Pancreatic acinar cell carcinoma: A review on molecular profiling of patient tumors

Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.

Adenosquamous carcinoma of the pancreas: Molecular characterization of 23 patients along with a literature review

Adenosquamous carcinoma of the pancreas(ASCP)is a rare entity. Like adenocarcinoma of the pancreas,overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalcemia. Various theories exist as to why this histological subtype exists, as normal pancreas tissue has no benign squamous epithelium. Due to the rarity of this disease, limited molecular analysis has been performed, and those reports indicate unique molecular features of ASCP. In this paper, we characterize 23 patients diagnosed with ASCP through molecular profiling using immunohistochemistry staining, fluorescent in situ hybridization, chromogenic in situ hybridization, and gene sequencing, Additionally, we provide a comprehensive literature review of what is known to date of ASCP.Molecular characterization revealed overexpression in MRP1(80%), MGMT(79%), TOP2A(75), RRM1(42%),TOPO1(42%), PTEN(45%), CMET(40%), and C-KIT(10%) among others. One hundred percent of samples tested were positive for KRAS mutations. This analysis shows heretofore unsuspected leads to be considered for treatments of this rare type of exocrine pancreas cancer. Molecular profiling may be appropriate to provide maximum information regarding the patient's tumor. Further work should be pursued to better characterize this disease.

Micro RNAs in the development of non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known aboutthe underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs(mi RNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target m RNAs. Several mi RNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of mi RNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including mi RNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of mi RNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of mi RNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.

Circulating levels of hydroxylated bradykinin function as an indicator of tissue HIF-1a expression

The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.

Imputation of single-cell gene expression with an autoencoder neural network

Background:Single-cell RNA-sequencing(scRNA-seq)is a rapidly evolving technology that enables measurement of gene expression levels at an unprecedented resolution.Despite the explosive growth in the number of cells that can be assayed by a single experiment,scRNA-seq still has several limitations,including high rates of dropouts,which result in a large number of genes having zero read count in the scRNA-seq data,and complicate downstream analyses.Methods:To overcome this problem,we treat zeros as missing values and develop nonparametric deep learning methods for imputation.Specifically,our LATE(Learning with AuToEncoder)method trains an autoencoder with random initial values of the parameters,whereas our TRANSLATE(TRANSfer learning with LATE)method further allows for the use of a reference gene expression data set to provide LATE with an initial set of parameter estimates.Results:On both simulated and real data,LATE and TRANSLATE outperform existing scRNA-seq imputation methods,achieving lower mean squared error in most cases,recovering nonlinear gene-gene relationships,and better separating cell types.They are also highly scalable and can efficiently process over 1 million cells in just a few hours on a GPU.Conclusions:We demonstrate that our nonparametric approach to imputation based on autoencoders is powerful and highly efficient.