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Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC. [ABSTRACT FROM AUTHOR]

Summary: Background: The dural puncture epidural technique is a modification of the combined spinal‐epidural technique. Data comparing the two techniques are limited. We performed this randomised study to compare the quality of labour analgesia following initiation of analgesia with the dural puncture epidural vs. the combined spinal‐epidural technique. Methods: Term parturients requesting labour epidural analgesia were allocated randomly to receive either dural puncture epidural or combined spinal‐epidural. Analgesia was initiated with 2 mg intrathecal bupivacaine and 10 μg fentanyl in parturients allocated to the combined spinal‐epidural group and with 20 ml ropivacaine 0.1% with 2 μg.ml‐1 fentanyl in parturients allocated to the dural puncture epidural group. Analgesia was maintained using patient‐controlled epidural analgesia with programmed intermittent epidural boluses. The primary outcome of the study was the quality of labour analgesia, which was defined by a composite of five components: asymmetric block after 30 min of initiation (difference in sensory level of more than two dermatomes); epidural top‐up interventions; catheter adjustment; catheter replacement; and failed conversion to neuraxial anaesthesia for caesarean delivery, requiring general anaesthesia or replacement of the neuraxial block. Results: One hundred parturients were included in the analysis (48 combined spinal‐epidural, 52 dural puncture epidural). There were no significant differences between the two groups in the primary composite outcome of quality of analgesia (33% in the combined spinal‐epidural group vs. 25% in the dural puncture epidural group), risk ratio (95%CI) 0.75 (0.40–1.39); p = 0.486. Median (IQR [range]) pain scores at 15 min were significantly lower in patients allocated to the combined spinal‐epidural group compared with the dural puncture epidural group (0 (0–1[0–8]) vs. 1 (0–4 [0–10]); p = 0.018). Conclusions: There were no significant differences in the quality of labour analgesia following initiation of a combined spinal‐epidural compared with a dural puncture epidural technique. [ABSTRACT FROM AUTHOR]

Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to Gαq-type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca2+ reporter demonstrated that the majority of the Ca2+ loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels (Trpc3KO compared with wildtype (WT)). This Ca2+ dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP-Trpc3KO reporter brain slice model). Contribution of the Gαq-coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3KO, and Trpc1/3/6/7 quadruple knockout (TrpcQKO), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3KO and TrpcQKO models, with the TrpcQKO showing greatest neuroprotection. These findings demonstrate the contribution of the Gαq-coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3 -high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC. [ABSTRACT FROM AUTHOR]

Text [(*)41] I. INTRODUCTION In 1977, the United States began the International Prisoner Transfer Program ("the Program"), also known as the Prisoner Transfer Treaties, which allows United States citizens imprisoned [...]