. More than 1 CTCs mL−1 are isolated, EpCAM serves as the positive control. Results also demonstrate prognostic significance of CCA CTCs in five patients.
Epigenetic repression of the tumor suppressor gelsolin (GSN) is frequently observed in cancers. Chronic inflammation can promote tumor progression via aberrant DNA methylation. In this study, we ...investigated the role of tumor-associated macrophages (TAMs) in DNA methylation of the
gene during gastric cancer progression. Immunofluorescence staining of 121 gastric cancer tissues showed aberrant localization of GSN and DNA methyltransferase 1 (DNMT1) and juxtaposition of DNMT1 and M2 TAMs. Decreased GSN protein and mRNA expression and increased DNA methylation in the
promoter were observed in gastric cancer cell lines and clinical specimens. To examine the effect of TAMs on DNA methylation in gastric cancer cells, we performed
coculture assays and found increased DNMT1 expression but decreased GSN expression in gastric cancer cells after coculture with U937 cells. Knockdown of DNMT1 expression in gastric cancer cells could abort U937 coculture-mediated GSN downregulation. Meanwhile, CCL5 was the main chemokine upregulated in coculture medium. Treatment with CCL5 could induce DNMT1 expression in gastric cancer cells via STAT3 signaling. Inhibiting DNMT1 activity with procainamide, inhibiting DNA methylation with 5-AZA, or inhibiting CCL5/CCR5 signaling with maraviroc reduced tumor growth
In conclusion, upregulation of DNMT1 by CCL5/CCR5/STAT3 signaling is critical for TAM-mediated
silencing in gastric cancer. This study identified potential targets for gastric cancer therapy.
.
Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination (HR) deficient cancer cells and elicit anticancer effect through a mechanism of synthetic lethality. In ...this study, we designed, synthesized and pharmacologically evaluated a series of 1,2,4triazolo4,3-apyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds 17m, 19a, 19c, 19e, 19i and 19k not only displayed more potent inhibitory activities (IC
s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1
, IC
s < 1.9 nM) and Capan-1 (BRCA2
, IC
s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC
s < 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance.
Studies have indicated a significant rise in the incidence of pancreatic adenocarcinoma. However, the epidemiology of other rare histologic subtypes of pancreatic cancer is not well understood. This ...study analyzed the incidence and survival of pancreatic cancer in Taiwan by histologic subtype, sex, age group, and year of diagnosis. The incidence trends of pancreatic cancer in Taiwan from 2002 to 2013 were calculated using data from the Taiwan Cancer Registry. The survival of pancreatic cancer patients was assessed using the life‐table method and Cox proportional hazards analysis. The incidence of pancreatic cancer increased from 4.62 per 100,000 in 2002 to 6.04 per 100,000 in 2013 in Taiwan. The most common histologic subtype of pancreatic cancer was adenocarcinoma followed by carcinoma and neuroendocrine tumors (NETs). Adenocarcinoma and NETs showed a rapid increase in incidence, while the incidences of other subtypes did not change significantly. Patients with adenocarcinoma showed a poor survival with a 5‐year survival of 5.2%. Patients with endocrinomas, NETs, and lymphoma displayed a better survival than those with adenocarcinoma, with a 5‐year survival ranging from 41.8% to 59.1%. The survival of adenocarcinoma, lymphoma, and NETs improved after the introduction of novel therapies. Understanding the risk factors and identifying the biomarkers for the early diagnosis of pancreatic cancer are important to prevent the development and improve the survival of pancreatic cancer.
The incidence of pancreatic cancer is increasing with variable trend in different histologic subtypes. The survival of pancreatic cancer varied among different histologic subtypes.
Background & Aims
Gemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S‐1 (GS) had ...noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen.
Methods
The eligible patients with chemonaive, measurable ABTC received 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2/day of S‐1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m2 respectively). The primary endpoint was the 12‐week disease control rate (12‐week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/β = 0.05/0.2) assumption, Simon's optimal two‐stage design indicated 12‐week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks.
Results
Fifty‐one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease‐related symptoms (82.4%). On intention‐to‐treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression‐free and overall survival were 5.4 months (95% confidence interval CI: 3.5‐7.0), and 12.7 months (95% CI: 6.1‐15.6) respectively. The study met its primary endpoint with a 12‐week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment‐related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S‐1 and gemcitabine were 87.1% and 92.5% respectively.
Conclusions
Modified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment.
ClinicalTrials.gov number: NCT02425137.
BACKGROUND AND PURPOSE Sirtuin 6 (SIRT6) is involved in regulation of glucose and fat metabolism. However, its possible contribution to cardiac dysfunction remains to be determined. In the present ...study, the effect of SIRT6 on cardiac hypertrophy induced by angiotensin II (AngII) and the underlying molecular mechanisms were investigated.
EXPERIMENTAL APPROACH The expression and deacetylase activity of SIRT6 were measured in hypertrophic cardiomyocytes induced by AngII. After SIRT6 overexpression by transfection, or depletion by RNA interference in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Further, the interaction between SIRT6 and the transcription factor NF‐κB was investigated by co‐immunoprecipitation, confocal immunofluorescence microscopy and luciferase reporter gene assay. The expression and deacetylase activity of SIRT6 were measured in vivo, using the abdominal aortic constriction (AAC) model of cardiac hypertrophy in rats.
KEY RESULTS In AngII‐induced hypertrophic cardiomyocytes and also in AAC‐induced hypertrophic hearts, the expression of SIRT6 protein was upregulated, while its deacetylase activity was decreased. Overexpression of wild‐type SIRT6 but not its catalytically inactive mutant, attenuated AngII‐induced cardiomyocyte hypertrophy. We further demonstrated a physical interaction between SIRT6 and NF‐κB catalytic subunit p65, whose transcriptional activity could be repressed by SIRT6 overexpression.
CONCLUSIONS AND IMPLICATIONS Our findings suggest that SIRT6 suppressed cardiomyocyte hypertrophy in vitro via inhibition of NF‐κB‐dependent transcriptional activity and that this effect was dependent on its deacetylase activity.
PDF
![Identification of [1,2,4]Tr...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0223-5234/small "Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities")
