Highlights • The transmission of hepatitis C virus (HCV) is increasing within the specific core group of men who have sex with men (MSM) because of increased sexual risk behaviours, including ...serosorting on the basis of HIV-positive status, chemsex, and intense mucosally traumatic sexual practices. • The advent of direct-acting antivirals has improved treatment responses of HCV infection significantly; however, sexually transmitted HCV reinfections occur in a substantial proportion of HIV-positive MSM following clearance of a primary infection. • Effective screening and preventive strategies tailored to the MSM communities are needed to facilitate the control of sexually acquired HCV infection.
APOBEC3G (A3G), a host protein that inhibits HIV-1 reverse transcription and replication in the absence of Vif, displays cytidine deaminase and single-stranded (ss) nucleic acid binding activities. ...HIV-1 nucleocapsid protein (NC) also binds nucleic acids and has a unique property, nucleic acid chaperone activity, which is crucial for efficient reverse transcription. Here we report the interplay between A3G, NC and reverse transcriptase (RT) and the effect of highly purified A3G on individual reactions that occur during reverse transcription. We find that A3G did not affect the kinetics of NC-mediated annealing reactions, nor did it inhibit RNase H cleavage. In sharp contrast, A3G significantly inhibited all RT-catalyzed DNA elongation reactions with or without NC. In the case of (−) strong-stop DNA synthesis, the inhibition was independent of A3G's catalytic activity. Fluorescence anisotropy and single molecule DNA stretching analyses indicated that NC has a higher nucleic acid binding affinity than A3G, but more importantly, displays faster association/disassociation kinetics. RT binds to ssDNA with a much lower affinity than either NC or A3G. These data support a novel mechanism for deaminase-independent inhibition of reverse transcription that is determined by critical differences in the nucleic acid binding properties of A3G, NC and RT.
A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective ...breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.
•Most breast tumors survive glutamine restriction, limiting its therapeutic use•A subset of triple-negative breast tumors are true glutamine auxotrophs•Conventional biomarkers of glutamine reliance do not identify true auxotrophs•Triple-negative tumors require cystine import via the xCT transporter
Unique features of tumours that can be exploited by targeted therapies are a key focus of current cancer research. One such approach is known as synthetic lethality screening, which involves ...searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Here, we summarize strategies that can be used to identify synthetic lethal interactions for anticancer drug discovery, describe examples of such interactions that are currently being investigated in preclinical and clinical studies of targeted anticancer therapies, and discuss the challenges of realizing the full potential of such therapies.
Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even, rarely, mortality. This form of toxicity potentially impacts the treatment outcome ...of tuberculosis in some patients. Covering only first-line antituberculosis drugs, this review addresses whether and how oxidative stress and, more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection, and preexisting liver disease. Importantly, these comorbid conditions are associated with oxidative stress and drugs related to antioxidants, especially those for management of mitochondrial dysfunction. Thus, the shared pathogenetic mechanism(s) for liver injury might be in operation due to disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. More translational research to unravel the pathogenesis, inclusive of the underlying molecular bases, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is clinical research pertaining to the advances in therapy, with antioxidants and beyond. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.
Background:
Physicians counseling athletes on the prognosis of sport-specific performance outcomes after anterior cruciate ligament reconstruction (ACLR) depend on the published literature. However, ...critical appraisal of the validity and biases in these studies is required to understand how ACLR affects an athlete’s ability to return to sport, the athlete’s sport-specific performance, and his or her ability to achieve preinjury levels of performance.
Purpose:
This review identifies the published prognostic studies evaluating sport-specific performance outcomes after ACLR. A risk of bias assessment and summaries of return to sport and career longevity results are provided for each included study.
Study Design:
Systematic review.
Methods:
Electronic databases (Ovid MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and PUBMED) were searched via a defined search strategy with no limits, to identify relevant studies for inclusion in the review. A priori defined eligibility criteria included studies measuring sport-specific performance within an athlete’s sport, before and after primary ACLR. Reference lists of eligible studies were hand-searched for additional relevant studies. Data extraction was performed by use of a standardized spreadsheet. Each included study was assessed by use of 6 bias domains of the Quality in Prognosis Studies tool to critically appraise study participation, study attrition, prognostic factors, outcome measurement, confounders, and statistical analysis and reporting. Two authors independently performed each stage of the review and reached consensus through discussion.
Results:
Fifteen pertinent prognostic studies evaluated sport-specific performance outcomes and/or return to play after ACLR for athletes participating in competitive soccer, football, ice hockey, basketball, Alpine ski, X-Games ski and snowboarding, and baseball. Twelve of these studies were considered to have a high level of bias.
Conclusion:
This review demonstrated that most high-performance or professional athletes returned to their preinjury level of sport after ACLR. The bulk of evidence suggests there was a measurable decrease in performance statistics, although this is highly sport-specific. A paucity of literature is available that addresses sport-specific performance in athletes after ACLR. This review has determined that the available literature is highly biased and must be read with caution.
Clinical Relevance:
By better understanding the validity and biases in the published literature, physicians can provide more informed prognoses about return to sport-specific performance after ACLR while considering risk factors relevant to their patients.
Registration:
CRD42016046709 (International Prospective Register of Systematic Reviews, https://www.crd.york.ac.uk/prospero/)
Undiagnosed infections accounted for the hidden proportion of HIV cases that have escaped from public health surveillance. To assess the population risk of HIV transmission, we estimated the ...undiagnosed interval of each known infection for constructing the HIV incidence curves.
We used modified back-calculation methods to estimate the seroconversion year for each diagnosed patient attending any one of the 3 HIV specialist clinics in Hong Kong. Three approaches were used, depending on the adequacy of CD4 data: (A) estimating one's pre-treatment CD4 depletion rate in multilevel model;(B) projecting one's seroconversion year by referencing seroconverters' CD4 depletion rate; or (C) projecting from the distribution of estimated undiagnosed intervals in (B). Factors associated with long undiagnosed interval (>2 years) were examined in univariate analyses. Epidemic curves constructed from estimated seroconversion data were evaluated by modes of transmission.
Between 1991 and 2010, a total of 3695 adult HIV patients were diagnosed. The undiagnosed intervals were derived from method (A) (28%), (B) (61%) and (C) (11%) respectively. The intervals ranged from 0 to 10 years, and were shortened from 2001. Heterosexual infection, female, Chinese and age >64 at diagnosis were associated with long undiagnosed interval. Overall, the peaks of the new incidence curves were reached 4-6 years ahead of reported diagnoses, while their contours varied by mode of transmission. Characteristically, the epidemic growth of heterosexual male and female declined after 1998 with slight rebound in 2004-2006, but that of MSM continued to rise after 1998.
By determining the time of seroconversion, HIV epidemic curves could be reconstructed from clinical data to better illustrate the trends of new infections. With the increasing coverage of antiretroviral therapy, the undiagnosed interval can add to the measures for assessing HIV transmission risk in the population.
People with HIV (PWH) co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at higher odds of severe diseases. Whereas the immunogenicity of mRNA vaccine and ...adenovirus-vectored vaccine was similar between PWH in stable condition and healthy adults, the effects of inactivated vaccines are not known.
Prospective longitudinal observational study in real-world setting.
Adult PWH in care and planning to receive either inactivated (day 0 and day 28) or mRNA-based (day 0 and day 21) vaccine against SARS-CoV-2 were recruited, with blood samples collected over 6 months for surrogate virus neutralization test (sVNT). Demographic and clinical data including age, sex, CD4 + cell count, and suppressed viral load (SVL) status were transcribed for analyses, by simple and multivariable linear regression models, and multivariable linear generalized estimating equations (GEE).
A total of 611 HIV patients, 91% male patients, were recruited, of whom 423 and 184 have received mRNA-based and inactivated vaccine, respectively. The seroconversion rate was 99% for mRNA-based vs, 86% for inactivated vaccine odds ratio (OR) = 21.56, P = 0.004. At 6 months, mRNA-based vaccine continued to give a higher response (94 vs. 57%, P < 0.001). The temporal pattern varied between the two vaccines. By GEE, mRNA-based vaccine ( B = 40.59, P < 0.001) and latest SVL status ( B = 10.76, P = 0.01) were positively associated with sVNT level, but not latest CD4 + cell count.
In HIV patients, inactivated vaccine gave a lower peak and shorter duration of sVNT responses compared with mRNA vaccine. The results suggested that different strategies may be needed in boosting the immunity in anticipation of the emergence of variants in the community.
In a cohort of persons living with HIV in Hong Kong, surrogate virus neutralization testing for COVID-19 yielded a median level of 89% after the third dose of an inactivated COVID-19 vaccine, ...compared with 37% after the second dose. These results support using a 3-dose primary series for enhanced immune protection.
The human APOBEC3 proteins are a family of DNA-editing enzymes that play an important role in the innate immune response against retroviruses and retrotransposons. APOBEC3G is a member of this family ...that inhibits HIV-1 replication in the absence of the viral infectivity factor Vif. Inhibition of HIV replication occurs by both deamination of viral single-stranded DNA and a deamination-independent mechanism. Efficient deamination requires rapid binding to and dissociation from ssDNA. However, a relatively slow dissociation rate is required for the proposed deaminase-independent roadblock mechanism in which APOBEC3G binds the viral template strand and blocks reverse transcriptase-catalysed DNA elongation. Here, we show that APOBEC3G initially binds ssDNA with rapid on-off rates and subsequently converts to a slowly dissociating mode. In contrast, an oligomerization-deficient APOBEC3G mutant did not exhibit a slow off rate. We propose that catalytically active monomers or dimers slowly oligomerize on the viral genome and inhibit reverse transcription.
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