Summary
Background
Treatment of hepatitis B virus (HBV) infection with current therapy suppresses HBV DNA, but loss of hepatitis B surface antigen (HBsAg; functional cure), is rare. Multiple ...compounds are under investigation.
Aims
To describe the pharmacology, including drug interactions, efficacy, safety and mechanisms of action of investigational compounds for HBV infection.
Methods
Descriptive review using PubMed and Google to identify literature/conference papers on investigational compounds (≥Phase 2) with data on efficacy and safety in HBV‐infected patients.
Results
Bulevirtide, JNJ‐56136379, ABI‐H0731, REP‐2139, and inarigivir decrease HBV DNA/RNA, with greater potency than current nucleos(t)ide analogues. REP‐2139 (25%‐75% of patients, 20‐48 weeks treatment) and inarigivir (26% of patients, 12‐24 weeks treatment) induce HBsAg loss. ARO‐HBV reduced (>1.5 log10 UI/mL) HBsAg in 85% of patients (12 weeks treatment). There are some safety concerns with investigational agents (e.g., increased bile acids with bulevirtide, and liver enzyme flares with REP‐2139) which will require a risk benefit assessment compared with current therapies. Single and multidose pharmacokinetic data are available for bulevirtide, JNJ‐56136379, ABI‐H0731; no such data are available for REP‐2139, ARO‐HBV, inarigivir. Initial drug interaction assessments have been performed with bulevirtide and inarigivir (only in vitro).
Conclusions
There are promising investigational therapies for HBV infection. Increasing the potential for HBsAg loss may result in more patients achieving functional cure. However, many knowledge gaps remain such as pharmacokinetics in those with HBV, cirrhosis and renal impairment but also the interaction potential between investigational therapies, risk‐benefit profiles, and potential for drug interactions with medications used to treat comorbidities associated with aging.
Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies
. In this strategy, the T cell genome is modified by integration of viral vectors ...or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells
. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.
Coastal forests sequester and store more carbon than their terrestrial counterparts but are at greater risk of conversion due to sea level rise. Saltwater intrusion from sea level rise converts ...freshwater-dependent coastal forests to more salt-tolerant marshes, leaving 'ghost forests' of standing dead trees behind. Although recent research has investigated the drivers and rates of coastal forest decline, the associated changes in carbon storage across large extents have not been quantified. We mapped ghost forest spread across coastal North Carolina, USA, using repeat Light Detection and Ranging (LiDAR) surveys, multi-temporal satellite imagery, and field measurements of aboveground biomass to quantify changes in aboveground carbon. Between 2001 and 2014, 15% (167 km2) of unmanaged public land in the region changed from coastal forest to transition-ghost forest characterized by salt-tolerant shrubs and herbaceous plants. Salinity and proximity to the estuarine shoreline were significant drivers of these changes. This conversion resulted in a net aboveground carbon decline of 0.13 ± 0.01 TgC. Because saltwater intrusion precedes inundation and influences vegetation condition in advance of mature tree mortality, we suggest that aboveground carbon declines can be used to detect the leading edge of sea level rise. Aboveground carbon declines along the shoreline were offset by inland aboveground carbon gains associated with natural succession and forestry activities like planting (2.46 ± 0.25 TgC net aboveground carbon across study area). Our study highlights the combined effects of saltwater intrusion and land use on aboveground carbon dynamics of temperate coastal forests in North America. By quantifying the effects of multiple interacting disturbances, our measurement and mapping methods should be applicable to other coastal landscapes experiencing saltwater intrusion. As sea level rise increases the landward extent of inundation and saltwater exposure, investigations at these large scales are requisite for effective resource allocation for climate adaptation. In this changing environment, human intervention, whether through land preservation, restoration, or reforestation, may be necessary to prevent aboveground carbon loss.
•There is a lack of a comprehensive monitoring system of current terrestrial disturbances.•Remote sensing offers enormous potential for global disturbance observation.•An idealized monitoring system ...should accurately detect disturbances and identify their cause(s)•An ecological perspective of remote sensing is vital to continue development of terrestrial disturbance monitoring.
Terrestrial disturbances are accelerating globally, but their full impact is not quantified because we lack an adequate monitoring system. Remote sensing offers a means to quantify the frequency and extent of disturbances globally. Here, we review the current application of remote sensing to this problem and offer a framework for more systematic analysis in the future. We recommend that any proposed monitoring system should not only detect disturbances, but also be able to: identify the proximate cause(s); integrate a range of spatial scales; and, ideally, incorporate process models to explain the observed patterns and predicted trends in the future. Significant remaining challenges are tied to the ecology of disturbances. To meet these challenges, more effort is required to incorporate ecological principles and understanding into the assessments of disturbance worldwide.
Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity ...disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating ...agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild-type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.
Reduced expression of the
Indy (
I'm Not Dead, Yet) gene in
D. melanogaster and its homolog in
C. elegans prolongs life span and in
D. melanogaster augments mitochondrial biogenesis in a manner akin ...to caloric restriction. However, the cellular mechanism by which
Indy does this is unknown. Here, we report on the knockout mouse model of the mammalian
Indy (
mIndy) homolog,
SLC13A5. Deletion of
mIndy in mice (
mINDY
−/− mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1α, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect
mINDY
−/−
mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of
mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.
Display omitted
► A
mIndy (
SLC13A5) knockout mouse was generated ► Loss of
mIndy decreases hepatic ATP/ADP ratio and activates AMPK ►
mIndy deletion promotes mitochondrial biogenesis and energy expenditure ► Loss of
mIndy protects from diet- and age-associated insulin resistance
Abstract
Background
Bamlanivimab and casirivimab-imdevimab are authorized for treatment of mild to moderate coronavirus disease 2019 (COVID-19) in high-risk patients. We compared the outcomes of ...patients who received these therapies to identify factors associated with hospitalization and other clinical outcomes.
Methods
Adult patients who received monoclonal antibody from 19 November 2020 to 11 February 2021 were selected and divided into those who received bamlanivimab (n = 2747) and casirivimab-imdevimab (n = 849). The 28-day all-cause and COVID-19–related hospitalizations were compared between the groups.
Results
The population included 3596 patients; the median age was 62 years, and 50% were female. All had ≥1 medical comorbidity; 55% had multiple comorbidities. All-cause and COVID-19–related hospitalization rates at 28 days were 3.98% and 2.56%, respectively. After adjusting for medical comorbidities, there was no significant difference in all-cause and COVID-19–related hospitalization rates between bamlanivimab and casirivimab-imdevimab (adjusted hazard ratios 95% confidence interval, 1.4 .9–2.2 and 1.6 .8–2.7, respectively). Chronic kidney, respiratory and cardiovascular diseases, and immunocompromised status were associated with higher likelihood of hospitalization.
Conclusions
This observational study on the use of bamlanivimab and casirivimab-imdevimab in high-risk patients showed similarly low rates of hospitalization. The number and type of medical comorbidities are associated with hospitalizations after monoclonal antibody treatment.
This real-world cohort study of 3596 high-risk patients with mild to moderate coronavirus disease 2019 demonstrates similarly low rates of hospitalization after bamlanivimab or casirivimab-imdevimab infusion. The number and type of medical comorbidities influence the risk of hospitalizations after antibody treatment.
The integrity of our DNA is challenged with at least 100,000 lesions per cell on a daily basis. Failure to repair DNA damage efficiently can lead to cancer, immunodeficiency, and neurodegenerative ...disease. Base excision repair (BER) recognizes and repairs minimally helix-distorting DNA base lesions induced by both endogenous and exogenous DNA damaging agents. Levels of BER-initiating DNA glycosylases can vary between individuals, suggesting that quantitating and understanding interindividual differences in DNA repair capacity (DRC) may enable us to predict and prevent disease in a personalized manner. However, population studies of BER capacity have been limited because most methods used to measure BER activity are cumbersome, time consuming and, for the most part, only allow for the analysis of one DNA glycosylase at a time. We have developed a fluorescence-based multiplex flow-cytometric host cell reactivation assay wherein the activity of several enzymes four BER-initiating DNA glycosylases and the downstream processing apurinic/apyrimidinic endonuclease 1 (APE1) can be tested simultaneously, at single-cell resolution, in vivo. Taking advantage of the transcriptional properties of several DNA lesions, we have engineered specific fluorescent reporter plasmids for quantitative measurements of 8-oxoguanine DNA glycosylase, alkyladenine DNA glycosylase, MutY DNA glycosylase, uracil DNA glycosylase, and APE1 activity. We have used these reporters to measure differences in BER capacity across a panel of cell lines collected from healthy individuals, and to generate mathematical models that predict cellular sensitivity to methylmethane sulfonate, H₂O₂, and 5-FU from DRC. Moreover, we demonstrate the suitability of these reporters to measure differences in DRC in multiple pathways using primary lymphocytes from two individuals.
Pecan scab is a devastating disease that causes damage to pecan (Carya illinoinensis (Wangenh.) K. Koch) fruit and leaves. The disease is caused by the fungus Venturia effusa (G. Winter) and the main ...management practice for controlling the disease is by application of fungicides at 2-to-3-week intervals throughout the growing season. Besides disease-related yield loss, application of fungicides can result in considerable cost and increases the likelihood of fungicide resistance developing in the pathogen. Resistant cultivars are available for pecan growers; although, in several cases resistance has been overcome as the pathogen adapts to infect resistant hosts. Despite the importance of host resistance in scab management, there is little information regarding the molecular basis of genetic resistance to pecan scab.The purpose of this study was to elucidate mechanisms of natural pecan scab resistance by analyzing transcripts that are differentially expressed in pecan leaf samples from scab resistant and susceptible trees. The leaf samples were collected from trees in a provenance collection orchard that represents the natural range of pecan in the US and Mexico. Trees in the orchard have been exposed to natural scab infections since planting in 1989, and scab ratings were collected over three seasons. Based on this data, ten susceptible trees and ten resistant trees were selected for analysis. RNA-seq data was collected and analyzed for diseased and non-diseased parts of susceptible trees as well as for resistant trees. A total of 313 genes were found to be differentially expressed when comparing resistant and susceptible trees without disease. For susceptible samples showing scab symptoms, 1,454 genes were identified as differentially expressed compared to non-diseased susceptible samples. Many genes involved in pathogen recognition, defense responses, and signal transduction were up-regulated in diseased samples of susceptible trees, whereas differentially expressed genes in pecan scab resistant samples were generally down-regulated compared to non-diseased susceptible samples.Our results provide the first account of candidate genes involved in resistance/susceptibility to pecan scab under natural conditions in a pecan orchard. This information can be used to aid pecan breeding programs and development of biotechnology-based approaches for generating pecan cultivars with more durable scab resistance.
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