Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinuclear compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, blocks metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Altogether, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.
BACKGROUND Centralization of complex surgical care has led patients to travel longer distances. Emerging evidence suggested a negative association between increased travel distance and mortality after pancreatectomy. However, the reason for this association remains largely unknown. We sought to unravel the relationships among travel distance, receiving pancreatectomy at high-volume hospitals, delayed surgery, and operative outcomes. STUDY DESIGN We identified 44,476 patients who underwent pancreatectomy for neoplasms between 2004 and 2013 at the reporting facility from the National Cancer Database. Multivariable analyses were performed to examine the independent relationships between increments in travel distance mortality (30-day and long-term survival) after adjusting for patient demographics, comorbidity, cancer stage, and time trend. We then examined how additional adjustment of procedure volume affected this relationship overall and among rural patients. RESULTS Median travel distance to undergo pancreatectomy increased from 16.5 to 18.7 miles (p for trend < 0.001). Although longer travel distance was associated with delayed pancreatectomy, it was also related to higher odds of receiving pancreatectomy at a high-volume hospital and lower postoperative mortality. In multivariable analysis, difference in mortality among patients with varying travel distance was attenuated by adjustment for procedure volume. However, longest travel distance was still associated with a 77% lower 30-day mortality rate than shortest travel among rural patients, even when accounting for procedure volume. CONCLUSIONS Our large national study found that the beneficial effect of longer travel distance on mortality after pancreatectomy is mainly attributable to increase in procedure volume. However, it can have additional benefits on rural patients that are not explained by volume. Distance can represent a surrogate for rural populations.
Prostate cancer (PCa) frequently develops antiapoptotic mechanisms and acquires resistance to anticancer drugs. Therefore, identifying PCa drug resistance determinants should facilitate designing more effective chemotherapeutic regimens. Recently, we described that the PCPH protein becomes highly expressed in human prostatic intraepithelial neoplasia and in PCa, and that the functional interaction between PCPH and protein kinase CD (PKCD) increases the invasiveness of human PCa. Here, we report that the functional interaction between PCPH and a different PKC isoform, PKCA, confers resistance against cisplatin-induced apoptosis to PCa cells. This interaction elicits a mechanism ultimately resulting in the posttranslational stabilization and subsequent elevated expression of Bcl-2. Stable knockdown of either PCPH, mt-PCPH, or PKCA in PCa cells decreased Ser70-phosphorylated Bcl-2 and total Bcl-2 protein, thereby increasing their cisplatin sensitivity. Conversely, forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCA concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance. Consistently, Bcl-2 knockdown sensitized PCa cells to cisplatin treatment and, more importantly, reversed the cisplatin resistance of PCa cells expressing the mt-PCPH oncoprotein. Moreover, reexpression of Bcl-2 in PCPH/mt-PCPH knockdown PCa cells reversed the cisplatin sensitization caused by PCPH or mt-PCPH down-regulation. These findings identify PCPH and mt-PCPH as important participants in the chemotherapy response of PCa cells, establish a role for PCPH-PKCA-Bcl-2 functional interactions in the drug response process, and imply that targeting PCPH expression before, or simultaneously with, chemotherapy may improve the treatment outcome for PCa patients.
IntroductionHereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC.MethodsOne hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age).ResultsFrequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.ConclusionType and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.
Treatment of CGD-associated liver abscesses with corticosteroids was associated with fewer subsequent hepatic interventions and improved outcome compared to invasive treatments.
BackgroundDespite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer.MethodsImmunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models.ResultsCNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017).ConclusionCNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.
Despite its declining incidence, gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. A multimodal approach to GC is critical to ensure optimal patient outcomes. Pretherapy fine resolution contrast-enhanced cross-sectional imaging, endoscopic ultrasound and staging laparoscopy play an important role in patients with newly diagnosed ostensibly operable GC to avoid unnecessary non-therapeutic laparotomies. Currently, margin negative gastrectomy and adequate lymphadenectomy performed at high volume hospitals remain the backbone of GC treatment. Importantly, adequate GC surgery should be integrated in the setting of a multimodal treatment approach. Treatment for advanced GC continues to expand with the emergence of additional lines of systemic and targeted therapies.
A minority of CGD patients required thoracic surgery for infections refractory to antibiotic or antifungal therapy. Patients who had these operations had significant morbidity and relatively poor long-term survival, particularly in the cases of chest wall resection or significant blood loss.
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