Features of synchronous and metachronous dual primary gastric and colorectal cancer.

BACKGROUND: Studies evaluating the characteristics of dual primary gastric and colorectal cancer (CRC) (DPGCC) are limited. AIM: To analyze the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with DPGCC. METHODS: From October 2010 to August 2021, patients with DPGCC were retrospectively reviewed. The patients with DPGCC were divided into two groups (synchronous and metachronous). We compared the overall survival (OS) between the groups using Kaplan-Meier survival methods. Univariate and multivariate analyses were performed using Cox's proportional hazards model to identify the independent prognostic factors for OS. RESULTS: Of the 76 patients with DPGCC, 46 and 30 had synchronous and metachronous cancers, respectively. The proportion of unresectable CRC in patients with synchronous cancers was higher than that in patients with metachronous cancers (28.3% vs 3.3%, P = 0.015). The majority of the second primary cancers had occurred within 5 years. Kaplan-Meier survival analysis showed that the patients with metachronous cancers had a better prognosis than patients with synchronous cancers (P = 0.010). The patients who had undergone gastrectomy (P < 0.001) or CRC resection (P < 0.001) had a better prognosis than those who had not. In the multivariate analysis, synchronous cancer [hazard ratio (HR) = 6.8, 95% confidence interval (95%CI): 2.0-22.7, P = 0.002)] and stage III-IV gastric cancer (GC) [HR = 10.0, 95%CI: 3.4-29.5, P < 0.001)] were risk prognostic factor for OS, while patients who underwent gastrectomy was a protective prognostic factor for OS [HR = 0.2, 95%CI: 0.1-0.6, P = 0.002]. CONCLUSION: Regular surveillance for metachronous cancer is necessary during postoperative follow-up. Surgical resection is the mainstay of therapy to improve the prognosis of DPGCC. The prognosis appears to be influenced by the stage of GC rather than the stage of CRC. Patients with synchronous cancer have a worse prognosis, and its treatment strategy is worth further exploration.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Cost and Outcome in Pediatric Ischemic Stroke.

The cost of childhood stroke receives little notice. The authors examined potential drivers of cost and outcome to test whether (1) neonatal strokes cost less than childhood strokes, (2) associated diseases influence cost, (3) arterial ischemic stroke is more costly than sinovenous thrombosis, and (4) cost correlates with outcome. The authors reviewed records of 111 children who sustained arterial ischemic stroke or sinovenous thrombosis between 2005 and 2010 to identify costs for the following year. They assessed outcomes in 46 with the Recovery and Recurrence Questionnaire and the Pediatric Quality of Life Inventory. Neonatal strokes cost less than childhood stroke. Strokes associated with congenital heart disease or vasculopathy cost the most, while perinatal or idiopathic strokes cost the least. Higher costs are correlated with worse impairment and poorer quality of life. Stroke etiology significantly influences the cost of pediatric stroke. Future cost-benefit studies must consider etiology when estimating the incremental costs associated with stroke.

CS5931, a novel polypeptide in Ciona savignyi, represses angiogenesis via inhibiting vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs).

CS5931 is a novel polypeptide from Ciona savignyi with anticancer activities. Previous study in our laboratory has shown that CS5931 can induce cell death via mitochondrial apoptotic pathway. In the present study, we found that the polypeptide could inhibit angiogenesis both in vitro and in vivo. CS5931 inhibited the proliferation, migration and formation of capillary-like structures of HUVECs (Human Umbilical Vein Endothelial Cell) in a dose-dependent manner. Additionally, CS5931 repressed spontaneous angiogenesis of the zebrafish vessels. Further studies showed that CS5931 also blocked vascular endothelial growth factor (VEGF) production but without any effect on its mRNA expression. Moreover, CS5931 reduced the expression of matrix metalloproteinases (MMP-2 and MMP-9) both on protein and mRNA levels in HUVEC cells. We demonstrated that CS5931 possessed strong anti-angiogenic activity both in vitro and in vivo, possible via VEGF and MMPs. This study indicates that CS5931 has the potential to be developed as a novel therapeutic agent as an inhibitor of angiogenesis for the treatment of cancer.

Cloning, characterization and expression of a cDNA encoding a granulin-like polypeptide in Ciona savignyi.

Previous study in our laboratory confirmed that a novel polypeptide, CS5931 derived from Ciona savignyi possesses potent antitumor activity. In the present study, the full length cDNA of CS5931 precursor, termed Cs-pgrn-1 was cloned. The complete cDNA sequence of this gene consists of 685 bp containing an open reading frame (ORF) of 522 bp (173 amino acid residues). In silico analysis revealed that the polypeptide consists of two identical domains, similar with granulin (GRN) found in other species, and each of the domain encodes a polypeptide identical with CS5931. Phylogenetic analysis confirmed that CS5931 shares high homology with Ciona intestinalis GRN and is conserved during evolution. The polypeptide also shows high similarity with human GRN A, B, and C. Prediction of 3D protein structure revealed the 3D structure of CS5931 is very similar with human GRN A. The CS5931 was expressed using a prokaryotic expression system and the purified polypeptide inhibited the growth of several tumor cell lines in vitro via apoptotic pathway. Our study revealed that CS5931 has the potential to be developed as a novel antitumor agent.

[Detection of changes in cerebral blood flow and cerebrovascular autoregulation by near-infrared spectroscopy in newborn piglets].

OBJECTIVE: A large body of experimental and clinical observations indicates that disturbances in cerebral blood flow (CBF) and impaired cerebrovascular autoregulation are important in the pathogenesis of germinal matrix-intraventricular hemorrhage (GMH-IVH) and periventricular leukomalacia (PVL), the 2 most important forms of brain injury in pretmature infants. Near-infrared spectroscopy (NIRS) has been used recently to estimate CBF in human newborns. The objectives of this study were to evaluate the correlation of NIRS estimations and cerebral blood flow in newborn piglets, which in turn may help provide the ideal NIRS estimation reflecting the changes of cerebral blood flow and cerebrovascular autoregulation. METHODS: Ten newborn piglets, aged 1 - 3 days, were randomly assigned to one of the following groups: normal control group (n = 6) and hypotension group (n = 4). Hypotension was induced by withdrawing blood from an arterial catheter. We NIRS was used to determine quantitative changes in cerebral concentrations of oxygenated hemoglobin (DeltaHbO(2)) and deoxygenated hemoglobin (DeltaHHb), then calculated NIRS estimations DeltatHb (DeltaHbO(2)+DeltaHHb) and DeltaHbD (DeltaHbO(2)-DeltaHHb). Cerebral blood flow (CBF) was determined by colored microspheres, and mean artery blood pressure (MABP) measured by arterial catheter pressure transducer was recorded simultaneously. Linear regression methods were used to analyze the relationships between NIRS estimations, CBF measured by micropheres, and MABP. RESULTS: The correlation of NIRS estimations and CBF was quantitated by calculating coherence scores. A coherence of 1.0 indicates perfect correlation, a coherence of 0 indicates a complete lack of correlation. In the norm group, the experimental study showed strong correlations beween DeltaHbD, DeltatHb and changes in global CBF (GCBF), cerebral cortex CBF (CBFc), coherence scores r(1a) = 0.409, r(1b) = 0.440, r(2a) = 0.394 and r(2b) = 0.400, respectively, P < 0.05. In the hypotension group, the decrease of CBF was significant when the MABP dropped to 35 mm Hg (P < 0.05). With the decreasing MABP, there was a notable increase of DeltaHHb (P < 0.01), a modest increase (P < 0.05) at the beginning and then a marked fall (P < 0.01) of DeltaHbO(2) and DeltatHb was noted when the MABP dropped to 35 mm Hg. DeltaHbD decreased in parallel with the decline in CBF determined by colored microspheres, DeltaHbD varied with CBF during hypotensive episodes. Notably, there was a very strong correlations between DeltaHbD and changes in CBF (coherence scores GCBF r(3a) = 0.890, CBFc r(3b) = 0.887, P < 0.01); Importantly, decreases in DeltatHb did not correlate significantly with decreases in CBF during hypotension (coherence scores GCBF r(4a) = 0.395, CBFc r(4b) = 0.375, P > 0.05). Concordant changes (correlation coefficient > 0.5) in DeltaHbD, CBF and MABP, consistent with impaired cerebrovascular autoregulation, were observed in newborn piglets when MABP was less than 35 mm Hg. When MABP was more than 35 mm Hg, newborn piglets with intact cerebrovascular autoregulation in which CBF are maintained constant despite alternations in MABP have shown inconsistent changes in DeltaHbD, CBF and MABP (correlation coefficient < 0.5). CONCLUSION: DeltaHbD signal is more sensitive to changes in CBF than DeltatHb signal, in terms of cerebral hemodynamic changes both in normal and hypotensive conditions, while DeltatHb in normal condition. The lower limit of CBF autoregulation in newborn piglets aged 1 - 3 days was 35 mm Hg, and correlation between NIRS estimation (DeltaHbD) and MABP could be used to identify cerebrovascular autoregulation in newborn piglets.