Quinoline-based Anti-oncogenic Molecules: Synthesis and Biological Evaluation.

Quinoline and its analogues are found in various natural products, many of which are active pharmacophores with significant bioactivities. This article discussed the plethora of quinoline derivatives and their analogues that have anti-cancer properties. The review will be helpful for the scientific community since several possible anticancer drugs based on quinolines are discussed here. In addition to this, the synthetic aspect of many such quinoline derivatives showing anti-cancer activities is also revealed in this article. These quinoline-based anti-oncogenic molecules can be synthesized using several acids, bases, and azides or with the help of reagents like Jone's reagent and Lawesson's reagent.

Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.

BACKGROUND: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1]. METHODS: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8+ tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data. RESULTS: ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (KD) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound 89Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing 89Zr immuno-PET reagents. CONCLUSION: 89Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.

Multifunctional Probes with High Utilization Rates: Self-Assembled Merocyanine Nanoparticles in Water as Acid-Base Indicators and Mitochondrion-Targeting Chemotherapeutic Agents.

Multifunctional probes with high utilization rates have great value in practical applications in various fields such as cancer diagnosis and therapy. Here we have synthesized two organic molecules based on merocyanine. They can self-assemble in water to form ∼1.5 nm nanoparticles. Both of them have good application potential in fluorescent anticounterfeit printing ink and pH detection. More importantly, they have excellent mitochondrial targeting ability, intracellular red light and near-infrared dual-channel imaging ability, strong antiphotobleaching ability, and in vivo and in vitro near-infrared imaging capabilities, showing superior chemotherapy capabilities and biocompatibility in the 4T1 tumor-bearing mouse model.

Irrigating Acetic Acid Solution During Colonoscopy for the Detection of Sessile Serrated Neoplasia: A Randomized Controlled Trial.

BACKGROUND: Misdiagnosed sessile serrated lesions (SSLs) are important precursors for interval colorectal cancers. AIMS: We investigated the usage of acetic acid (AA) solution for improving the detection of SSLs in the right colon in a randomized controlled trial. METHODS: A tandem observation of the right colon was performed in 412 consecutive patients. A first inspection was performed under white light high-definition endoscopy. In the AA group, a low concentration vinegar solution (AA: 0.005%) irrigated by a water pump in the right colon was compared with a plain solution of normal saline (NS) in the diagnostic yield of SSLs during the second inspection. Secondary outcomes in overall polyp detection were measured. RESULTS: Qualitative comparisons showed significant differences in the detection rates of all polyps except adenomas, with remarkable improvement in the demonstration of advanced (> 20 mm), SSLs, and hyperplastic polyps during the second inspection of the right colon using the AA solution. Significant improvement was also noted in the AA group, as far as the mean number of polyps/patient detected, not only in SSLs (AA group: 0.14 vs. NS group: 0.01, P < 0.001), but also in all histological types and all size-categories in the right colon. Small (≤ 9 mm) polyps were detected at a higher rate in the sigmoid colon expanding the effect of the method in the rest of the colon. CONCLUSION: AA-assisted colonoscopy led to a significant increase in SSLs detection rate in the right colon in a safe, quick, and effective manner.

Protective effect of syringic acid via restoring cells biomechanics and organelle structure in human lens epithelial cells.

We have previously reported that syringic acid (SA) extracted from D. aurantiacum var. denneanum (kerr) may be used to prevent diabetic cataract (DC). However, the underlying mechanisms through which SA prevents DC in human lens epithelial cells (HLECs) remained unclear. In the present study, we employed single-molecule optics technologies, including transmission electron microscopy (TEM), atomic force microscopy (AFM), laser scanning confocal microscopy (LSCM) and Raman spectroscopy, to monitor the effect of SA on HLECs biomechanics and organelle structure in real-time. TEM suggested that SA improved the ultrastructure of HLECs with regard to nuclear chromatin condensation and reducing mitochondrial swelling and degeneration, which may aid in the maintenance of HLECs integrity in the presence of glucose. AFM revealed a reduced surface roughness and stiffness following SA treatment, suggesting an improved viscoelasticity of HELCs. Raman spectrometry and LSCM further revealed that these changes were related to a modification of cell liquidity and cytoskeletal structure by SA. Taken together, these results provide insights into the effects of SA on the biomechanics of HLECs and further strengthen the evidence for its potential use as a novel therapeutic strategy for DC prevention.

Inhibition of hyaluronan synthesis by 4-methylumbelliferone ameliorates non-alcoholic steatohepatitis in choline-deficient L-amino acid-defined diet-induced murine model.

Hyaluronan (HA) as a glycosaminoglycan can bind to cell-surface receptors, such as TLR4, to regulate inflammation, tissue injury, repair, and fibrosis. 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, is a drug used for the treatment of biliary spasms. Currently, therapeutic interventions are not available for non-alcoholic steatohepatitis (NASH). In this study, we investigated the effects of 4-MU on NASH using a choline-deficient amino acid (CDAA) diet model. CDAA diet-fed mice showed NASH characteristics, including hepatocyte injury, hepatic steatosis, inflammation, and fibrogenesis. 4-MU treatment significantly reduced hepatic lipid contents in CDAA diet-fed mice. 4-MU reversed CDAA diet-mediated inhibition of Ppara and induction of Srebf1 and Slc27a2. Analysis of serum ALT and AST levels revealed that 4-MU treatment protected against hepatocellular damage induced by CDAA diet feeding. TLR4 regulates low molecular weight-HA-induced chemokine expression in hepatocytes. In CDAA diet-fed, 4-MU-treated mice, the upregulated chemokine/cytokine expression, such as Cxcl1, Cxcl2, and Tnf was attenuated with the decrease of macrophage infiltration into the liver. Moreover, HA inhibition repressed CDAA diet-induced mRNA expression of fibrogenic genes, Notch1, and Hes1 in the liver. In conclusion, 4-MU treatment inhibited liver steatosis and steatohepatitis in a mouse model of NASH, implicating that 4-MU may have therapeutic potential for NASH.

Tumor Microenvironment-Responsive Reagent DFS@HKUST-1 for Photoacoustic Imaging-Guided Multimethod Therapy.

Although multimethod therapy has shown great promise for effective cancer treatment, it is still a great challenge to develop simple and effective strategies to construct multifunctional therapeutic reagents. According to the characteristics of the tumor microenvironment, such as a mild acidic environment and overexpression of H2O2, an intelligent therapeutic reagent with photoacoustic (PA) imaging-guided photothermal therapy, chemodynamic therapy, and in situ chemotherapy was constructed by simply loading disulfiram (DSF) in a Cu-based porous metal-organic framework (HKUST-1). The resultant material DFS@HKUST-1 shows near-infrared adsorption around 600-900 nm and effective photoacoustic imaging properties and photothermal conversion efficiency upon 808 nm irradiation. Besides, after DFS@HKUST-1 is enriched in the tumor, the acidic environment of the tumor will slowly trigger the decomposition of HKUST-1, leading to the release of Cu2+ ions to react with DSF and endogenous H2O2 to generate the Cu/DSF complex (CuET) and cytotoxic •OH for chemotherapy and chemodynamic therapy, respectively. Therefore, DFS@HKUST-1 can serve as a promising tumor microenvironment response therapeutic reagent for photoacoustic imaging-guided multimethod therapy.

Lack of cross-reactivity of human and porcine reagents to quantify manatee (Trichechus manatus) cytokines.

Veterinary medical examinations, including both physical examination and diagnostic tests, are important to monitor the health of both managed-care and wild marine mammals. However, limited species-specific reagents and assays are available that may contribute to a broader medical examination. This project evaluated if commercially available human and porcine antibodies and reagents would cross-react with manatee (Trichechus manatus) cytokines as the first step to validate a new diagnostic tool for manatees. Overall, as a result of limited cross-reactivity, human and porcine commercial reagents did not allow for the quantification of manatee cytokines. At this point, caution must be exercised when using human or porcine immunoassay reagents to quantify manatee cytokines if the reagents have not been fully validated. Future efforts will continue to explore and test the cross-reactivity of reagents to measure manatee cytokines as new species-specific and commercial reagents become available.

Innovative perception on using Tiron to modulate the hepatotoxicity induced by titanium dioxide nanoparticles in male rats.

The extensive application of titanium dioxide nanoparticles (TiO2 NPs) in the food industry arouses a debate regarding the probable risk associated with their use. Several recent studies reported that most nanoparticles (NPs) have adverse actions on the liver. The objective of this study is to examine whether Tiron plays a modulatory role against apoptotic damage induced by TiO2 NPs in rat livers. Forty rats were randomly divided into 4 groups; a control group received phosphate-buffered saline, an intoxicated group received 100 mg/kg/day of TiO2 NPs for 60 days, a treated group received 470 mg/kg/day of Tiron for the last 14 days after TiO2 NPs administration, and a Tiron group received Tiron only as previously mentioned. Oral administration of TiO2 NPs significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). In the liver, TiO2 NPs increased oxidative stress through increasing lipid peroxidation and decreasing GSH concentration and the levels of the SOD and GPx enzymes. TiO2 NPs significantly upregulated the proapoptotic Bax gene and downregulated the antiapoptotic Bcl-2 gene. Histopathological examination of hepatic tissue reinforced the previous biochemical results. Apoptotic lesions were also obvious in this group. Treatment with Tiron as an antioxidant significantly decreased serum biochemistry, ameliorated oxidative stress in hepatic tissue, upregulated Bcl-2, decreased Bax expression and attenuated the histopathology of hepatic injury. These findings indicate that Tiron effectively diminishes the hazardous effects of TiO2 NPs on rat liver.

Assessment of two contact activation reagents for the diagnosis of congenital factor XI deficiency.

INTRODUCTION: Congenital FXI deficiency, a coagulopathy associated with low bleeding risk but thrombotic protection, is usually diagnosed by prolonged APTT and confirmed by coagulation assays. Recent evidences suggest that FXI deficiency might be underestimated. Sensitive and reliable methods to detect FXI deficiency are required. AIM: To examine the sensitivity of two methods and two contact activators on FXI deficiency screening. METHODS: 140 cases with FXI deficiency, 9 severe and 131 moderate, caused by 11different mutations were recruited. APTT and FXI:C were assessed in ACL-TOP 500coagulometer with silica-based (SynthASil) and ellagic acid-based (SynthAFax) reagents. F12 rs1801020 SNP was genotyped with Taqman probes. RESULTS: Severe FXI deficiency significantly prolonged APTT with both reagents. However, a high proportion of moderate deficiencies would not be detected using APTT, with false negatives of 22% for SynthASil and 12% for SynthAFax. False negatives results mainly corresponded to cases with qualitative deficiency (CRM+: p.Pro538Leu), which also had higher FXI coagulant activity. Using SynthASil, the common F12 rs1801020 variant, associated to low FXII levels, significantly prolonged APTT in moderate FXI deficiency subjects. FXI:C values were significantly higher with SynthAFax than with SynthASil (47.7±12.7 vs. 40.4±14.9), so SynthAFax rendered higher rate of false negatives than SynthASil (7% vs.2%). CONCLUSIONS: Moderate FXI deficiency, particularly CRM+, might be underestimated using current diagnostic methods. The activator, FXI and FXII levels may contribute to a higher rate of false negatives using APTT. Our results suggests that the best screening method for FXI deficiency is FXI:C using silica.

The international normalized ratio (INR): What reagent, what instrument? The assessment of the agreement between INR values according to different reagent/instrument combinations.

WHAT IS KNOWN AND OBJECTIVE: The international normalized ratio (INR) is widely used to monitor patients on vitamin K antagonists. This study aimed to assess the agreement of INR values obtained with different thromboplastin/instrument combinations. MATERIAL AND METHODS: International normalized ratio was determined on plasmas from 330 patients undergoing antivitamin K treatment (with acenocoumarol), using two calibration methods and four reagent/instrument combinations: Both Neoplastine CI and Neoplastine CI Plus on STA-R instrument from Diagnostica STAGO, Asnières, France; and both Thromborel S and Innovin on SYSMEX 2100i instrument from Siemens Health Care Diagnostics, Marbung, Germany. The agreement analysis was done using the Bland-Altman plot and the Cohen Kappa coefficient. RESULTS: The mean of the differences between the INR values and the limits of agreement were -0.07 [-0.51 to 0.38] for the Neoplastine CI plus and Neoplastine CI reagents, -0.08 [-1.18 to 1.03] for the Thromborel S and Innovin reagents when the INR was calculated, -0.1 [-1.15 to 0.95] for the Thromborel S and Innovin reagents when the INR was directly calibrated and -0.1 [-0.7 to 0.5] for the Neoplastine CI plus and Thromborel S. Cohen's kappa coefficients were 0.94, 0.76, 0.85 and 0.82, respectively. NEW FINDINGS AND CONCLUSION: The agreement between the four reagent/instrument combinations was high enough to classify patients as inefficaciously or efficaciously anticoagulated. The data interpretation should always be related to the clinical purpose.

Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders?

Neuroinflammation is a common characteristic of several mental health conditions such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia (SCHZ). Inflammatory processes trigger and/or further deteriorate mental functions and are regarded as targets for therapeutic drug development. Cotinine is an alkaloid present in tobacco leaves and the main metabolite of nicotine. Cotinine is safe, non-addictive and has pharmacokinetic properties adequate for therapeutic use. Research has shown that cotinine has antipsychotic, anxiolytic, and antidepressant properties and modulates the serotonergic, cholinergic and dopaminergic systems. Consistent with the modulation of these neurotransmitter systems, cotinine behaves as a positive allosteric modulator of the nicotinic acetylcholine receptors (nAChRs) and has anti-inflammatory effects. The decrease in neuroinflammation induced by the stimulation of the cholinergic system seems to be a key element explaining the beneficial effects of cotinine in a diverse range of neurological and psychiatric conditions. This review discusses new evidence of the role of neuroinflammation as a key aspect in bipolar disorder, PTSD and major depression, as well as the potential use of cotinine to reduce neuroinflammation in those conditions.

[Mascs of functional disorders of the biliary tract].

The survey of its own and literature data describes the clinical "masks" of the primary and second functional disorders of the biliary tract, describes the mechanisms of their formation, which include the plural disturbances of the organs interactions, psycho - emotional and vegetative disturbances, development ofbiliar and pancreatic insufficiency. It is shown that Hymecromone (Odeston) can be successfully used, as the base means, with the treatment of patients with primary and second functional disorders of the biliary tract with different clinical "masks" of this pathology.

Validez y fiabilidad de indicadores sintéticos para la vigilancia y control de la tuberculosis / Validity and reliability of synthetics indicators for tuberculosis surveillance and control

Introducción: se considera necesaria la aplicación de nuevos indicadores sintéticos que permitan evaluar la calidad del trabajo de los servicios de salud en la etapa de posible eliminación de la tuberculosis en Cuba. Objetivos: apreciar la validez, fiabilidad, asequibilidad y factibilidad de dos indicadores sobre intensidad y calidad de la detección de casos de tuberculosis. Métodos: estudio descriptivo-cualitativo. La validación se realizó en distintos momentos entre marzo del 2009 y diciembre del 2011, mediante valoraciones de expertos. Se elaboraron escalas numéricas ordinales para las categorías valorativas de las variables intermedias de los indicadores, calculamos sus medias aritméticas y el índice de posición. Para el indicador sintético de la localización de casos, evaluamos la validez de aspecto, contenido, capacidad predictiva, consistencia, coherencia, constructo, asequibilidad y factibilidad mediante el mínimo =1 y el máximo =5. Las variables del indicador sintético de detección de casos se calificaron según su validez, fiabilidad y comparabilidad marcando 1 = nada, hasta 5 = muy. Ambos indicadores se sometieron a una aproximación a la calificación de válidos, reproducibles y factibles con 3 = sí; 2 = en parte y 1 = 0. Adicionalmente, se aplicó un cuestionario semiestructurado para explorar opiniones de los usuarios sobre su utilidad, factibilidad y limitaciones. Resultados: el indicador sintético de detección de casos obtuvo calificación máxima 5 para cinco criterios evaluados y 4,7 y 4,8 para otros dos criterios. La mayoría de los criterios obtuvieron promedios entre 4 y 5 (IP ≥ 0,90) para las variables del indicador sintético de detección de casos, y entre 4,2 y 4,9 (IP 0,80 a 0,95) para las variables intermedias. Ambos indicadores en una tercera evaluación obtuvieron la calificación máxima 5 y, en general, se consideran útiles y fáciles de manejar, sin embargo su aplicación está limitada por falta de habilidades y de recursos de los usuarios. Conclusión: en general los indicadores fueron considerados útiles y factibles(AU)

Objectives: to appreciate the validity, reliability, accessibility and feasibility of two composite indicators reflecting intensity and quality of tuberculosis case detection. Methods: is it a descriptive-qualitative study. The Indicators validation was carried out in different moments between March of 2009 and December of 2011, by expert's evaluations. Ordinal numerical scales for the evaluative categories of the indicators intermediate variables were elaborated, calculating their arithmetical means and the position index (PI). For the cases finding indicator (Isiloc), were evaluate the aspect validity, context, predictive capacity, consistency, coherence, construct, accessibility and feasibility (minimum = 1 and maximum = 5). The variables for cases detection indicator (Isidec) were rated in terms of validity, reliability, comparability, specificity, sensibility, operability, affordability and feasibility (1= none to 5 = very). Both indicators were valued to the grade of valid, reproducible and feasible (3 = yes, 2 = partly and 1 = 0). Furthermore, we applied a semi-structured questionnaire to explore opinions of the users about their usefulness, feasibility and limitations. Results: isiloc obtained highest rating (5, PI = 1) for five evaluated approaches and 4,7 and 4,8 (PI 0,93 and 0,95) for other two approaches. For Isidec most of the approaches obtained averages between 4 and 5 (P≥0,90, and the intermediate variables obtained mostly averages between 4,2 and 4,9 (IP 0,80 to 0,95). Both indicators in a third approaches obtained the highest rating (5, PI = 1) and were generally considered useful and feasible, although its application was limited by the lack of skills and resources of the users. Conclusion: validation of these indicators has been satisfactory and should continue to apply its field test(AU)

Brilliant Blue G assisted epiretinal membrane surgery.

We report intensely staining epiretinal membrane (ERM) with Brilliant Blue G (BBG) under air for two minutes. ERM peeling was performed in 21 cases. After removal of posterior hyaloid, 0.2 mL BBG was first applied on the macula, to stain ERM under air conditions for 2 minutes. Internal limiting membrane (ILM) was intensely stained and peeled in all cases following ERM removal. In 4 cases, the ERM was also observed to be intensely stained with BBG and peeled with an ILM forceps. Postoperatively, the ganglion cell layer thickness was lower in three of the cases, however VA improved in all cases and multifocal electroretinogram revealed no toxicity. Light microscopy of ERM revealed masses of cells whereas; the ILM did not. The increased staining characteristics of ERM and ILM may be resulted from longer contact time of BBG under air pressure.