Novel synthetic routes to thienocarbazoles via palladium or copper catalyzed amination or amidation of arylhalides and intramolecular cyclization

Palladium or copper catalyzed aminations or amidations were performed to obtain diarylamines and diarylacetamides precursors of thienocarbazoles. The fact that an ortho-bromodiarylamine didn’t cyclize to the corresponding thienocarbazole under conditions known for carbazoles from ortho-halodiphenylamines, conducted us to a highgly efficient method of palladium-catalyzed intramolecular cyclisation with N-deprotection of ortho-halodiarylacetamides to thienocarbazoles. Other method of intramolecular cyclization of diarylamines based on the reoxidation of the Pd(0) formed by Cu(OAc)2 , avoiding the use of stoichiometric amounts of Pd(OAc)2, gave thienocarbazoles in a moderate yield, including a ring A methoxylated compound. An attempt to combine palladium and copper catalyses in a “one pot” reaction of amination and intramolecular cyclization gave as major product a N-benzo[b]thiophene substituted carbazole and the required thienocarbazole in low yield.Fundação para a Ciência e Tecnologia. Fundação Calouste Gulbenkian - Research Incitment Programme. Escola Superior Agrária - Instituto Politécnico de Bragança

Photochemistry and photophysics of thienocarbazoles

Two methylated thienocarbazoles and two of their synthetic nitro-precursors have been examined by absorption, luminescence, laser flash photolysis and photoacoustic techniques. Their spectroscopic and photophysical characterization involves fluorescence spectra, fluorescence quantum yields and lifetimes, and phosphorescence spectra and phosphorescence lifetimes for all the compounds. Triplet-singlet difference absorption spectra, triplet molar absorption coefficients, triplet lifetimes, intersystem crossing S-1 similar tosimilar to--> T-1 and singlet molecular oxygen yields were obtained for the thienocarbazoles. In the case of the thienocarbazoles it was found that the lowest-lying singlet and triplet excited states, S, and T-1, are of pi,pi* origin, whereas for their precursors S-1 is n,pi*, and T-1 is pi,pi*. In both thienocarbazoles it appears that the thianaphthene ring dictates the S, T, yield, albeit there is less predominance of that ring in the triplet state of the linear thienocarbazole, which leads to a decrease in the observed Phi(T) value.info:eu-repo/semantics/publishedVersio

Xanthine oxidoreductase promotes the inflammatory state of mononuclear phagocytes through effects on chemokine expression, peroxisome proliferator-activated receptor-gamma sumoylation, and HIF-₁ alpha

The protective effects of pharmacological inhibitors of xanthine oxidoreductase (XOR) have implicated XOR in many inflammatory diseases. Nonetheless, the role played by XOR during inflammation is poorly understood. We previously observed that inhibition of XOR within the inflammatory mononuclear phagocytes (MNP) prevented neutrophil recruitment during adoptive transfer demonstrating the role of XOR in MNP-mediated neutrophil recruitment. To further explore the role of XOR in the inflammatory state of MNP, we studied MNP isolated from inflammatory lungs combined with analyses of MNP cell lines. We demonstrated that XOR activity was increased in inflammatory MNP following insufflation of Th-1 cytokines in vivo and that activity was specifically increased by MNP differentiation. Inhibition of XOR reduced levels of CINC-1 secreted by MNP. Expression of peroxisome proliferator-activated receptor γ (PPARγ) in purified rat lung MNP and MNP cell lines reflected both the presence of PPARγ isoforms and PPARγ SUMOylation, and XOR inhibitors increased levels of SUMO-PPARγ in MNP cell lines. Both ectopic overexpression of XOR cDNA and uric acid supplementation reduced SUMO-PPARγ in MNP cells. Levels of the M2 markers CD36, CD206, and arginase-1 were modulated by uric acid and oxonic acid, whereas siRNA to SUMO-1 or PIAS-1 also reduced arginase-1 in RAW264.7 cells. We also observed that HIF-1α was increased by XOR inhibitors in inflammatory MNP and in MNP cell lines. These data demonstrate that XOR promotes the inflammatory state of MNP through effects on chemokine expression, PPARγ SUMOylation, and HIF-1α and suggest that strategies for inhibiting XOR may be valuable in modulating lung inflammatory disorders

Identification of Markers that Distinguish Monocyte-Derived Fibrocytes from Monocytes, Macrophages, and Fibroblasts

The processes that drive fibrotic diseases are complex and include an influx of peripheral blood monocytes that can differentiate into fibroblast-like cells called fibrocytes. Monocytes can also differentiate into other cell types, such as tissue macrophages. The ability to discriminate between monocytes, macrophages, fibrocytes, and fibroblasts in fibrotic lesions could be beneficial in identifying therapies that target either stromal fibroblasts or fibrocytes. and in sections from human lung. We found that markers such as CD34, CD68, and collagen do not effectively discriminate between the four cell types. In addition, IL-4, IL-12, IL-13, IFN-γ, and SAP differentially regulate the expression of CD32, CD163, CD172a, and CD206 on both macrophages and fibrocytes. Finally, CD49c (α3 integrin) expression identifies a subset of fibrocytes, and this subset increases with time in culture.These results suggest that discrimination of monocytes, macrophages, fibrocytes, and fibroblasts in fibrotic lesions is possible, and this may allow for an assessment of fibrocytes in fibrotic diseases

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Safety and efficacy of a novel polyethylene glycol hydrogel sealant for watertight dural repair

OBJECT: The authors prospectively evaluated the safety and efficacy of a novel polyethylene glycol (PEG) hydrogel sealant in patients undergoing elective cranial surgery with documented cerebrospinal fluid (CSF) leakage after sutured dural repair. METHODS: The PEG hydrogel sealant was used at 11 different study sites in 111 patients with documented intraoperative CSF leakage after neurosurgical dural repair for a variety of conditions. Intraoperative CSF leakage was either spontaneous or induced by a Valsalva maneuver. Patients were monitored for 3 months postoperatively with physical examinations, clinical laboratory analyses, and diagnostic imaging. The PEG hydrogel sealant was 100% effective in stopping CSF leakage in all patients. There were no sealant-related adverse events and all clinical outcomes were consistent with expectations for seriously ill patients undergoing prolonged neurosurgical procedures. CONCLUSIONS: The PEG hydrogel sealant provides a safe and effective watertight closure when used as an adjunct to sutured dural repair during cranial surgery

Genomic expression discovery predicts pathways and opposing functions behind phenotypes

Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems

Mathematical modeling of noise and discovery of genetic expression classes in gliomas

The microarray array experimental system generates noisy data that require validation by other experimental methods for measuring gene expression. Here we present an algebraic modeling of noise that extracts expression measurements true to a high degree of confidence. This work profiles the expression of 19 200 cDNAs in 35 human gliomas; the experiments are designed to generate four replicate spots/gene with switching of probes. The validity of the extracted measurements is confirmed by: (1) cluster analysis that generates a molecular classification differentiating glioblastoma from lower-grade tumors and radiation necrosis; (2) By what other investigators have reported in gliomas using paradigms for assaying molecular expression other than gene profiling; and (3) Real-time RT-PCR. The results yield a genetic analysis of gliomas and identify classes of genetic expression that link novel genes to the biology of gliomas