Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent ...PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
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•Neuropsychological stress accelerates PDAC development via ADRB2-signaling•ADRB2-signaling upregulates NGF and BDNF, thereby increasing nerve density•Blockade of the ADRB2 and NGF/Trk pathways prolongs survival in KPC mice•ADRB2 and NGF-BDNF/Trk pathways may be promising targets in PDAC treatment
Renz et al. show that catecholamines promote ADRB2-dependent pancreatic ductal adenocarcinoma development and secretion of neurotrophins (NT), which in turn promote tumor innervation leading to increased NE and tumor growth. Blockade of ADRB2 or NT receptors improves gemcitabine's therapeutic effect.
The novel coronavirus SARS-CoV-2 (coronavirus disease 19, or COVID-19) primarily causes pulmonary injury, but has been implicated to cause hepatic injury, both by serum markers and histologic ...evaluation. The histologic pattern of injury has not been completely described. Studies quantifying viral load in the liver are lacking. Here we report the clinical and histologic findings related to the liver in 40 patients who died of complications of COVID-19. A subset of liver tissue blocks were subjected to polymerase chain reaction (PCR) for viral ribonucleic acid (RNA). Peak levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated; median ALT peak 68 U/l (normal up to 46 U/l) and median AST peak 102 U/l (normal up to 37 U/l). Macrovesicular steatosis was the most common finding, involving 30 patients (75%). Mild lobular necroinflammation and portal inflammation were present in 20 cases each (50%). Vascular pathology, including sinusoidal microthrombi, was infrequent, seen in six cases (15%). PCR of liver tissue was positive in 11 of 20 patients tested (55%). In conclusion, we found patients dying of COVID-19 had biochemical evidence of hepatitis (of variable severity) and demonstrated histologic findings of macrovesicular steatosis and mild acute hepatitis (lobular necroinflammation) and mild portal inflammation. We also identified viral RNA in a sizeable subset of liver tissue samples.
In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of ...pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-
;
-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-
;LSL-
;
-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b
myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC.
Subdiaphragmatic vagotomy or
knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target.
.
Pancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has
attempts at expression-based molecular classification. The goal of this work is to profile ...purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples.
We used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts.
Our analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes.
Our findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.
Necroptosis is a programmed form of non-apoptotic cell death that requires the kinase activity of the receptor interacting protein kinase 3 (RIPK3). Although in vitro data suggests that cancer cells ...lacking expression of RIPK3 are invasive, the physiological role of RIPK3 in a disease-relevant setting remains unknown. Here we provide evidence that RIPK3 has a critical role in suppressing colorectal cancer (CRC). RIPK3-deficient mice were highly susceptible to colitis-associated CRC and exhibited greater production of pro-inflammatory mediators and tumor promoting factors. Tumorigenesis in RIPK3-deficiency resulted from uncontrolled activation of NF-κB, STAT3, AKT and Wnt-β-catenin signaling pathways that enhanced the ability of intestinal epithelial cells (IECs) to aberrantly proliferate in the face of the sustained inflammatory microenvironment and promote CRC. We found that RIPK3 expression is reduced in tumors from patients with inflammatory bowel diseases, and further confirmed that expression of RIPK3 is downregulated in human CRC and correlated with cancer progression. Thus, our results reveal that the necroptosis adaptor RIPK3 has key anti-inflammatory and anti-tumoral functions in the intestine, and define RIPK3 as a novel colon tumor suppressor.
Adrenal Vascular Changes in COVID-19 Autopsies Iuga, Alina C; Marboe, Charles C; M Yilmaz, Mine ...
Archives of pathology & laboratory medicine,
10/2020, Letnik:
144, Številka:
10
Journal Article
Recenzirano
Odprti dostop
While SARS-CoV-2 infection seems to more severely affect patients with a history of hypertension,2 most critically ill patients with COVID-19 need vasopressors for persistent hypotension.3 Two of 3 ...hospitalized patients described had recorded high blood pressure values and 1 was hypotensive on arrival. Localized fibrinoid necrosis is also mentioned in a report of pathological findings in SARS virus infection.4 SARS-CoV-2 virus gains entry to the cell via the angiotensin-converting enzyme 2 receptor,5 which is most abundant in lung alveolar cells, but also present in endothelia and other tissues, providing a possible mechanism for vascular injury.6 Adrenal hormones are involved in modulating inflammatory responses7 and adrenal gland dysfunction has been described in patients with community-acquired pneumonia.8 In general, adrenal function is not routinely assessed in an intensive care unit setting. According to several critical care societies, acute respiratory distress syndrome management can include corticosteroids, as they may decrease the time on a ventilator and reduce mortality.9 Corticosteroids are also administered if there is suspicion of adrenal insufficiency or if they are indicated because of an underlying condition.
: Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage ...the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes.
: In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections.
: HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %).
: In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed.
Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an ...array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn’s disease (CD), ulcerative colitis (UC), and celiac disease.
DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells.
Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases.
In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.
To assess the prevalence and severity of nonalcoholic liver disease (NAFLD) in children in a diverse population sample in New York City.
Liver specimens were examined from children 2-19 years old who ...died of unexpected causes within 48 hours of medical presentation and underwent autopsy in New York City from 2005 to 2010. Records were reviewed for age, sex, weight, height, and race. Two hepatopathologists evaluated each liver specimen to determine pathologic diagnosis.
The final study cohort (n = 582) was 50% black, 33% Hispanic, 12% white, 3% Asian, and 2% other; 36% had a body mass index >85%. There were 26 cases of NAFLD (4.5%) of which 10 had nonalcoholic steatohepatitis (1.7%). There were no cases with severe fibrosis or cirrhosis. One percent (3/290) of black children had NAFLD and none had nonalcoholic steatohepatitis. White and Hispanic children had the highest percentages of NAFLD at 8.3% and 7.9%, respectively. In multiple logistic regression models, we observed that body mass index z-score (P < .001) was associated with NAFLD, and that white (P = .003) and Hispanic (P = .005) children had higher odds of having NAFLD compared with black children.
This review of liver tissue demonstrates a lower prevalence and severity of NAFLD in black children compared with the general obese pediatric population. Hispanic children did not have a significantly increased rate of NAFLD compared with white children, most likely related to the large proportion of Caribbean Hispanic children in New York City.
Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received ...neoadjuvant therapy and pancreaticoduodenectomy is not clear. In this study, we performed a detailed examination of neural invasion in pancreaticoduodenectomy specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and in 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in the untreated group (80%, 48/60) than in the treated group (58%, 123/212). For the 123 treated cases that were positive for PNI, extratumoral PNI, intratumoral PNI, intrapancreatic PNI only, extrapancreatic PNI, and intraneural invasion were identified in 86 (69.9%), 37 (30.1%), 11 (8.9%), 112 (91.1%), and 35 cases (28.5%), respectively. The presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor, and American Joint Committee on Cancer stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared with tumors with PNI involving nerves ≤0.8 mm but not with other clinicopathologic parameters and survival. In the treated group, the presence of PNI or intraneural invasion correlated significantly with shorter disease-free survival and overall survival compared with no PNI or PNI only, respectively. PNI was an independent prognostic factor for both disease-free survival and overall survival in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.
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