Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features.

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.

A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development.

The decision of stem cells to proliferate and differentiate is finely controlled. The Caenorhabditis elegans germline provides a tractable system for studying the mechanisms that control stem cell proliferation and homeostasis [1-4]. Autophagy is a conserved cellular recycling process crucial for cellular homeostasis in many different contexts [5], but its function in germline stem cell proliferation remains poorly understood. Here, we describe a function for autophagy in germline stem cell proliferation. We found that autophagy genes such as bec-1/BECN1/Beclin1, atg-16.2/ATG16L, atg-18/WIPI1/2, and atg-7/ATG7 are required for the late larval expansion of germline stem cell progenitors in the C. elegans gonad. We further show that BEC-1/BECN1/Beclin1 acts independently of the GLP-1/Notch or DAF-7/TGF-ß pathways but together with the DAF-2/insulin IGF-1 receptor (IIR) signaling pathway to promote germline stem cell proliferation. Similar to DAF-2/IIR, BEC-1/BECN1/Beclin1, ATG-18/WIPI1/2, and ATG-16.2/ATG16L all promote cell-cycle progression and are negatively regulated by the phosphatase and tensin homolog DAF-18/PTEN. However, whereas BEC-1/BECN1/Beclin1 acts through the transcriptional regulator SKN-1/Nrf1, ATG-18/WIPI1/2 and ATG-16.2/ATG16L exert their function through the DAF-16/FOXO transcription factor. In contrast, ATG-7 functions in concert with the DAF-7/TGF-ß pathway to promote germline proliferation and is not required for cell-cycle progression. Finally, we report that BEC-1/BECN1/Beclin1 functions non-cell-autonomously to facilitate cell-cycle progression and stem cell proliferation. Our findings demonstrate a novel non-autonomous role for BEC-1/BECN1/Beclin1 in the control of stem cell proliferation and cell-cycle progression, which may have implications for the understanding and development of therapies against malignant cell growth in the future.

Proteomic response of ß-lactamases-producing Enterobacter cloacae complex strain to cefotaxime-induced stress.

Bacteria of the Enterobacter cloacae complex are among the ten most common pathogens causing nosocomial infections in the USA. Consequently, increased resistance to ß-lactam antibiotics, particularly expanded-spectrum cephalosporins like cefotaxime (CTX), poses a serious threat. Differential In-Gel Electrophoresis (DIGE), followed by LC-MS/MS analysis and bioinformatics tools, was employed to investigate the survival mechanisms of a multidrug-resistant E. hormaechei subsp. steigerwaltii 51 carrying several ß-lactamase-encoding genes, including the 'pandemic' blaCTX-M-15 After exposing the strain with sub-minimal inhibitory concentration (MIC) of CTX, a total of 1072 spots from the whole-cell proteome were detected, out of which 35 were differentially expressed (P ≤ 0.05, fold change ≥1.5). Almost 50% of these proteins were involved in cell metabolism and energy production, and then cell wall organization/virulence, stress response and transport. This is the first study investigating the whole-cell proteomic response related to the survival of ß-lactamases-producing strain, belonging to the E. cloacae complex when exposed to ß-lactam antibiotic. Our data support the theory of a multifactorial synergistic effect of diverse proteomic changes occurring in bacterial cells during antibiotic exposure, depicting the complexity of ß-lactam resistance and giving us an insight in the key pathways mediating the antibiotic resistance in this emerging opportunistic pathogen.