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The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.

Background and Aim Tumor genotyping may allow for improved prognostication and targeted therapy for pancreatic ductal adenocarcinoma (PDAC). We aimed to compare endoscopic ultrasonography (EUS) with fine needle aspiration (FNA) to fine needle biopsy (FNB) for obtaining sufficient tissue for genomic analysis and theranostic potential. Methods A retrospective cohort study of patients that underwent EUS‐FNA or EUS‐FNB with either positive or suspicious cytology for PDAC between March 2016 and December 2017. Demographic, procedural, and cytology data were recorded. Genetic alterations were recorded, and Kaplan–Meier survival curves were calculated. Results The study included 167 patients: 145 patients had FNA and 22 patients underwent FNB. Overall, 117 samples (70.1%) were sufficient for targeted next‐generation sequencing. FNB resulted in a higher proportion of patients with sufficient samples compared with FNA (90.9% vs 66.9%; P = 0.02). In multivariable modeling, only FNB (odds ratio 4.95, 95% confidence interval 1.11–22.05, P = 0.04) was associated with sufficient sampling for genomic testing. FNB was more likely to obtain sufficient tissue from tumors ≤ 3 cm (100% vs 68.4%, P = 0.017) and tumors located in the head/neck of the pancreas (100% vs 63.1%, P = 0.03) compared with FNA. The most commonly identified alterations were in KRAS (88%), TP53 (68%), and SMAD4 (16%). Conclusions Endoscopic ultrasonography can reliably obtain sufficient tissue from PDAC for targeted genomic sequencing for prognostication and theranostics. FNB should be considered when tumor genotyping is requested, especially for tumors ≤ 3 cm or tumors located in the head/neck of the pancreas.

Energy efficiency has become a ubiquitous design requirement for digital circuits. Aggressive supply-voltage scaling has emerged as the most effective way to reduce energy use. In this work, we review circuit behavior at low voltages, specifically in the subthreshold (V dd , V th ) regime, and suggest new strategies for energy-efficient design. We begin with a study at the device level, and we show that extreme sensitivity to the supply and threshold voltages complicates subthreshold design. The effects of this sensitivity can be minimized through simple device modifications and new device geometries. At the circuit level, we review the energy characteristics of subthreshold logic and SRAM circuits, and demonstrate that energy efficiency relies on the balance between dynamic and leakage energies, with process variability playing a key role in both energy efficiency and robustness. We continue the study of energy-efficient design by broadening our scope to the architectural level. We discuss the energy benefits of techniques such as multiple-threshold CMOS (MTCMOS) and adaptive body biasing (ABB), and we also consider the performance benefits of multiprocessor design at ultralow supply voltages.

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