In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The ...viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight.
Because of the aggressive and recurrent nature of cancers, repeated and multimodal treatments are often necessary. Traditional cancer therapies have a risk of serious toxicity and side effects. ...Hence, it is crucial to develop an alternative treatment modality that is minimally invasive, effectively treats cancers with low toxicity, and can be repeated as required. We developed a light-activatable microneedle (MN) system that can repeatedly and simultaneously provide photothermal therapy and chemotherapy to superficial tumors and exert synergistic anticancer effects. This system consists of embeddable polycaprolactone MNs containing a photosensitive nanomaterial (lanthanum hexaboride) and an anticancer drug (doxorubicin; DOX), and a dissolvable poly(vinyl alcohol)/polyvinylpyrrolidone supporting array patch. Because of this supporting array, the MNs can be completely inserted into the skin and embedded within the target tissue for locoregional cancer treatment. When exposed to near-infrared light, the embedded MN array uniformly heats the target tissue to induce a large thermal ablation area and then melts at 50 °C to release DOX in a broad area, thus destroying tumors. This light-activated heating and releasing behavior can be precisely controlled and switched on and off on demand for several cycles. We demonstrated that the MN-mediated synergistic therapy completely eradicated 4T1 tumors within 1 week after a single application of the MN and three cycles of laser treatment. No tumor recurrence and no significant body weight loss of mice were observed. Thus, the developed light-activatable MN with a unique embeddable feature offers an effective, user-friendly, and low-toxicity option for patients requiring long-term and multiple cancer treatments.
Summary Hepatitis B flare, defined as an event with abrupt rise of alanine aminotransferase (ALT) levels to >5 times the upper limit of normal during chronic hepatitis B virus (HBV) infection, is ...considered to be the result of a human leukocyte antigen-I restricted, cytotoxic T lymphocyte mediated immune response against HBV and its downstream mechanisms. It may occur spontaneously, during or after antiviral therapy and in the setting of immunosuppression and/or chemotherapy. The clinical spectrum of hepatitis B flares varies from asymptomatic to symptomatic and typical overt acute hepatitis, even with hepatic decompensation or failure. Flares may also occur in viraemic patients with cirrhosis with higher incidence of decompensation/mortality, hence requiring immediate antiviral therapy. An upsurge of serum HBV DNA and hepatitis B surface antigen levels usually precedes the abrupt rise of ALT levels. Rising or stable and high HBV DNA during flares represent ineffective immune clearance and further hepatocytolysis, even hepatic decompensation, may occur. Such patients require immediate antiviral therapy. In contrast, bridging hepatic necrosis and/or alpha-fetoprotein levels >100 ng/ml or decreasing HBV DNA during flares represent a more effective immune clearance and frequently leads to seroclearance of HBV DNA and/or hepatitis B e antigen with remission. If patients are non-cirrhotic and there is no concern of developing decompensation, patients may be observed for 3–6 months before deciding on the need of antiviral therapy. Severe and repeated flares are prone to develop into decompensation or lead to the development of cirrhosis, thus a timely treatment to prevent the hepatitis B flare is better than to cope with the flare. Screening, monitoring and prophylactic or pre-emptive antiviral therapy is mandatory for patients who are going to receive immunosuppressants or chemotherapy.
Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial ...DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca2+, or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.
Orthologous proteins of species adapted to different temperatures exhibit differences in stability and function that are interpreted to reflect adaptive variation in structural “flexibility.” ...However, quantifying flexibility and comparing flexibility across proteins has remained a challenge. To address this issue, we examined temperature effects on cytosolic malate dehydrogenase (cMDH) orthologs from differently thermally adapted congeners of five genera of marine molluscs whose field body temperatures span a range of ∼60 °C. We describe consistent patterns of convergent evolution in adaptation of function temperature effects on K
M of cofactor (NADH) and structural stability (rate of heat denaturation of activity). To determine how these differences depend on flexibilities of overall structure and of regions known to be important in binding and catalysis, we performed molecular dynamics simulation (MDS) analyses. MDS analyses revealed a significant negative correlation between adaptation temperature and heat-induced increase of backbone atom movements root mean square deviation (rmsd) of main-chain atoms. Root mean square fluctuations (RMSFs) of movement by individual amino acid residues varied across the sequence in a qualitatively similar pattern among orthologs. Regions of sequence involved in ligand binding and catalysis—termed mobile regions 1 and 2 (MR1 and MR2), respectively—showed the largest values for RMSF. Heat-induced changes in RMSF values across the sequence and, importantly, in MR1 and MR2 were greatest in cold-adapted species. MDS methods are shown to provide powerful tools for examining adaptation of enzymes by providing a quantitative index of protein flexibility and identifying sequence regions where adaptive change in flexibility occurs.
Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the ...efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio HR 0·78 95% CI 0·67–0·89; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 95% CI 0·68–0·94; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 0·60–0·97, one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 25% of 573 patients vs six 1% of 570), increased aspartate aminotransferase (103 18% vs 16 3%), hyperglycaemia (88 15% vs one <1%), and rash (45 8% vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 16% of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 3% of 573 vs one <1% of 570) and increased aspartate aminotransferase (14 2% vs one <1%). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.
Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided ...into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.
This study presents a dissolving microneedle patch, composed of starch and gelatin, for the rapid and efficient transdermal delivery of insulin. The microneedles completely dissolve after insertion ...into the skin for 5min, quickly releasing their encapsulated payload into the skin. A histological examination shows that the microneedles have sufficient mechanical strength to be inserted in vitro into porcine skin to a depth of approximately 200μm and in vivo into rat skin to 200–250μm depth. This penetration depth does not induce notable skin irritation or pain sensation. To evaluate the feasibility of using these dissolving microneedles for diabetes treatment insulin-loaded microneedles were administered to diabetic rats using a homemade applicator. Pharmacodynamic and pharmacokinetic results show a similar hypoglycemic effect in rats receiving insulin-loaded microneedles and a subcutaneous injection of insulin. The relative pharmacological availability and relative bioavailability of insulin were both approximately 92%, demonstrating that insulin retains its pharmacological activity after encapsulation and release from the microneedles. Storage stability analysis confirms that more than 90% of the insulin remained in the microneedles even after storage at 25 or 37°C for 1month. These results confirm that the proposed starch/gelatin microneedles enable stable encapsulation of bioactive molecules and have great potential for transdermal delivery of protein drugs in a relatively painless, rapid, and convenient manner.
ABSTRACT
Elucidating the physiological mechanisms that underlie thermal stress and discovering how species differ in capacities for phenotypic acclimatization and evolutionary adaptation to this ...stress is critical for understanding current latitudinal and vertical distribution patterns of species and for predicting their future state in a warming world. Such mechanistic analyses require careful choice of study systems (species and temperature‐sensitive traits) and design of laboratory experiments that reflect the complexities of in situ conditions. Here, we critically review a wide range of studies of intertidal molluscs that provide mechanistic accounts of thermal effects across all levels of biological organization – behavioural, organismal, organ level, cellular, molecular, and genomic – and show how temperature‐sensitive traits govern distribution patterns and capacities for coping with thermal stress. Comparisons of congeners from different thermal habitats are especially effective means for identifying adaptive variation. We employ these mechanistic analyses to illustrate how species differ in the severity of threats posed by rising temperature. Counterintuitively, we show that some of the most heat‐tolerant species may be most threatened by increases in temperatures because of their small thermal safety margins and minimal abilities to acclimatize to higher temperatures. We discuss recent molecular biological and genomic studies that provide critical foundations for understanding the types of evolutionary changes in protein structure, RNA secondary structure, genome content, and gene expression capacities that underlie adaptation to temperature. Duplication of stress‐related genes, as found in heat‐tolerant molluscs, may provide enhanced capacity for coping with higher temperatures. We propose that the anatomical, behavioural, physiological, and genomic diversity found among intertidal molluscs, which commonly are of critical importance and high abundance in these ecosystems, makes this group of animals a highly appropriate study system for addressing questions about the mechanistic determinants of current and future distribution patterns of intertidal organisms.
Aromatic imides are a class of attractive organic materials with inherently electroactive groups and large π electron‐deficient scaffolds, which hold potential as electrode materials for organic ...secondary batteries (OSBs). However, the undecorated aromatic imides are usually plagued by low capacity, high solubility in electrolyte, and poor electronic/ionic conductivity. Molecular engineering has been demonstrated to be an effective strategy to address unsatisfying characteristics of the aromatic imides, thereby expanding their scope for applications in OSBs. In this review, the recent research progress in modulation of the capacity, dissolution, and electronic/ionic conductivity of aromatic imides for organic lithium batteries, organic sodium batteries, and redox flow batteries are summarized. In addition, the challenge and prospective of aromatic imides in organic secondary battery applications are also discussed.
Electrochemical behaviors of the well‐known redox active aromatic imides can be rationally optimized by molecular engineering strategies, making them potential electrode materials for organic secondary batteries. The modified aromatic small‐molecule imides and polyimides present the high specific capacity, fast electronic conductivity, and superior ionic diffusivity, which enable their batteries to contribute satisfactory energy and power density.
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