Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell-mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients' blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.

Background Selected patients with advanced non-small cell lung cancer (NSCLC) benefit from immunotherapy, especially immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1) inhibitor. Peripheral blood biomarkers would be most convenient to predict treatment outcome and immune-related adverse events (irAEs) in candidate patients. This study explored associations between inflammation-related peripheral blood markers and onset of irAEs and outcome in patients with advanced NSCLC receiving PD-1 inhibitors. Methods A retrospective analysis was conducted of 102 patients with advanced NSCLC receiving PD-1 inhibitors from January 2017 to May 2019. Cox regression models were employed to assess the prognostic effect of low/high neutrophil/ lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and prognostic nutrition index (PNI) on overall survival (OS) and progression-free survival (PFS). Logistic regression models were used to analyze the correlation between peripheral blood markers and the onset of irAEs. Result NLR < 5, LDH < 240 U/L, or PNI ≥ 45 was favorably associated with significantly better outcomes compared with higher, higher, or lower values, respectively. The multivariate analysis determined that these parameters were independently associated with both better PFS (p = 0.049, 0.046, 0.014, respectively) and longer OS (p = 0.007, 0.031, < 0.001, respectively). Patients with three favorable factors among NLR, LDH, and PNI had better PFS and OS than did those with two, one, or none. PNI and NLR were associated with the onset of irAEs. Conclusion In patients with advanced NSCLC treated with PD-1 inhibitors, pretreatment NLR, LDH, and PNI may be useful predictive markers of clinical outcome and irAEs.

The directional transport of the phytohormone auxin depends on the phosphorylation status and polar localization of PIN-FORMED (PIN) auxin efflux proteins. While PINIOD (PID) kinase is directly involved in the phosphorylation of PIN proteins, the phosphatase holoenzyme complexes that dephosphorylate PIN proteins remain elusive. Here, we demonstrate that mutations simultaneously disrupting the function of Arabidopsis thaliana FyPP1 (for Phytochrome-associated serine/threonine protein phosphatase1) and FyPP3, two homologous genes encoding the catalytic subunits of protein phosphatase6 (PP6), cause elevated accumulation of phosphorylated PIN proteins, correlating with a basal-to-apical shift in subcellular PIN localization. The changes in PIN polarity result in increased root basipetal auxin transport and severe defects, including shorter roots, fewer lateral roots, defective columella cells, root meristem collapse, abnormal cotyledons (small, cup-shaped, or fused cotyledons), and altered leaf venation. Our molecular, biochemical, and genetic data support the notion that FyPP1/3, SAL (for SAPS DOMAIN-LIKE), and PP2AA proteins (RCN1 [for ROOTS CURL IN NAPHTHYLPHTHALAMIC ACID1] or PP2AA1, PP2AA2, and PP2AA3) physically interact to form a novel PP6-type heterotrimeric holoenzyme complex. We also show that FyPP1/3, SAL, and PP2AA interact with a subset of PIN proteins and that for SAL the strength of the interaction depends on the PIN phosphorylation status. Thus, an Arabidopsis PP6-type phosphatase holoenzyme acts antagonistically with PID to direct auxin transport polarity and plant development by directly regulating PIN phosphorylation. INTRODUCTIONAuxin is a fundamental plant hormone that regulates almost every aspect of plant growth and development, including embryogenesis, organogenesis, apical dominance, tissue regeneration, and tropisms (reviewed in Bennett and Scheres, 2010;Grunewald and Friml, 2010;Peris et al., 2010). Auxin is transported from its sites of biosynthesis to its sites of action by a polarized auxin transport system. Molecular genetic studies in Arabidopsis thaliana have lead to the identification and functional characterization of several key players of the polarized auxin transport system, such as the auxin uptake carriers AUXIN RESISTANT1/LIKE AUX1 (AUX1/ LAX) (Swarup et al., 2008), the auxin efflux carriers, including PIN-FORMED (PIN) family proteins Chen et al., 1998;Müller et al., 1998;Friml et al., 2002;Petrásek et al., 2006), and P-glycoprotein auxin transporters ABCB1 (for ATP BINDING CASSETTE PROTEIN SUBFAMILY B1), ABCB4, and ABCB19 (Terasaka et al., 2005;Bouchard et al., 2006;Blakeslee et al., 2007;Lin and Wang, 2005). PIN proteins are asymmetrically targeted to the plant cell plasma membranes, resulting in distinct polar subcellular localization in a given tissue. For example, PIN1 is localized in the basal (rootward, lower) plasma membrane of stele cells and xylem cells in the vascular system, which is required for long-distance auxin flow from the shoot apex to the root tip Friml e...

ObjectiveTo define potential factors that could predict concomitant neoplastic diseases in patients diagnosed with PM/DM, which could inform screening decisions.MethodsTwo researchers independently reviewed articles from Pubmed (MEDLINE), EMBASE, Cochrane Plus Library and ISI Web of Knowledge with no restrictions on study design or language. Given that some of the studies combined PM and DM patients as research subjects while others included only DM patients, data were subjected to meta-analyses for all combined PM/DM studies and studies that included only DM patients to obtain informative results.ResultsFor PM/DM patients, the following factors are all associated with an increased risk of malignancy: older age, age greater than 45, male sex, dysphagia, cutaneous necrosis, cutaneous vasculitis, rapid onset of myostis (<4 weeks), elevated CK, higher ESR, higher CRP levels. Several factors were associated with lower-than-average risk, including the presence of ILD, arthritis/arthralgia, Raynaud's syndrome, or anti-Jo-1 antibody. For DM patients, results indicated an increased risk of malignancy with older age, male sex, the presence of cutaneous necrosis, elevated ESR (>35 mm/hr), higher CRP levels, or anti-p155 antibody. In addition, the presence of anti-ENA antibodies seem to be related to reduced risk of malignancy.ConclusionAwareness and implementation of early-stage cancer screening in PM/DM patients who have these identified factors – such as being older than 45, male sex, cutaneous necrosis, cutaneous vasculitis – are of crucial importance from public health and clinical perspectives and provide insight into the etiopathogenesis of CAM.

Background: The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs). Methods: The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs. Results: We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs. Conclusion: Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.