A catalytic deaminative alkylation of unactivated olefins is described. The protocol is characterized by its mild conditions, wide scope, including the use of ethylene as substrate, and exquisite ...site-selectivity pattern for both α-olefins and internal olefins, thus unlocking a new catalytic platform to forge sp 3–sp 3 linkages, even in the context of late-stage functionalization.
Starting from readily available alkenyl methyl ethers, the stereoselective preparation of highly substituted alkenes by two complementary multicatalytic sequential isomerization/cross-coupling ...sequences is described. Both elementary steps of these sequences are challenging processes when considered independently. A cationic iridium catalyst was identified for the stereoselective isomerization of allyl methyl ethers and was found to be compatible with a nickel catalyst for the subsequent cross-coupling of the in situ generated methyl vinyl ethers with various Grignard reagents. The method is compatible with sensitive functional groups and a multitude of olefinic substitution patterns to deliver products with high control of the newly generated CC bond. A highly enantioselective variant of this Ir/Ni sequence has been established using a chiral iridium precatalyst. A complementary Pd/Ni catalytic sequence has been optimized for alkenyl methyl ethers with a remote CC bond. The final alkenes were isolated with a lower level of stereocontrol. Upon proper choice of the Grignard reagent, we demonstrated that C(sp 2)C(sp 2) and C(sp 2)C(sp 3) bonds can be constructed with both systems delivering products that would be difficult to access by conventional methods.
The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an ...exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus(HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways,oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury(fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases(lymphoproliferative disease,atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCVrelated diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.
Background Systemic inflammation and immune response play a crucial role in tumor growth, and the neutrophil to lymphocyte ratio (NLR) may be a simple way to assess the host inflammatory response. ...The NLR has been shown to be a prognostic indicator in many human tumors; in early colon cancers, it has been evaluated only in a few studies and its role remains controversial. Methods We analyzed data from 503 colon cancer patients. The best cutoff value for NLR was defined by receiver operating characteristic curve analysis. We grouped 276 Dukes A/B colon cancers, not receiving adjuvant chemotherapy, into low (<2.36) and high (>2.36) NLR and subjected to further analyses related to disease-free survival (DFS). A propensity score-matched analysis and the inverse probability of treatment weighting (IPTW) were performed to avoid confounding bias. Results The NLR correlated with tumor stage and oncologic outcome. The best NLR cutoff value was identical in the whole cohort and in Dukes A/B patients. Low NLR patients had a significantly better DFS rate than high NLR patients (hazard ratio HR, 0.27; P = .0001); along with elevated carcinoembryonic antigen levels and Dukes B stage, high NLR was an independent prognostic factor of worse prognosis (HR, 2.86; P = .0033). Even in Dukes A patients, NLR discriminated between relapsing and nonrelapsing patients. Propensity score and IPTW analyses confirmed such results, thus excluding possible misinterpretation. Conclusion Preoperative NLR, an inexpensive and readily available biomarker, can predict tumor relapse and should be assessed for implementation of tailored therapy in early stage colon cancer.
Hepatitis C virus(HCV)infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease.Among the extrahepatic ...manifestations,neuropsychiatric disorders have been reported in up to 50%of chronic HCV infected patients.Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations.Main HCV-associated neurological conditions include cerebrovascular events,encephalopathy,myelitis,encephalomyelitis,and cognitive impairment,whereas"brain fog",depression,anxiety,and fatigue are at the top of the list of psychiatric disorders.Moreover,HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia,and has also been recently recognized as an independent risk factor for stroke.These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy.The brain is a suitable site for HCV replication,where the virus may directly exert neurotoxicity;other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells,alterations in neurotransmitter circuits,autoimmune disorders,and cerebral or systemic inflammation.A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment;however,further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders.
Background
Cancer outcome is considered to result from the interplay of several factors, among which host inflammatory and immune status are deemed to play a significant role. The ...neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) have been profitably used as surrogate markers of host immunoinflammatory status and have also been shown to correlate with outcome in several human tumors. However, only a few studies on these biomarkers have been performed in gastric cancer patients, yielding conflicting results.
Methods
Data were retrieved from a prospective institutional database. Overall survival (OS) of 401 patients undergoing surgery for gastric cancer between January 2000 and June 2015 as well as disease-free survival (DFS) rates in 297 radically resected patients were calculated. MaxStat analysis was used to select cutoff values for NLR and LMR.
Results
NLR and LMR did not significantly correlate with tumor stage. Patients with a high NLR and a low LMR experienced more tumor recurrences (
p
< 0.001) and had a higher hazard ratio (HR) for both OS (HR = 2.4 and HR = 2.10;
p
< 0.001) and DFS (HR = 2.99 and HR = 2.46;
p
< 0.001) than low NLR and high LMR subjects. Both biomarkers were shown to independently predict OS (HR = 1.65,
p
= 0.016; HR = 2.01,
p
= 0.002, respectively) and DFS (HR = 3.04,
p
= 0.019; HR = 4.76,
p
= 0.002, respectively). A score system combining both biomarkers was found to significantly correlate with long-term results.
Conclusions
A simple prognostic score including preoperative NLR and LMR can be used to easily predict outcome in gastric cancer patients undergoing surgery.
Hepatitis C virus (HCV) infection is a systemic disease with hepatic and extrahepatic manifestations, including neuropsychiatric conditions. Depression is a frequent disorder, which has been reported ...in one-third of patients with HCV infection and has an estimated prevalence of 1.5 to 4.0 times higher than that observed in patients with chronic hepatitis B virus infection or the general population. HCV seems to play a direct and indirect role in the development of depression. Impaired quality of life and increasing health care costs have been reported for patients with HCV infection with depression. Treatment-induced HCV clearance has been associated with improvement of depression and quality of life.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic disorder characterized by peripheral eosinophilia, severe eosinophilic asthma, sinusitis, transient pulmonary infiltrates, and ...features of medium/small-vessel vasculitis. EGPA belongs to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides, although only 30 to 40% of patients display ANCA positivity, which is mainly of myeloperoxidase (MPO) specificity. Particularly, ANCA-positive patients typically show vasculitic features. Interleukin (IL)-5 has been demonstrated to play a crucial role in determining eosinophilic airway inflammation in EGPA patients. Specifically, maturation, activation, and survival of eosinophils especially depend on IL-5 availability. Therefore, blocking IL-5 biological activity may be a rewarding strategy for control of eosinophilic inflammation. Several monoclonal antibodies with the ability to interfere with the biological activity of IL-5 have been developed, namely, mepolizumab, reslizumab, and benralizumab. Here, we discuss the role of these drugs in the management of severe eosinophilic asthma in the context of EGPA and report the outcome of two EGPA patients with severe eosinophilic asthma treated at our outpatient clinic.
Transient elastography by FibroScan® (Echosens, Paris, France) is a non-invasive method that can provide a reliable measurement of liver fibrosis through the evaluation of liver stiffness. Despite ...its limitations and risks, liver biopsy has thus far been the only procedure able to provide data to quantify fibrosis. Scientific evidence and clinical practice have made it possible to use FibroScan® in the diagnostic work-up of several liver diseases to monitor patients’ long-term treatment response and for complication prevention. For these reasons, this procedure is widely used in clinical practice and is still being investigated for further applications. The aim of this narrative review is to provide a comprehensive overview of the main applications of transient elastography in the current clinical practice.
Chronic immune stimulation by hepatitis C virus (HCV) may cause occurrence of several autoantibodies in infected patients, with or without features of clinically overt autoimmune diseases. The recent ...introduction of direct-acting antivirals (DAAs) has dramatically changed the natural history of chronic HCV infection. The aim of this study was to assess the effects of DAA therapy on serum autoantibodies in chronic hepatitis C (CHC) patients.
The medical records of 113 CHC patients were reviewed to assess autoantibody behavior following DAA-directed HCV eradication. Statistical analysis was performed to assess correlations between DAA treatment and autoantibody titers, HCV genotypes, and viral loads.
Anti-nuclear (ANA), anti-smooth muscle cell (ASMA) and anti-mitochondrial (AMA) antibody testing was available in 77 patients; 31 out of 77 patients (40%) had one or more serum autoantibodies prior to treatment. Measurement of autoantibody titers before and after HCV eradication was performed in 20 of 31 patients. DAA treatment significantly affected ANA and ASMA titers, leading to disappearance or reduction of autoantibody titers; conversely, AMA were not influenced by DAA treatment. No correlations were observed between autoantibody specificity and both HCV genotypes and viral loads at baseline. Likewise, serum autoantibody titers were independent of HCV genotypes.
DAA-directed HCV clearance may interrupt chronic immune stimulation by removing the drive for autoantibody induction. The isolated persistence of autoantibodies in the small fraction of patients who did not show clearance following DAA treatment may require long-term vigilance.
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