Tissue engineering enables the generation of functional human cardiac tissue with cells derived in vitro in combination with biocompatible materials. Human-induced pluripotent stem cell-derived ...cardiomyocytes provide a cell source for cardiac tissue engineering; however, their immaturity limits their potential applications. Here we sought to study the effect of mechanical conditioning and electric pacing on the maturation of human-induced pluripotent stem cell-derived cardiac tissues.
Cardiomyocytes derived from human-induced pluripotent stem cells were used to generate collagen-based bioengineered human cardiac tissue. Engineered tissue constructs were subjected to different mechanical stress and electric pacing conditions.
The engineered human myocardium exhibits Frank-Starling-type force-length relationships. After 2 weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility (0.63±0.10 mN/mm
vs 0.055±0.009 mN/mm
for no stress), tensile stiffness, construct alignment, and cell size. Stress conditioning also increased SERCA2 (Sarco/Endoplasmic Reticulum Calcium ATPase 2) expression, which correlated with a less negative force-frequency relationship. When electric pacing was combined with static stress conditioning, the tissues showed an additional increase in force production (1.34±0.19 mN/mm
), with no change in construct alignment or cell size, suggesting maturation of excitation-contraction coupling. Supporting this notion, we found expression of RYR2 (Ryanodine Receptor 2) and SERCA2 further increased by combined static stress and electric stimulation.
These studies demonstrate that electric pacing and mechanical stimulation promote maturation of the structural, mechanical, and force generation properties of human-induced pluripotent stem cell-derived cardiac tissues.
Objective
The study objective was to examine the association between phentermine/topiramate therapy and weight loss and adverse events in adults with overweight or obesity by meta‐analysis and ...systematic review.
Methods
Medical Subject Headings and free‐text terms were selected to search for eligible trials in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase up to April 18, 2020. The quality of randomized controlled trials was evaluated by the Cochrane risk‐of‐bias tool. Meta‐analysis was performed using random‐effect models.
Results
Phentermine/topiramate therapy resulted in an average weight loss of 7.73 kg (95% CI: 6.60‐8.85) in general compared with placebo. The weight loss was related to the dose of phentermine/topiramate. Compared with placebo, the average weight loss was 3.55 kg (95% CI: 2.22‐4.88) for 3.75/23 mg, 7.27 kg (95% CI: 6.40‐8.13) for 7.5/46 mg, and 8.25 kg (95% CI: 6.92‐9.79) for 15/92 mg. For phentermine/topiramate participants in different weight‐loss subgroups, the weight loss of participants with ≥5%, ≥10%, and ≥15% baseline weight loss was 3.18 (95% CI: 2.75‐3.67), 5.32 (95% CI: 4.53‐6.25), and 5.65 (95% CI: 3.55‐9.01), respectively. Compared with placebo, the adverse events associated with the treatment mainly included dysgeusia (odds ratio OR = 8.86, 95% CI: 5.65‐13.89), paresthesia (OR = 8.51, 95% CI: 6.20‐11.67), dry mouth (OR = 6.71, 95% CI: 5.03‐8.94), disturbance in attention (OR = 4.48, 95% CI: 2.39‐8.41), irritability (OR = 4.10, 95% CI: 2.29‐7.33), hypoesthesia (OR = 3.81, 95% CI: 1.32‐11.00), constipation (OR = 2.43, 95% CI: 2.02‐2.93), and dizziness (OR = 2.26, 95% CI: 1.72‐2.98). Phentermine/topiramate also reduced waist circumference, blood pressure, blood sugar levels, and lipid levels.
Conclusions
Phentermine/topiramate has considerable benefit in reducing body weight, and the efficacy was closely related to the dosage. However, it increased the risk of nervous system‐related adverse events.
Recent advances in pluripotent stem cell biology and directed differentiation have identified a population of human cardiovascular progenitors that give rise to cardiomyocytes, smooth muscle, and ...endothelial cells. Because the heart develops from progenitors in 3D under constant mechanical load, we sought to test the effects of a 3D microenvironment and mechanical stress on differentiation and maturation of human cardiovascular progenitors into myocardial tissue. Progenitors were derived from embryonic stem cells, cast into collagen hydrogels, and left unstressed or subjected to static or cyclic mechanical stress. Compared to 2D culture, the unstressed 3D environment increased cardiomyocyte numbers and decreased smooth muscle numbers. Additionally, 3D culture suppressed smooth muscle α-actin content, suggesting diminished cell maturation. Cyclic stress-conditioning increased expression of several cardiac markers, including β-myosin heavy chain and cardiac troponin T, and the tissue showed enhanced calcium dynamics and force production. There was no effect of mechanical loading on cardiomyocyte or smooth muscle specification. Thus, 3D growth conditions favor cardiac differentiation from cardiovascular progenitors, whereas 2D conditions promote smooth muscle differentiation. Mechanical loading promotes cardiomyocyte structural and functional maturation. Culture in 3-D facilitates understanding how cues such as mechanical stress affect the differentiation and morphogenesis of distinct cardiovascular cell populations into organized, functional human cardiovascular tissue. Stem Cells 2015;33:2148-2157.
Abstract
Light-induced 2 + 2 cycloaddition is the most straightforward way to generate cyclobutanes, which are core structures of many natural products, drugs and bioactive compounds. Despite ...continuous advances in selective 2 + 2 cycloaddition research, general method for intermolecular photocatalysis of acyclic olefins with specific regio- and diastereoselectivity, for example,
syn
-head-to-head (
syn
-HH) cyclobutane derivatives, is still lack of development but highly desired. Herein, we report a cage-confined photocatalytic protocol to enable unusual intermolecular 2 + 2 cycloaddition for
α,β
-unsaturated carbonyl compounds. The
syn
-HH diastereomers are readily generated with diastereoselectivity up to 99%. The cage-catalyst is highly efficient and robust, covering a diverse substrate range with excellent substituent tolerance. The mimic-enzyme catalysis is proposed through a host-guest mediated procedure expedited by aqueous phase transition of reactant and product, where the supramolecular cage effect plays an important role to facilitate substrates inclusion and pre-orientation, offering a promising avenue for general and eco-friendly cycloaddition photocatalysis with special diastereoselectivity.
Peripheral T cell lymphomas are heterogeneous diseases which remain treatment challenges. Recent advances in molecular and genomic profiling have provided unprecedented insight into disease ...pathogenesis driven by distinct cells of origins and molecular pathways. The discovery and clinical application of molecular biomarkers in PTCL subtypes has the potential to transform personalized care for patients with PTCL in diagnosis, prognosis, and therapy. Targeting CD30+ PTCL with the antibody-drug conjugate brentuximab vedotin in the relapsed setting and in combination with chemotherapy in the frontline setting has improved patient survivals. Epigenetic modifying agents, including HDAC inhibitors and hypomethylating agents, have demonstrated broad clinical efficacy and durability and are in clinical development for combination strategies for both relapsed and frontline settings. Wide-ranging novel agents targeting critical intracellular pathways and tumor microenvironment are in active exploration to define clinical activities. This review summarizes PTCL-specific biomarkers which are increasingly incorporated in clinical practice to guide precision diagnosis and personalized treatment.
Background
This study investigated the activation of mitogen‐activated protein kinases in the spinal dorsal horn to explore the mechanisms underlying morphine‐induced acute and chronic hyperalgesia ...in mice.
Methods
Male adult mice were given a single subcutaneous injection (SC) of morphine (1 μg/kg) or twice‐daily administration of morphine (10 mg/kg/day) for 8 days. Thermal hyperalgesia and mechanical allodynia were assessed using the radiant heat and von Frey filament test. Levels of phospho (p)‐extracellular signal–regulated kinases (p‐ERK), p‐c‐Jun N‐terminal kinase (p‐JNK), p‐p38, p‐PKCγ, N‐methyl‐d‐aspartate receptor (NMDAr), and c‐Fos protein in the spinal dorsal horn were examined by Western blot assays.
Results
A single ultra‐low dose or repeated administration of morphine induced hyperalgesia in mice and caused a significant increase in the levels of p‐ERK and p‐JNK, but not p‐p38, in the spinal dorsal horn. The level of c‐Fos protein was significantly elevated following administration of morphine. The protein levels of p‐PKCγ and NMDAr subunits (NR2B and NR2A) were also altered. Pretreatment with the NMDAr antagonist MK‐801 or the protein kinase C (PKC) inhibitor calphostin C (CC) suppressed the morphine‐induced increase in p‐ERK, p‐JNK, and c‐Fos. Administration of MK‐801 and CC also relieved morphine‐induced hyperalgesia.
Conclusion
These findings suggest that activation of the spinal ERK and JNK signaling pathways contribute to morphine‐induced acute and chronic hyperalgesia in mice.
In this study, we evaluated our findings which suggest the activation of the spinal extracellular signal–regulated kinases, and the c‐Jun N‐terminal kinase signaling pathway contributes to morphine‐induced acute hyperalgesia in mice.
Applicability problems of the widely-used aggregation-based representation of DFIG wind farms focus on the modelling "error and impact" in transient stability computation. In order to identify ...crucial LVRT behaviors of DFIGs, specifically in system-level analysis, control strategies including vector-orientation, closed-loop rotor-current regulation, and Crowbar protection are given a full consideration. It is proved that, the DFIG works with its electrical and mechanical dynamics decoupled, and the result is that the DFIG behaves as an ideal controlled-power source. The DFIG's power-modulation functions defined by the grid code distinguish it from the conventional synchronous generator, which also conveniently offers dominant dynamics for studying errors of aggregation. Next, errors caused by the coupling between distribution factors and LVRT behaviors of wind farms (but ignored in aggregation) are discussed. With some existing grid codes, these factors not only generate a distributive profile of residual voltages along the feeders, but more importantly nonuniform power responses among individual wind turbines. Impacts of aggregation's errors on transient stability of power systems are analyzed. The trend in the error and impact of aggregation is analytically surveyed in a rudimentary system, and further numerically verified in a multi-machine system.
FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the ...biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.
Materials with tunable long persistent luminescence (LPL) properties have wide applications in security signs, anti‐counterfeiting, data encrypting, and other fields. However, the majority of ...reported tunable LPL materials are pure organic molecules or polymers. Herein, a series of metal‐organic coordination polymers displaying color‐tunable LPL were synthesized by the self‐assembly of HTzPTpy ligand with different cadmium halides (X=Cl, Br, and I). In the solid state, their LPL emission colors can be tuned by the time‐evolution, as well as excitation and temperature variation, realizing multi‐mode dynamic color tuning from green to yellow or green to red, and are the first such examples in single‐component coordination polymer materials. Single‐crystal X‐ray diffraction analysis and theoretical calculations reveal that the modification of LPL is due to the balanced action from single molecule and aggregate triplet excited states caused by an external heavy‐atom effect. The results show that the rational introduction of different halide anions into coordination polymers can realize multi‐color LPL.
By delicate design of coordination polymers incorporating different halogens, multi‐mode color‐tunable long persistent luminescence (LPL) from green to yellow or green to red was possible. The LPL emission colors can be tuned by time, excitation, and temperature, revealing the counter‐balanced mechanisms from single‐molecule and aggregate triplet excited states resulting from an external heavy‐atom effect.
The outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is poor, particularly in patients ineligible for stem cell transplantation or who fail induction therapy or ...salvage therapy. The phase 1b portion of this open-label, dose-escalation (3+3+3 design) study examined the maximum tolerated dose (MTD) and preliminary safety and activity of the regimen in transplant-ineligible adults with histologically confirmed relapsed/refractory DLBCL after at least 1 prior therapy. Patients received once-daily 560 mg ibrutinib, 375 mg/m2 intravenous rituximab day 1 of cycles 1 to 6, and 10, 15, 20, or 25 mg lenalidomide days 1 to 21 of each 28-day cycle. Forty-five patients were treated; median time since diagnosis was 14.1 months, and 51% of the patients had non–germinal center B-cell–like (non-GCB) DLBCL, 33% had transformed DLBCL, 60% were refractory, and 27% were primary refractory. Because of dose-limiting toxicities, a de-escalation cohort (10 mg lenalidomide) was initiated, and with subsequent re-escalation up to 25 mg lenalidomide, the MTD was not reached. In response-evaluable patients, the overall response rate (ORR) was 44% (complete response CR, 28%); among them, the ORR was 65% (CR, 41%) in non-GCB and 69% and 56% in relapsed (n = 16) and secondary refractory (n = 27) disease, respectively. Overall and for non-GCB, median response duration was 15.9 months, with 2 patients receiving therapy beyond 3 years. Phase 2 was initiated with 20 mg lenalidomide in relapsed/refractory non-GCB, whereas the phase 1b 25-mg lenalidomide cohort was being completed; an additional 25-mg cohort in phase 2 is currently ongoing. This study was registered at www.clinicaltrials.gov as #NCT02077166.
•The safety profile of ibrutinib, lenalidomide, and rituximab in combination was manageable in patients with relapsed/refractory DLBCL.•The combination demonstrated promising and durable activity in relapsed/refractory DLBCL, particularly in patients with non-GCB DLBCL.
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