Considering a Schwarzschild black hole surrounded by a fully ionized hydrogen plasma, we study the effect of the gravitational field of the plasma particles on the shadow. We take a formalism in ...which this effect is unified with the refractive effect of the plasma medium studied previously, but the two effects are characterized by two independent parameters. For semi-realistic values of parameters, we find their corrections to the shadow radius are both negligible, and the gravitational correction can overtake the refractive correction for active galactic nuclei of masses larger than
10
9
M
⊙
. With unrealistically large values of parameters, we illustrate the two effects on the light trajectories and the intensity map.
CAR-T therapy has shown great success treating blood cancers, but drawbacks include high manufacturing costs and potentially fatal toxicities such as cytokine release syndrome. In this issue of Cell ...Stem Cell, Li et al. (2018) describe how engineered iPSC-derived NK cells armed with NK-tailored CAR constructs (CAR-iPSC-NK cells) provide better options for anti-cancer immunotherapy.
CAR-T therapy has shown great success treating blood cancers, but drawbacks include high manufacturing costs and potentially fatal toxicities such as cytokine release syndrome. In this issue of Cell Stem Cell, Li et al. (2018) describe how engineered iPSC-derived NK cells armed with NK-tailored CAR constructs (CAR-iPSC-NK cells) provide better options for anti-cancer immunotherapy.
Summary During the past decade, monospecific antibodies targeting cell-surface receptors in different tumour types have achieved substantial success and have been at the forefront of cancer ...treatment. However, redundant signalling and crosstalk between different pathways within tumour cells and between tumour cells and their microenvironment can limit the efficacy of receptor-targeted monospecific-based therapies. Advances in antibody engineering technologies have enabled strategies that simultaneously target multiple receptors to circumvent the limitations of conventional monospecific therapies and achieve enhanced therapeutic efficacy. In the past 5 years, a range of multifunctional, receptor-targeting, antibody-based molecules have emerged, which allow targeting of multiple surface receptors on tumour cells and endothelial or immune cells in the tumour microenvironment. In this Review, we discuss the rationales and strategies for the use of multifunctional receptor-targeting antibodies, their mechanisms of action, and the promises and challenges they hold as cancer therapeutics. This knowledge provides opportunities to improve current targeted therapy outcomes for patients with cancer.
Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need.
We ...conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval CI, 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea.
Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).
Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and ...frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear.
Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH.
circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m
A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model.
Our study reveals a plausible mechanism by which the m
A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.
Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy ...of ledipasvir/sofosbuvir (LDV/SOF) by age groups of <65 years versus ≥65 years among subjects enrolled in phase 3 trials. Four open‐label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment‐emergent adverse events (AEs), and graded laboratory abnormalities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were ≥65 years of age, of whom 24 were aged ≥75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/2029) of subjects aged <65 years and 98% (258/264) of subjects aged ≥65 years. The most common AEs in both LDV/SOF groups that occurred in ≥10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatment‐related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. Conclusions: LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects. (Hepatology 2016;63:1112–1119)
The importance of network-based approach to identifying biological markers for diagnostic classification and prognostic assessment in the context of microarray data has been increasingly recognized. ...To our knowledge, there have been few, if any, statistical tools that explicitly incorporate the prior information of gene networks into classifier building. The main idea of this paper is to take full advantage of the biological observation that neighboring genes in a network tend to function together in biological processes and to embed this information into a formal statistical framework.
We propose a network-based support vector machine for binary classification problems by constructing a penalty term from the Finfinity-norm being applied to pairwise gene neighbors with the hope to improve predictive performance and gene selection. Simulation studies in both low- and high-dimensional data settings as well as two real microarray applications indicate that the proposed method is able to identify more clinically relevant genes while maintaining a sparse model with either similar or higher prediction accuracy compared with the standard and the L1 penalized support vector machines.
The proposed network-based support vector machine has the potential to be a practically useful classification tool for microarrays and other high-dimensional data.
Due to the excellent photonic and electrical properties of metal halide perovskite materials, perovskite light-emitting devices have the potential to replace OLED devices as the next-generation of ...commercial light-emitting devices. In this article, we controlled the surface morphology of PbBr2 using an in situ dynamic thermal crystallization process, which increased the specific surface area of the films and promoted the solid-state diffusion rate. The CsPbBr3 PeLEDs prepared using this method achieved a maximum current efficiency of 7.1 cd/A at the voltage of 5 V, which was 200% higher than devices prepared using traditional spin-coating processes. These results proved that the in situ thermal dynamic crystallization process effectively improved the film quality of perovskite materials.
Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with ...cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.
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