New 4-imino-4H-Chromeno[2,3-d]Pyrimidin-3(5H)-Amine: Synthesis, Cytotoxic Effects on Tumoral Cell Lines and in Silico ADMET Properties

The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR and mass spectroscopy. These new compounds were tested for their antiproliferative activities on seven representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3 and MCF7) and also on fibroblasts. Among them, only the compounds 6c showed micromolar cytotoxic activity on tumor cell lines (1.8 50 50 > 25 μM). Finally, in silico ADMET studies ware performed to investigate the possibility of using of the identified compound 6c as potential anti-tumor compound.

Extending the functions of the homeotic transcription factor Cdx2 in the digestive system through nontranscriptional activities

The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis,also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut.At the molecular level,structure/function studies have demonstrated that the Cdx2 protein is a transcription factor containing a conserved homeotic DNA-binding domain made ofthree alpha helixes arranged in a helix-turn-helix motif,preceded by a transcriptional domain and followed by a regulatory domain.The protein interacts with several thousand sites on the chromatin and widely regulates intestinal functions in stem/progenitor cells as well as in mature differentiated cells.Yet,this transcription factor also acts trough original nontranscriptional mechanisms.Indeed,the identification of novel protein partners of Cdx2 and also of a splicing variant revealed unexpected functions in the control of signaling pathways like the Wnt and NF-k B pathways,in double-strand break DNA repair and in premessenger RNA splicing.These novel functions of Cdx2 must be considered to fully understand the complexity of the role of Cdx2 in the healthy intestine and in diseases.

Testing for hepatitis B virus alone does not increase vaccine coverage in non-immunized persons

AIM To determine whether hepatitis B virus(HBV)-testing could serve as a gateway to vaccinate non-immunized individuals in a low-prevalent country.METHODS Non-immunized subjects participating in a multi-center, HBV-testing campaign in Paris, France were identified and contacted via telephone 3-9 mo after testing in order to determine vaccination status. Vaccination coverage was evaluated in per-protocol(for all respondents) and intent-to-treat analysis(assuming all non-responders did not vaccinate).RESULTS In total, 1215/4924(24.7%) enrolled subjects with complete HBV serology were identified as nonimmunized and eligible for analysis. There were 99/902 successfully contacted subjects who had initiated HBV vaccination after screening: per-protocol, 11.0%(95%CI: 9.0-13.2); intent-to-treat, 8.2%(95%CI: 6.7-9.8). In multivariable analysis, vaccination was more likely to be initiated in individuals originating from moderate or high HBV-endemic countries(P < 0.001), patients with limited healthcare coverage(P = 0.01) and men who have sex with men(P = 0.02). When asked about the reasons for not initiating HBV vaccination, the most frequent response was "will be vaccinated later"(33.4%), followed by "did not want to vaccinate"(29.8%), and "vaccination was not proposed by the physician"(21.5%). Sub-group analysis indicated a stark contrast in vaccination coverage across centers, ranging from 0%-56%.CONCLUSION HBV-vaccination after HBV screening was very low in this study, which appeared largely attributed to physician-patient motivation towards vaccination. Increased vaccination coverage might be achieved by emphasizing its need at the organizational level.

Anti-Aging Efficacy of a New Alendronate-Pravastatin Cosmetic Combination: A Randomized Double Blind Comparative Study

Progeria is a rare genetic disease that causes accelerated aging and death in children at a mean age of 13.5 years. An?aminobisphosphonate-statin combination has been shown to reduce the toxicity of the mutated protein, progerin, in progeria patient cell cultures and in a mouse model of the disease. This combination is currently being tested in a European Therapeutic Trial for progeria in Marseille (ClinicalTrials.gov identifier NCT00731016). Progerin has been shown to be produced by skin cells during physiological aging. The objective of this study was to assess the efficiency of a new and original cosmetic formulation containing alendronate and pravastatin sodium salts, reduce crow’s feet wrinkles, and cheek hollow in a double blind, randomized and placebo controlled comparative study. Three cosmetic preparations were evaluated using Fast Optical in vivo Topometry of human Skin (FOITS): one containing sodium alendronate and sodium pravastatin, a placebo, and a commercial anti-aging product. Fifty-seven female and twenty-five male volunteers between 51 and 71-year-old were selected. Each subject tested two of the three products once a day, in the evening, by spreading each selected product on one side of the face. Skin micro-relief was analyzed at 0, 28, 56 and 84 days. Statistical analysis of 7 clinical qualitative (left or right side of face, gender, and 3 skin types) and 6 quantitative parameters (age, weight at each test time, wrinkle clinical grade at inclusion time) showed no statistical differences between the three tested products. In contrast, most of the 8 quantitative FOITS parameters describing skin micro-relief were statistically improved by the alendronate-pravastatin combination compared to the placebo or to the commercial anti-aging product. A cosmetic preparation containing alendronate and pravastatin sodium salts exhibited anti-aging effects by reducing crow’s feet wrinkles and restoring cheek volume.

Vitamin D in addition to peg-interferon-alpha/ribavirin in chronic hepatitis C virus infection: ANRS-HC25-VITAVIC study

AIM: To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin(Peg IFN/RBV) therapy could improve the efficacy of Peg IFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus(HCV) infection.METHODS:Genotype 1 or 4 HCV-infected patients with null response to previous Peg IFN/RBV treatment and with hypovitaminosis D(<30 ng/m L)prospectively received cholecalciferol 100000 IU per week for 4 wk[from week-4(W-4)to W0],followed by 100000 IUper month in combination with Peg IFN/RBV for 12 mo(from W0 to W48).The primary outcome was the rate of early virological response defined by an HCV RNA<12 IU/m L after 12 wk Peg IFN/RBV treatment.RESULTS:A total of 32 patients were included,19(59%)and 13(41%)patients were HCV genotype1 and 4,respectively.The median baseline vitamin D level was 15 ng/m L(range:7-28).In modified intention-to-treat analysis,29 patients who received at least one dose of Peg IFN/RBV were included in the analysis.All patients except one normalized their vitamin D serum levels.The rate of early virologic response was 0/29(0%).The rate of HCV RNA<12IU/m L after 24 wk of Peg IFN/RBV was 1/27(4%).The safety profile was favorable.CONCLUSION:Addition of vitamin D to Peg IFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1or 4 HCV infection.

How Polydopamine Modulates Biological Responses to PTFE Prostheses

Diaphragm repair after congenital diaphragmatic hernia is associated with hernia recurrence due to prosthesis failure. Expanded polytetrafluoroethylene (e-PTFE), a synthetic non-degradable biomaterial, is currently used for those diaphragmatic defect repairs. The drawback of e-PTFE is its poor wettability that leads to coating difficulties, bonding that could favor implant integration. However, polydopamine (PDA) can be deposited as well on organic as on inorganic substrates. Therefore, we assessed the biological responses of a clinically used e-PTFE biomaterial treated with PDA in two different manners: one impregnated with PDA and the other coated with a one side PDA film. Mechanical properties of the raw e-PTFE, the PDA soaked biomaterial and the PDA coated surface were characterized by colloidal probe atomic force microscopy. Behaviors of primary human fibroblasts and Wharton’s jelly stem cells were investigated by electron microscopy. Findings reveal that the mechanical properties at the microscopic scale are not modified by the PDA treatments. Cells spread onto both PDA functionalized substrates. In addition, microscopic observations disclose numerous focal cell contacts, evidencing cell attachment, and cytoplasmic projections particularly with the nanoscale PDA coating. Results clearly suggest that PDA in general but above all the PDA coating enhance cellular colonization of the implant material.

The Laser Technology:New Trends in Biology and Medicine

In fifty years, laser technology has made great progress, and its many applications make it essential in everyday life. However, this technology is still open to numerous developments. Across multiple applications, there is particular focus in the field of medicine, for diagnosis for tailored therapies, and as a research tool in biology. Whereas its use is now well-demonstrated in ophthalmologic and dermatologic treatments, and surgery, one of the most fascinating aspects of laser technology in the field of biology emerged in the late 1990s with the development of devices able to perform fine dissections of biological tissues using a laser beam. The so-called laser-associated microdissection offers a rapid, precise method of isolating and removing targeted cells or groups of cells from complex biological tissues. It represents the missing link between clinical observations and the intrinsic physiological mechanisms of biological tissues. The molecular examination of pathologically altered cells and tissues for DNA, RNA, and protein expression has revolutionized research and diagnosis in pathology, enabling assessment of the role of the cell type in the normal physiological or disease process. Alongside conventional diagnostic and therapeutic approaches, another field of application contribute to the development of targeted treatments at the nanoscale level of laser technology, mainly in the field of cancer, leading to design new and innovative strategies in drug delivery and image-guided surgery. Most of these approaches, but although not exhaustively, will be presented here.

Rare dentin defects:Understanding the pathophysiological mechanisms of COLXVA1 mutations

Dentin is a mineralized tissue with a chemical composition similar to bone but with a higher mineralized density and rigidity.It constitutes the central structure of the tooth between the internal pulp and external enamel toward the oral cavity or cementum toward the underlying roots.Inherited dentin defects occur in a variety of rare genetic diseases.They can manifest as“isolated”occurrences such as in dentinogenesis imperfecta(DI)or dentin dysplasia(DD)or can be associated with other symptoms in diseases such as osteogenesis imperfecta,Goldblatt syndrome,microcephalic osteodysplastic primordial dwarfism type Ⅱ,among others.

The germline genetics of mild-to-moderate penetrance:An intriguing role of PRAME in multiple carcinogenesis

Germline genetics of high penetrance such as BRCA genes,mutations might be sufficient for carcinogenesis,but this only explains fewer than 10%of cancers.We assume that most cancers are the result of germline mutations of low to moderate penetrance,combined with acquired mutations due to external carcinogenic stressors.With their accumulation over time,aging is associated with an increased risk of multiple cancer development in a given individual.For decades,germline genetics have been based on familial linkage studies enabling most high-penetrance genes to be identified.More recently,population-wide studies have led to the identification of considerable numbers of polymorphisms associated with cancer risk.However,most of them are of unknown functional value,thus limiting their translational application.

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13±0.01]mg/L)(P=0.003).PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis(P=0.670).PS100-Beta values were correlated with Child-Pugh score(P<0.001),Model for End-Stage Liver Disease(MELD)score(P=0.004),C-reactive protein(P<0.001),ammonemia(P<0.001),and chronic liver failure consortium(CLIF-C)organ failure(P<0.001)and CLIF-C acute-on-chronic(P=0.038)scores,but not with leukocytes(P=0.053),procalcitonin(PCT)(P=0.107),or the lymphocyte-to-neutrophil ratio in ICU patients(P=0.522).In a multivariate model including age,ammonemia,PS100-Beta,PCT,MELD,presence of transjugular portosystemic shunt,and sodium level,the diagnostic performance was 0.765 for the diagnosis of overt HE.Patients with a PS100-Beta level<0.12 mg/L had a better overall survival(P=0.019)and a better survival without liver transplantation(P=0.013).Conclusions Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis,and even more so in those displaying overt HE,and the levels are correlated with outcome.This suggests an increase in the permeability of the BBB in these patients.

Blood–brain barrier dysfunction in intensive care unit

The central nervous system is characterized by a peculiar vascularization termed blood–brain barrier(BBB),which regulates the exchange of cells and molecules between the cerebral tissue and the whole body.BBB dysfunction is a life-threatening condition since its presence corresponds to a marker of severity in most diseases encountered in the intensive care unit(ICU).During critical illness,inflammatory response,cytokine release,and other phenomena activating the brain endothelium contribute to alterations in the BBB and increase its permeability to solutes,cells,nutrients,and xenobiotics.Moreover,patients in the ICU are often old,with underlying acute or chronic diseases,and overly medicated due to their critical condition;these factors could also contribute to the development of BBB dysfunction.An accurate diagnostic approach is critical for the identification of the mechanisms underlying BBB alterations,which should be rapidly managed by intensivists.Several methods were developed to investigate the BBB and assess its permeability.Nevertheless,in humans,exploration of the BBB requires the use of indirect methods.Imaging and biochemical methods can be used to study the abnormal passage of molecules through the BBB.In this review,we describe the structural and functional characteristics of the BBB,present tools and methods for probing this interface,and provide examples of the main diseases managed in the ICU that are related to BBB dysfunction.

Pancreatic enucleation:a valid surgical option with encouraging quality of life

In their study“Pancreatic Enucleation Patients Share the Same Quality of Life as the General Population at Long-Term Follow-Up”,Giuliani et al.(1)assess short-and long-term outcomes including quality of life after pancreatic enucleation(PE).PE aims to preserve endocrine and exocrine function while ensuring surgical ablation of a presumed benign pancreatic tumor(neuroendocrine tumors,mucinous cystadenoma,serous cystadenoma,branch duct intraductal papillary mucinous neoplasms and solid pseudopapillary tumors).

HIV reservoir: antiviral immune responses and immune interventions for curing HIV infection

Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.

Advances in Research on COVID-19 Vaccination for People Living with HIV

Introduction In December 2019,multiple cases of aggravated pneumonia of unidentified origin were reported inWuhan,China.These were confirmed to be caused by a novel coronavirus.The World Health Organization(WHO)named the disease coronavirus disease 2019(COVID-19).The International Committee on Taxonomy of Viruses officially identified the novel virus severe acute respiratory syndrome coronavirus 2(SARSCoV-2).[1]Although China is now a low endemic areawith a downward trend in the number of confirmed and suspected cases,[2]the threat of the COVID-19 pandemic remains critical.By mid-March 2022,the cumulative number of reported confirmed cases of COVID-19 worldwide exceeded 450 million,with more than 6 million deaths.[3]Since there is no specific therapeutic drug for the treatment of COVID-19,it is important to control the epidemic by actively promoting SARS-CoV-2 vaccination globally,reducing the risk of viral transmission and the incidence of severe COVID-19,thus improving prognoses.[4]