Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis.

Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.

Towards Goals to Refine Prophylactic and Therapeutic Strategies Against COVID-19 Linked to Aging and Metabolic Syndrome.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gave rise to the coronavirus disease 2019 (COVID-19) pandemic. A strong correlation has been demonstrated between worse COVID-19 outcomes, aging, and metabolic syndrome (MetS), which is primarily derived from obesity-induced systemic chronic low-grade inflammation with numerous complications, including type 2 diabetes mellitus (T2DM). The majority of COVID-19 deaths occurs in people over the age of 65. Individuals with MetS are inclined to manifest adverse disease consequences and mortality from COVID-19. In this review, we examine the prevalence and molecular mechanisms underlying enhanced risk of COVID-19 in elderly people and individuals with MetS. Subsequently, we discuss current progresses in treating COVID-19, including the development of new COVID-19 vaccines and antivirals, towards goals to elaborate prophylactic and therapeutic treatment options in this vulnerable population.

A comprehensive review of DOACs for cancer associated VTE prophylaxis or treatment.

Cancer is a leading cause of venous thromboembolism (VTE), which contributes to significant morbidity and mortality in these patients. Increased thrombotic risk in cancer patients is modified by tumor-specific biology, disease-directed interventions, and individual comorbidities. Risk stratification for prophylaxis and treatment requires regular reevaluation of these factors, which can be facilitated by validated prediction tools. This review also discusses large clinical trial data (SELECT-D, HOKUSAI-VTE, ADAM VTE, CARAVAGGIO) demonstrating that direct oral anticoagulants (DOACs) are effective in the treatment of cancer-associated VTE, with comparable efficacy to the traditional choice of low molecular weight heparin. In the prophylactic setting derived from patients with cancer with increased VTE risk, DOACs also reduced the incidence of VTE with only modest increases in bleeding risk. The ease of DOAC administration and acceptable risk profile in the carefully selected patient make them an appealing choice for anticoagulation. In instances where the risk of gastrointestinal bleeding is of concern, apixaban, in particular, may still be a suitable option in place of LMWH. These improvements in our anticoagulation approach to cancer-associated VTE are well-timed to accompany the recent advances in disease-directed therapies that are enabling patients to live longer with cancer and therefore at increased risk of complications such as VTE.

Systemic Photoprotection in Skin Cancer Prevention: Knowledge among Dermatologists.

BACKGROUND: Systemic photoprotection (i.e., administration of substances such as nicotinamide, carotenoids, and vitamin D) may be important to reduce photocarcinogenesis or to support long-term protection against UV irradiation. Clinical trials showed that oral nicotinamide is effective in reducing the onset of new nonmelanoma skin cancers (NMSCs), while other oral photoprotectors failed to achieve the reduction of new melanoma or NMSC formation in humans. The aim of this study was to summarize the current state of knowledge of systemic photoprotection and to evaluate the knowledge and attitude of dermatologists regarding these treatments. METHODS: The survey was conducted on a sample of dermatologists recruited according to a snowball sampling procedure. The questionnaire consisted of a first part asking for characteristics of the participant and a second part with 12 specific questions on their knowledge about systemic photoprotection, particularly their knowledge of astaxanthin, ß-carotene, nicotinamide, and vitamin D3. RESULTS: One hundred eight dermatologists answered the survey. Most of them (85.2%) stated that oral photoprotectors have a role in the prevention of skin cancer, and responses mainly mentioned nicotinamide. More than half of them (54.6%) had prescribed all the considered oral photoprotectors, but the majority of them had prescribed nicotinamide, mainly for 2 to 3 months during summer, almost invariably (n = 106) associated with topical photoprotectors. Most dermatologists (>80%) were aware of scientific publications demonstrating an effect of systemic photoprotectors on NMSC. CONCLUSIONS: Most Italian dermatologists have positive views on oral photoprotection in skin cancer and are aware of the demonstrated potential of nicotinamide in the prevention of NMSCs.

Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma.

With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug-drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.

Modern biologics for rabies prophylaxis and the elimination of human cases mediated by dogs.

Introduction: Rabies is a major viral zoonosis and neglected tropical disease, with a global distribution. Humans, domestic animals, and wild mammals are susceptible to infection. Etiological agents reside in the Order Mononegavirales, Family Rhabdoviridae, Genus Lyssavirus. This acute, progressive encephalitis causes the highest case fatality of any conventional infectious disease. Tens of millions of humans become exposed annually to the bites of infected mammals, predominantly in Asia and Africa. Despite the existence of effective vaccines and immune globulins, tens of thousands of people, typically children in the developing world, succumb. Areas covered: Concentrating upon both historical and major published references from the peer-reviewed literature over the past 5 years, we describe current biologics for rabies prevention, newly recommended principles for prophylaxis, and relevant future products in the developmental pipeline. Expert opinion: Modern human rabies biologics are pure, potent, safe, and efficacious, when used in a timely and appropriate manner. Few individuals survive after clinical signs. Anti-viral compounds are not licensed. Experimental therapy, while obviously desirable, is highly controversial. Education on bite prevention and integrated risk management are critical. Access to affordable care, dose-sparing, and shortened regimens of human rabies biologics remain key.

Barriers to malaria prevention among immigrant travelers in the United States who visit friends and relatives in sub-Saharan Africa: A cross-sectional, multi-setting survey of knowledge, attitudes, and practices.

BACKGROUND: Despite achievements in the reduction of malaria globally, imported malaria cases to the United States by returning international travelers continue to increase. Immigrants to the United States from sub-Saharan Africa (SSA) who then travel back to their homelands to visit friends and relatives (VFRs) experience a disproportionate burden of malaria illness. Various studies have explored barriers to malaria prevention among VFRs and non-VFRs-travelers to the same destinations with other purpose for travel-but few employed robust epidemiologic study designs or performed comparative analyses of these two groups. To better quantify the key barriers that VFRs face to implement effective malaria prevention measures, we conducted a comprehensive community-based, cross-sectional, survey to identify differences in malaria prevention knowledge, attitudes, and practices (KAP) among VFRs and others traveling to Africa and describe the differences between VFRs and other types of international travelers. METHODS AND FINDINGS: Three distinct populations of travelers with past or planned travel to malaria-endemic countries of SSA were surveyed: VFRs diagnosed with malaria as reported through a state health department; members of the general VFR population (community); and VFR and non-VFR travelers presenting to a travel health clinic, both before their pretravel consultation and again, after return from travel. A Community Advisory Board of African immigrants and prior qualitative research informed survey development and dissemination. Across the three groups, 489 travelers completed surveys: 351 VFRs and 138 non-VFRs. VFRs who reported taking antimalarials on their last trip rated their concern about malaria higher than those who did not. Having taken five or more trips to SSA was reported more commonly among VFRs diagnosed with malaria than community VFRs (44.0% versus 20.4%; p = 0.008). Among travel health clinic patients surveyed before and after travel, VFR travelers were less successful than non-VFRs in adhering to their planned use of antimalarials (82.2% versus 98.7%; p = 0.001) and employing mosquito bite avoidance techniques (e.g., using bed nets: 56.8% versus 81.8%; p = 0.009). VFRs who visited the travel health clinic were more likely than VFR respondents from the community to report taking an antimalarial (83.0% versus 61.9%; p = 0.009), or to report bite avoidance behaviors (e.g., staying indoors when mosquitoes were out: 80.9% versus 59.5%; p = 0.009). CONCLUSIONS: We observed heterogeneity in malaria prevention behaviors among VFRs and between VFR and non-VFR traveler populations. Although VFRs attending the travel health clinic appear to demonstrate better adherence to malaria prevention measures than VFR counterparts surveyed in the community, specialized pretravel care is not sufficient to ensure chemoprophylaxis use and bite avoidance behaviors among VFRs. Even when seeking specialized pretravel care, VFRs experience greater barriers to the use of malaria prevention than non-VFRs. Addressing access to health care and upstream barrier reduction strategies that make intended prevention more achievable, affordable, easier, and resonant among VFRs may improve malaria prevention intervention effectiveness.

Pioglitazone, Nuclear Receptors, and Aerodigestive Prevention.

There has been intense interest in nuclear receptor targeting for cancer prevention. With the exception of estrogen antagonism in breast carcinoma there has not been widespread adoption or success of this strategy in clinical cancer prevention. Keith and colleagues have performed a careful study, which utilized the PPARγ nuclear receptor agonist, pioglitazone, a common type II diabetes agent, in subjects at risk for lung carcinoma. Although the results are not promising with this strategy, the study provides evidence for feasibility accrual and biomarker strategies that could be utilized to gain additional insight in future trials.

[New horizons for acute and prophylactic treatments of migraine]. / Les avancées dans les traitements de crise et de fond de la maladie migraineuse.

The current treatment of migraine attacks is triptans and NSAIDs, but the calcitonin gene-related peptide (CGRP) has emerged as a key neuropeptide target for migraine therapy. Despite an off target class effect on liver enzymes, two CGRP receptor antagonists, ubrogepant and rimegepant, remain in development, together with a 5-HT1F receptor agonist (lasmiditan), for which cardiovascular contraindications that limit the utility of triptans do not exist. Importantly, to avoid an excessive use of acute medication with the risk of medication overuse, prophylactic therapeutics are the best choice. To date, monoclonal antibodies which block CGRP actions are on the market all over the world but not yet in France. The research is very active in different directions and targets notably hypothalamic neuropeptides because the hypothalamus hosts many key neuropeptide systems that seem to play a role in migraine physiopathology. These neuropeptides include orexins, oxytocin, neuropeptide Y (NPY) and pituitary adenylate cyclase-activating polypeptide (PACAP). In addition, other promising drugs for the treatment of migraine are nitric oxide synthase inhibitors and acid-sensing ion channel (ASIC) blockers.

Novel Approaches to Control Malaria in Forested Areas of Southeast Asia.

The emergence and spread of drug resistance in the Greater Mekong Subregion (GMS) have added urgency to accelerate malaria elimination while reducing the treatment options. The remaining foci of malaria transmission are often in forests, where vectors tend to bite during daytime and outdoors, thus reducing the effectiveness of insecticide-treated bed nets. Limited periods of exposure suggest that chemoprophylaxis could be a promising strategy to protect forest workers against malaria. Here we discuss three major questions in optimizing malaria chemoprophylaxis for forest workers: which antimalarial drug regimens are most appropriate, how frequently the chemoprophylaxis should be delivered, and how to motivate forest workers to use, and adhere to, malaria prophylaxis.

Seasonal malaria chemoprevention combined with community case management of malaria in children under 10 years of age, over 5 months, in south-east Senegal: A cluster-randomised trial.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year. It may be appropriate to include older children, and to provide protection for more than 4 months. We evaluated the effectiveness of SMC using sulfadoxine-pyrimethamine plus amodiaquine given over 5 months to children under 10 years of age in Saraya district in south-east Senegal in 2011. METHODS AND FINDINGS: Twenty-four villages, including 2,301 children aged 3-59 months and 2,245 aged 5-9 years, were randomised to receive SMC with community case management (CCM) (SMC villages) or CCM alone (control villages). In all villages, community health workers (CHWs) were trained to treat malaria cases with artemisinin combination therapy after testing with a rapid diagnostic test (RDT). In SMC villages, CHWs administered SMC to children aged 3 months to 9 years once a month for 5 months. The study was conducted from 27 July to 31 December 2011. The primary outcome was malaria (fever or history of fever with a positive RDT). The prevalence of anaemia and parasitaemia was measured in a survey at the end of the transmission season. Molecular markers associated with resistance to SMC drugs were analysed in samples from incident malaria cases and from children with parasitaemia in the survey. SMC was well tolerated with no serious adverse reactions. There were 1,472 RDT-confirmed malaria cases in the control villages and 270 in the SMC villages. Among children under 5 years of age, the rate difference was 110.8/1,000/month (95% CI 64.7, 156.8; p < 0.001) and among children 5-9 years of age, 101.3/1,000/month (95% CI 66.7, 136.0; p < 0.001). The mean haemoglobin concentration at the end of the transmission season was higher in SMC than control villages, by 6.5 g/l (95% CI 2.0, 11; p = 0.007) among children under 5 years of age, and by 5.2 g/l (95% CI 0.4, 9.9; p = 0.035) among children 5-9 years of age. The prevalence of parasitaemia was 18% in children under 5 years of age and 25% in children 5-9 years of age in the control villages, and 5.7% and 5.8%, respectively, in these 2 age groups in the SMC villages, with prevalence differences of 12.5% (95% CI 6.8%, 18.2%; p < 0.001) in children under 5 years of age and 19.3% (95% CI 8.3%, 30.2%; p < 0.001) in children 5-9 years of age. The pfdhps-540E mutation associated with clinical resistance to sulfadoxine-pyrimethamine was found in 0.8% of samples from malaria cases but not in the final survey. Twelve children died in the control group and 14 in the SMC group, a rate difference of 0.096/1,000 child-months (95% CI 0.99, 1.18; p = 0.895). Limitations of this study include that we were not able to obtain blood smears for microscopy for all suspected malaria cases, such that we had to rely on RDTs for confirmation, which may have included false positives. CONCLUSIONS: In this study SMC for children under 10 years of age given over 5 months was feasible, well tolerated, and effective in preventing malaria episodes, and reduced the prevalence of parasitaemia and anaemia. SMC with CCM achieved high coverage and ensured children with malaria were promptly treated with artemether-lumefantrine. TRIAL REGISTRATION: www.clinicaltrials.gov NCT01449045.

Progress in Drug and Formulation Development for the Chemoprevention of Oral Squamous Cell Carcinoma: A Review.

BACKGROUND: Cancer is a life-threatening global problem with high incidence rates. Prioritizing the prevention of cancer, chemopreventive agents have drawn much attention from the researchers. OBJECTIVE: This review focuses on the discussion of the progress in the development of chemopreventive agents and formulations related to the prevention of oral cancer. METHODS: In this perspective, an extensive literature survey was carried out to understand the mechanism, control and chemoprevention of oral cancer. Different patented agents and formulations have also exhibited cancer preventive efficacy in experimental studies. This review summarizes the etiology of oral cancer and developments in prevention strategies. RESULTS: The growth of oral cancer is a multistep activity necessitating the accumulation of genetic as well as epigenetic alterations in key regulatory genes. Many risk factors are associated with oral cancer. Genomic technique for sequencing all tumor specimens has been made available to help detect mutations. The recent development of molecular pathway and genetic tools has made the process of diagnosis easier, better forecast and efficient therapeutic management. Different chemical agents have been studied for their efficacy to prevent oral cancer and some of them have shown promising results. CONCLUSION: Use of chemopreventive agents, either synthetic or natural origin, to prevent carcinogenesis is a worthy concept in the management of cancers. Preventive measures are helpful in controlling the occurrence or severity of the disease. The demonstrated results of preventive agents have opened an arena for the development of promising chemopreventive agents in the management of oral squamous cell carcinoma.

Chemopreventive mechanisms of galangin against hepatocellular carcinoma: A review.

Hepatocellular carcinoma (HCC) is one of the most common cancers and has a high mortality rate in less developed countries, especially in China. Galangin (GA), one of the most important and naturally active flavonoids, extracted primarily from the root of Alpinia officinarum Hance, has been demonstrated to be effective in the treatment of HCC. It is a substance with defensive actions and a broad range of biological properties, including inhibitory effects on bacteria, fungi, viruses, the control of hypertension and diabetes, and chemoprevention of several cancers. Experiments have shown that GA prevents HCC through multiple anti-cancer mechanisms, anti-genotoxic activity against environmental and dietary carcinogens; anti-proliferative effects through reversal of the Warburg effect in HCC; arrest of the cell cycle in the G0/G1 phase; induction of apoptosis via stimulation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and the mitochondrial-dependent apoptosis pathway; induction of autophagy; and inhibition of angiogenesis, metastasis, and multidrug resistance (MDR). In addition, synergistic effects with other chemotherapy drugs have been demonstrated. Therefore, this review is focused on the anti-HCC mechanisms of GA.

Molecular Mechanisms of Neurotoxicity Induced by Polymyxins and Chemoprevention.

Neurotoxicity is one major unwanted side-effects associated with polymyxin (i.e., colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This Review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuroprotective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt, and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be upregulated by neuroprotective agents including curcumin, rapamycin and minocycline. Further research is needed toward the development of novel polymyxin formulations in combination with neuroprotective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.

[Monoclonal antibodies in infectious diseases: new partners in the therapeutic arsenal]. / Anticorps monoclonaux en infectiologie - Des nouveaux partenaires dans l'arsenal thérapeutique.

Development of therapeutic antibodies for treating infectious diseases is more recent than for cancer and inflammatory diseases. To date, seven antibodies have been approved worldwide and only five in France. Medical indications are so far limited to the prophylaxis of bronchiolitis caused by respiratory syncytial virus (RSV), treatment of multidrug-resistant HIV disease, exposure to rabies and anthrax pulmonary disease, prevention of diarrhea recurrence due to Clostridium difficile, and atypical hemolytic uremic syndrome caused by Escherichia coli. In a near future, new technologies would allow accelerating the development of anti-infectious monoclonal antibodies to improve the anti-bacterial and anti-viral therapeutic arsenal.

TITLE: Anticorps monoclonaux en infectiologie - Des nouveaux partenaires dans l'arsenal thérapeutique. ABSTRACT: Le développement des anticorps thérapeutiques en infectiologie est beaucoup plus récent qu'en cancérologie, à l'exception d'un anticorps anti-virus respiratoire syncytial (VRS), mais il est désormais un domaine en pleine expansion. À l'échelle mondiale, sept de ces anticorps ont déjà été approuvés par des autorités de santé, dont seulement cinq en France. À ce jour, les indications sont restreintes à la prévention de la bronchiolite liée au VRS, au traitement de la maladie VIH/Sida en échec thérapeutique, à l'exposition au virus de la rage et à la maladie du charbon, à la colite post-antibiotique à Clostridium difficile, et au syndrome hémolytique et urémique atypique à Escherichia coli entéro-hémorragique. Dans un futur proche, l'essor des nouvelles technologies devrait permettre d'accélérer le développement d'anticorps monoclonaux anti-infectieux afin d'étoffer l'arsenal antibiotique et antibactérien déjà à disposition. .

Increasing prevalence of self-reported HIV preexposure prophylaxis use in published surveys: a systematic review and meta-analysis.

: When combining results from all published surveys, about one in nine global study participants (10.7%) reported ever using preexposure prophylaxis (PrEP) by 2017, a significant increase since US FDA approval in 2012 [odds ratio (OR) = 1.6/year, P < 0.00001]. Moreover, nearly one in six US-based study participants (17.3%) and nearly one in four MSM who met the Centers for Disease Control and Prevention's PrEP indications (24.5%) reported ever using PrEP by 2016. The odds of reporting PrEP use are approximately doubling each year (OR = 1.8/year, P < 0.00001; OR = 2.0/year, P < 0.00001).