Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation.

Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a few of the approximately 600 human E3 ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases. Here we identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12. SP3N features a minimal design, where a known FKBP12 ligand is appended with a flexible alkylamine tail that conveys degradation properties. We found that SP3N is a precursor and that the alkylamine is metabolized to an active aldehyde species that recruits the SCFFBXO22 ligase for FKBP12 degradation. Target engagement occurs via covalent adduction of Cys326 in the FBXO22 C-terminal domain, which is critical for ternary complex formation, ubiquitylation and degradation. This mechanism is conserved for two recently reported alkylamine-based degraders of NSD2 and XIAP, thus establishing alkylamine tethering and covalent hijacking of FBXO22 as a generalizable TPD strategy.

Progress towards elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission update.

The top 20 highest burdened countries (in disability-adjusted life years) account for more than 75% of the global burden of viral hepatitis. An effective response in these 20 countries is crucial if global elimination targets are to be achieved. In this update of the Lancet Gastroenterology & Hepatology Commission on accelerating the elimination of viral hepatitis, we convene national experts from each of the top 20 highest burdened countries to provide an update on progress. Although the global burden of diseases is falling, progress towards elimination varies greatly by country. By use of a hepatitis elimination policy index conceived as part of the 2019 Commission, we measure countries' progress towards elimination. Progress in elimination policy has been made in 14 of 20 countries with the highest burden since 2018, with the most substantial gains observed in Bangladesh, India, Indonesia, Japan, and Russia. Most improvements are attributable to the publication of formalised national action plans for the elimination of viral hepatitis, provision of publicly funded screening programmes, and government subsidisation of antiviral treatments. Key themes that emerged from discussion between national commissioners from the highest burdened countries build on the original recommendations to accelerate the global elimination of viral hepatitis. These themes include the need for simplified models of care, improved access to appropriate diagnostics, financing initiatives, and rapid implementation of lessons from the COVID-19 pandemic.

Risk factors associated with HCV co-infection amongst MSM and transgender women living with HIV in Mexico City: A case-control study.

INTRODUCTION AND OBJECTIVES: Hepatitis C virus infection (HCV) is a major cause of co-morbidity in people living with HIV (PLWHIV). The modes of HCV transmission in the local population of PLWHIV are still unclear. We conducted this study to identify risk factors for HCV transmission amongst PLWHIV in central Mexico. MATERIAL AND METHODS: We enrolled HIV/HCV co-infected cases and HIV controls receiving care in two outpatient clinics in Mexico City. Structured questionnaires were applied, covering demographics, history of percutaneous exposures, sexual behaviors, self-reported STD and recreational drug use. The statistical analysis for between-group comparisons were multivariate logistic regression models to assess the risk factors associated with HCV co-infection. We limited the final analysis to men who have sex with men (MSM) to avoid confounders potentially related to HCV acquisition in other populations. RESULTS: Three hundred and thirty-four MSM with HIV (175 with HCV co-infection and 159 without) were analysed. We did not identify percutaneous exposures as risk factors for HCV. Intravenous drug use (IVDU) occurred in two cases and one control case. Risk factors independently associated with acquiring HCV co-infection were: history of an ulcerative STD (aOR=2.65, 95%CI=1.44-4.88), a HCV positive partner (aOR=5.25, 95%CI=2.78-9.91), having practiced insertive fisting (aOR=2.62, 95%CI=1.01-6.90), and rectal administration of drugs during sex (aOR=2.46, 95%CI=1.25-4.84). CONCLUSIONS: Risky sexual behaviors and chemsex seem to be the main drivers of HIV/HCV co-infection amongst PLWHIV in Central Mexico. IVDU and percutaneous exposures have a minor role in the local HCV epidemic. These findings highlight the importance of testing for HCV in sexually active MSMs.

Cirrhosis etiology trends in developing countries: Transition from infectious to metabolic conditions. Report from a multicentric cohort in central Mexico.

Background: Cirrhosis is a public health threat associated with high mortality. Alcoholic Liver Disease (ALD) is the leading cause in Latin America and Metabolic Associated Fatty Liver Disease (MAFLD) in western countries. In Mexico, ALD and chronic Hepatitis C Virus infection (HCV) were the most frequent aetiologies during the past decades. We aimed to describe the trends in the aetiologies of cirrhosis in a middle-income country. Methods: We performed a retrospective cohort study including patients diagnosed with cirrhosis between 2000 and 2019 from six different tertiary care hospitals in central Mexico. We collected information regarding cirrhosis etiology, year of diagnosis, hepatocellular carcinoma development, liver transplantation, and death. We illustrated the change in the tendencies of cirrhosis aetiologies by displaying the proportional incidence of each etiology over time stratified by age and gender, and we compared these proportions over time using chi square tests. Findings: Overall, 4,584 patients were included. In 2019, MAFLD was the most frequent cirrhosis etiology (30%), followed by ALD (24%) and HCV (23%). During the study period, MAFLD became the leading etiology, ALD remained second, and HCV passed from first to fourth. When analysed by gender, ALD was the leading etiology for men and MAFLD for women. The annual incidence of HCC was 3·84 cases/100 persons-year, the median survival after diagnosis was 12·1 years, and seven percent underwent LT. Interpretation: Increased alcohol consumption and the obesity epidemic have caused a transition in the aetiologies of cirrhosis in Mexico. Public health policies must be tailored accordingly to mitigate the burden of alcohol and metabolic conditions in developing countries. Funding: None.

Biodegradation of hexadecane using sediments from rivers and lagoons of the Southern Gulf of Mexico.

The Southern Gulf of Mexico is an area highly impacted by crude oil extraction, refining activities and the presence of natural petroleum seepage. Oceanic currents in the Gulf of Mexico continually facilitate the transport of hydrocarbons to lagoons and rivers. This research evaluated hexadecane (HXD) degradation in marine sediment samples from lagoons and rivers that are fed by the Southern Gulf of Mexico, specifically six samples from rivers, three samples from lagoons, and one sample from a marine outfall. The highest rates of biodegradation were observed in sediments from the mouths of the Gonzalez River and the Champotón Lagoon. The lowest consumption rate was found in sediment from the mouth of the Coatzacoalcos River. With regards to the Ostión Lagoon and the Grijalva River, there was a low rate of consumption, but a high efficiency of degradation which took place at the end of the experiments. No correlation was found between the consumption rate and the environmental physicochemical parameters.

Pocket ultrasound device as a complement to physical examination for ascites evaluation and guided paracentesis.

The pocket ultrasound device (PUD) is a new tool that may be of use in the early detection of ascites. Abdominal ultrasound-guided paracentesis has been reported to decrease the rate of complications due to the procedure, but must be performed in a healthcare setting; this new tool may be a useful on an ambulatory basis. The aim of this study was to determine the diagnostic usefulness of the PUD in the diagnosis of ascites and the safety of guided paracentesis. We conducted a retrospective study that included adult patients suspected of having ascites and in whom an evaluation was performed with the PUD to identify it. Concordance with abdominal ultrasound (AUS) was determined with the Kappa coefficient. Sensitivity (Se), specificity (Sp) and likelihood ratios (LR) were determined and compared with physical examination, AUS, computed tomography and procurement of fluid by paracentesis. Complications resulting from the guided paracentesis were analyzed. 89 participants were included and 40 underwent a paracentesis. The PUD for ascites detection had 95.8 % Se, 81.8 % Sp, 5.27 +LR and 0.05 -LR. It had a concordance with AUS of 0.781 (p < 0.001). Technical problems during the guided paracentesis were present in only two participants (5 %) and three patients (7.5 %) developed minor complications that required no further intervention. There were no severe complications or deaths. This study suggests that the PUD is a reliable tool for ascites detection as a complement to physical examination and appears to be a safe method to perform guided paracentesis.

A genetic variant in the interleukin 28B gene as a major predictor for sustained virologic response in chronic hepatitis C virus infection.

BACKGROUND AND AIMS: The IL28B single nucleotide polymorphism (SNP) rs12979860 is a major predictor of treatment outcomes in hepatitis C virus (HCV) infection, but its distribution widely varies among populations and ethnicities. We undertook this study to investigate the distribution of IL28B SNP rs12979860 in Mexican patients with HCV infection and to assess its usefulness in predicting response to pegylated interferon-alpha and ribavirin (PegIFN-α/RVB) therapy. METHODS: Three hundred and fifty patients with chronic HCV infection were studied. The frequency of sustained virologic response (SVR), non-responders and relapses following a course of standard therapy was longitudinally assessed in 295 of these patients. IL28B SNP rs12979860 was genotyped from genomic DNA using real-time RT-PCR. The number needed to treat (NNT) to achieve a SVR was calculated. RESULTS: Seventy six (22%) patients were CC homozygous, 210 (60%) were heterozygous and 64 (18%) showed TT homozygosity for the IL28B SNP rs12979860. After a standard course of PegIFN-α/RVB, 69% of patients with the CC genotype, 46% of the heterozygous group and 38% of those with the TT genotype (p = 0.001) achieved a SVR. Conversely, the percentage of non-responders was 15, 43, and 48% (p <0.0001), respectively. The NNT to achieve a SVR was strongly influenced by the IL28B rs12979860 genotype and ranged from 2-10. CONCLUSIONS: The IL-28B rs12979860 CC genotype was found in 22% of Mexican patients chronically infected by HCV. Genotyping IL28B SNP rs12979860 is useful to predict the response to a standard regimen with PegIFN-α/RVB, especially in those infected with HCV genotype 1.

Diagnosis and treatment of hepatocellular carcinoma: An update.

Hepatocellular carcinoma (HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium "washout" in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and loco-regional therapies (alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion's stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib.

Mexican consensus on the diagnosis and management of hepatocellular carcinoma.

INTRODUCTION: There has been an increase in the incidence of hepatocellular carcinoma (HCC) worldwide and information on this disease is limited in Mexico. AIMS: To analyze the available evidence on the diagnosis and treatment of HCC in the Mexican population. MATERIAL AND METHODS: The Mexican Association of Hepatology organized a meeting that 24 medical specialists interested in HCC attended. An electronic database search was carried out to identify documents published from 2000 with the keywords «Hepatocellular carcinoma¼ and «Mexico¼, «epidemiology¼, «diagnosis¼, and «treatment¼. RESULTS: The incidence of HCC in Mexico has increased over the last few decades. The mean age of disease presentation is in patients from 60 to 70 years old, and the man:woman ratio appears to be equal. HCC is frequently associated with underlying hepatopathy and the primary cause reported in our country is chronic hepatitis C virus) infection. Surveillance is recommended for high-risk groups in Child-Pugh stages A and B, and for those in stage C if the patient is on a waiting list or regarded as a candidate for liver transplantation. HCC should be evaluated by a multidisciplinary team of experts in the field. CONCLUSIONS: HCC is a neoplasia that is on the rise in Mexico, with epidemiologic characteristics similar to those of other populations. Diagnosis and treatment should be individualized in accordance with these Consensus guidelines.

The metazoan parasite communities of the shoal flounder (Syacium gunteri) as bioindicators of chemical contamination in the southern Gulf of Mexico.

BACKGROUND: Because agriculture and offshore oil extraction are significant economic activities in the southern Gulf of Mexico, high concentrations of nutrients and hydrocarbons are expected. As parasite communities are sensitive to environmental impacts, these contaminants should have an effect on metrics such as species richness, relative abundance and similarity. Consequently, these community metrics can be used as indicators of aquatic environmental health. Our objectives were to describe the parasite communities of the shoal flounder Syacium gunteri and to determine potential thresholds above which environmental contaminants become major controlling factors of parasite community metrics. METHODS: The study area included 33 sampling sites in the southern Gulf of Mexico, where benthic sediments, water and shoal flounder individuals were collected. Data on ecto- and endo-parasites from flounder and nutrients, contaminants and physicochemical variables from the water and sediments were obtained. The statistical associations of the parasite community metrics at the component and infracommunity levels and the environmental data were analysed using redundancy analysis (RDA). RESULTS: Overall, 203 shoal flounder were examined for parasites, recovering 13 metazoan parasite species, and 48 physicochemical (e.g. temperature, nutrients) and contaminant (e.g. hydrocarbons, heavy metals) variables were obtained. The larval stages of the cestode Oncomegas wageneri and the nematodes Pseudoterranova decipiens and Hysterothylacium sp. were numerically dominant at the component and infracommunity levels. The parasite community metrics had significant negative statistical associations with both nitrate and total PAHs. With the exception of these two chemicals, which exceeded the threshold effect levels (TELs), no other environmental variable exceeded the range considered safe for marine organisms. CONCLUSIONS: The community metrics chosen generally had robust statistically significant associations with both physicochemical and contaminant variables, which supports the ecological relevance of these parameters as indicators of aquatic environmental health. Within the study area, the shoal flounder and their parasites live in a polluted environment with relatively high levels of hydrocarbons and nitrate. Regarding nitrate, we emphasise that if uncontrolled sewage discharge continues in the southern Gulf of Mexico, hypoxic conditions similar to those caused by the Mississippi river can be expected in the near future.

Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer.

Re-treatment with highly purified nIFNα in Mexican nonresponder patients with chronic genotype 1 hepatitis C.

BACKGROUND AND AIMS: We undertook this study to evaluate the virological response to and presence of adverse events to natural interferon α (nIFNα; Multiferon®) treatment in previously nonresponsive Mexican patients chronically infected with genotype 1 hepatitis C. METHODS: Thirty-nine patients received a 4-week induction of 5 days/week of 6 MU nIFNα plus weight-based ribavirin followed by 3 MU of nIFNα three times a week for 44 weeks. The relationship between viral response and incidence of adverse events was analyzed. RESULTS: Early viral response (EVR) was age- and sex-dependent, with older male patients being less responsive. Sustained viral response (SVR) was evaluated according to: a) intention to treat analysis, b) 48-week treatment and 24-week follow-up (16 patients), and c) patients with EVR (11 patients). None of the factors was significantly different in groups a) and b); however, in group c) there was a better response with a marked viral load decline in younger patients and in patients aged 50 years and older. Five of 39 (13%) patients who completed treatment presented with an SVR. The most common adverse effect was asthenia in 27% of patients. CONCLUSIONS: nIFNα could be a useful strategy for re-treatment in chronic hepatitis C, genotype 1, in previously nonresponsive patients. Confirmation of these data in a larger population is required.

Sources, fluxes and risk of organic micropollutants to the Cantabrian Sea (Spain).

The sources, distribution and risk of 51 organic micropollutants (OMPs) in the Cantabrian coastal environment (NW Spain) were evaluated. Gas chromatography coupled to tandem mass spectrometry was used to determine polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, phthalates esters, bisphenol A and alkylphenols. 45 OMPs were detected in coastal/estuarine waters. Wastewater treatment plant effluents and emissary discharges were identified as the main sources of contamination. The accumulation of OMPs in sediments and the bioaccumulation in 21 days caged mussels were also assessed. Chemical results were combined with the "Combined Monitoring-based and Modeling-based Priority Setting Scheme" COMMPS procedure for risk assessment analysis. Finally, the chemical status of the different sampling locations was estimated using site risk indexes. Those indexes can be conveniently displayed in quality geographical maps and are considered a valuable tool for the environmental management and risk assessment of the region under study.

An update on the management of hepatitis C: guidelines for protease inhibitor-based triple therapy from the Latin American Association for the Study of the Liver.

Hepatitis C is a common cause of end-stage liver disease, and the main indication for liver transplantation in Latin America. Treatment of hepatitis C infected patients improves important long-term outcomes as mortality. Sustained viral response is reached in near 50% of patients with the previous management based in pegylated interferon and ribavirin. Recently new drugs were available increasing sustained viral response significantly, changing the standard of care to triple therapy. This guidelines provides a framework for practitioner in Latin America, to the management of patients with hepatitis C chronic infection. 

Organic micropollutants in coastal waters from NW Mediterranean Sea: sources distribution and potential risk.

This study provides a first estimation on the sources, distribution and risk of organic micropollutants (OMPs) in coastal waters from NW Mediterranean Sea. Polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, phthalates and alkylphenols were analyzed by solid phase extraction and gas chromatography coupled to tandem mass spectrometry (SPE-GC-EI-MS/MS). River waters and wastewater treatment plant effluents discharging to the sea were identified as the main sources of OMPs to coastal waters, with an estimated input amount of around of 25,800 g d(-1). The concentration of ΣOMPs in coastal areas ranged from 17.4 to 8442 ng L(-1), and was the highest in port waters, followed by coastal and river mouth seawaters. A summarized overview of the patterns and sources of OMP contamination on the investigated coastal sea waters of NW Mediterranean Sea, as well as of their geographical distribution was obtained by Principal Component Analysis of the complete data set after its adequate pretreatment. Alkylphenols, bisphenol A and phthalates were the main contributors to ΣOMPs and produced an estimated significant pollution risk for fish, algae and the sensitive mysid shrimp organisms in seawater samples. The combination of GC-MS/MS, chemometrics and risk analysis is proven to be useful for a better control and management of OMP discharges.

Development of a multi-residue method for the determination of organic micropollutants in water, sediment and mussels using gas chromatography-tandem mass spectrometry.

This study describes the development of a multiresidue method based on gas chromatography-electron ionization-tandem mass spectrometry (GC-EI-MS/MS) for the detection of sixteen polycyclic aromatic hydrocarbons (PAHs), five phthalate esters (PEs), seven polychlorinated biphenyls (PCBs), six polybrominated diphenyl ethers (PBDEs), six alkylphenols (APs), three organochlorined pesticides and their isomers or degradation products (OCPs) and bisphenol A in seawater, river water, wastewater treatment plant (WWTP) effluents, sediments and mussels. Solid phase extraction (SPE) was used for the extraction of target analytes in aqueous samples, and ultrasound assisted extraction for solid samples. GC-EI-MS/MS acquisition conditions in selected reaction monitoring (SRM) using two transitions per compound were optimized. In this way, quantification and unequivocal identification of organic micropollutants were performed in compliance with the Decision 2002/657/EC. Good linearity responses with coefficients of determination higher than 0.99 were obtained. Methodological detection limits (MDLs) in seawater ranged from 0.1 to 6 ng L(-1); in river water from 0.1 to 4.8 ng L(-1); in WWTP effluents from 1 to 75 ng L(-1); in sediments from 1 to 150 ng g(-1) and in mussels from 1 to 125 ng g(-1). MDLs and recovery yields were compared with other published methods and similarities or even improvements were achieved. The optimized method was applied to analyze five samples from each matrix collected in coastal areas, showing its potential use for marine pollution monitoring.