Diaphragmatic plication among lung transplant patients: A single-center experience.

BACKGROUND: There is lack of data reporting outcomes among patients needing diaphragmatic plication (DP) during or after lung transplantation (LT). We sought to assess the association of DP with post-transplant spirometry among other outcomes. METHODS: We included all patients who underwent LT between 2012 and 2016 (n = 324, mean age 56.3±13.4 years; M:F 198:126). We compared early and late outcomes based on the need for DP. RESULTS: The frequency of diaphragmatic dysfunction (DD) on pre-transplant fluoroscopy was 52.2%. A total of 38 DP procedures were performed among 37 patients (11.4% of LT patients). DP was done for anatomic (sizing or spacing issues) or functional indications (symptomatic DD). While patients with DP had significantly lower spirometry throughout the 3-year follow-up period, their slope of decline, functional assessments at the first annual visit, the risk of CLAD, and mortality were similar to patients without DP. A sub-group analysis limited to patients with restrictive lung diseases as the transplant indication had similar findings. CONCLUSIONS: Pre-transplant DD is common among LT candidates although it did not predict the need for DP. DP may be performed for functional or anatomic indications especially for addressing the donor-recipient size mismatch. Despite the lack of favorable effect on post-transplant spirometry, patients undergoing DP have acceptable and comparable early and late outcomes.

ATS Core Curriculum 2020. Adult Critical Care Medicine.

The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3- to 4-year recurring cycle of topics. These topics will be presented at the 2020 International Conference. Below is the adult critical care medicine core including complications of chemotherapy, acute-on-chronic liver failure, alcohol withdrawal syndrome, mechanical circulatory support, direct oral anticoagulants, upper gastrointestinal hemorrhage, and vasopressor selection.

Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein.

Overexpression of ribonucleotide reductase subunit M2 (RRM2), involved in deoxyribonucleotide synthesis, drives the chemoresistance of pancreatic cancer to nucleoside analogs (e.g., gemcitabine). While silencing RRM2 by synthetic means has shown promise in reducing chemoresistance, targeting endogenous molecules, especially microRNAs (miRNAs), to advance chemotherapeutic outcomes has been poorly explored. Based on computational predictions, we hypothesized that the let-7 tumor suppressor miRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in innately gemcitabine-resistant pancreatic cancer cell lines. Direct binding of let-7 miRNAs to the 3' UTR of RRM2 transcripts identified post-transcriptional regulation of RRM2 influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and chemosensitivity responses in a poorly differentiated pancreatic cancer cell line, MIA PaCa-2. Defective processing of let-7a precursors to mature forms, in part, explained the discrepancies observed with let-7a expressional outcomes. Consistently, the ratios of mature to precursor let-7a were progressively reduced in gemcitabine-sensitive L3.6pl and Capan-1 cell lines induced to acquire gemcitabine resistance. Besides known regulators of let-7 biogenesis (e.g., LIN-28), short hairpin RNA library screening identified several novel RNA binding proteins, including the SET oncoprotein, to differentially impact let-7 biogenesis and chemosensitivity in gemcitabine-sensitive versus -resistant pancreatic cancer cells. Further, LIN-28 and SET knockdown in the cells led to profound reductions in cellular proliferation and colony-formation capacities. Finally, defective processing of let-7a precursors with a positive correlation to RRM2 overexpression was identified in patient-derived pancreatic ductal adenocarcinoma (PDAC) tissues. These data demonstrate an intricate post-transcriptional regulation of RRM2 and chemosensitivity by let-7a and that the manipulation of regulatory proteins involved in let-7a transcription/processing may provide a mechanism for improving chemotherapeutic and/or tumor growth control responses in pancreatic cancer.

CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells.

Overcoming the inherent chemoresistance of pancreatic cancers remains a major goal of therapeutic investigations in this disease. In this study, we discovered a role for the human concentrative nucleoside transporter-1 (hCNT1; SLC28A1), a high-affinity pyrimidine nucleoside transporter, in determining the chemosensitivity of human pancreatic cancer cells to gemcitabine, the drug used presently as a standard of care. Compared with normal pancreas and pancreatic ductal epithelial cells, hCNT1 expression was frequently reduced in pancreatic tumors and tumor cell lines. In addition, hCNT1-mediated (3)H-gemcitabine transport was lower in pancreatic cancer cell lines and correlated with cytotoxic IC(50) estimations of gemcitabine. In contrast to gemcitabine-sensitive pancreatic cancer cell lines, MIA PaCa-2, a gemcitabine-resistant pancreatic cancer cell line, exhibited relatively restrictive, cell cycle-dependent hCNT1 expression and transport. hCNT1 translation was suppressed in the late G1-enriched MIA PaCa-2 cell population possibly in an miRNA-dependent manner, which corresponded with the lowest hCNT1-mediated gemcitabine transport during this phase. Although hCNT1 protein was induced during G1/S transition, increased hCNT1 trafficking resulted in maximal cell surface recruitment and transport-overshoot in the G2/M phase-enriched cell population. hCNT1 protein was directed predominantly to proteasomal or lysosomal degradation in S or G2/M phase MIA PaCa-2 cells, respectively. Pharmacological inhibition of hCNT1 degradation moderately increased cell surface hCNT1 expression and cellular gemcitabine transport in MIA PaCa-2 cells. Constitutive hCNT1 expression reduced clonogenic survival of MIA PaCa-2 cells and steeply augmented gemcitabine transport and chemosensitization. In addition to supporting a putative tumor suppressor role for hCNT1, our findings identify hCNT1 as a potential candidate to render drug-resistant pancreatic cancer cells amenable to chemotherapy.