Wound healing is one of the most complex biological processes to occur in life. Repair of tissue following injury involves dynamic interactions between multiple cell types, growth factors, ...inflammatory mediators and components of the extracellular matrix (ECM). Aberrant and uncontrolled wound healing leads to a non-functional mass of fibrotic tissue. In the eye, fibrotic disease disrupts the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition (EMT). Myofibroblasts rapidly produce excessive amounts of ECM and exert tractional forces across the ECM, resulting in the distortion of tissue architecture. Transforming growth factor-beta (TGFβ) plays a major role in myofibroblast transdifferentiation and has been implicated in numerous fibrotic eye diseases including corneal opacification, pterygium, anterior subcapsular cataract, posterior capsular opacification, proliferative vitreoretinopathy, fibrovascular membrane formation associated with proliferative diabetic retinopathy, submacular fibrosis, glaucoma and orbital fibrosis. This review serves to introduce the pathological functions of the myofibroblast in fibrotic eye disease. We also highlight recent developments in elucidating the multiple signaling pathways involved in fibrogenesis that may be exploited in the development of novel anti-fibrotic therapies to reduce ocular morbidity due to scarring.
•TGFβ plays a major role in EMT leading to different forms of eye fibrotic disease.•The myofibroblast results from this EMT contributing to the fibrotic pathology.•Multiple and overlapping signaling pathways are involved in ocular fibrogenesis.
The long noncoding RNA TINCR shows aberrant expression in human squamous carcinomas. However, its expression and function in gastric cancer remain unclear. We report that TINCR is strongly ...upregulated in human gastric carcinoma (GC), where it was found to contribute to oncogenesis and cancer progression. We also revealed that TINCR overexpression is induced by nuclear transcription factor SP1. Silencing TINCR expression inhibited cell proliferation, colony formation, tumorigenicity and apoptosis promotion, whereas TINCR overexpression promoted cell growth, as documented in the SGC7901 and BGC823 cell lines. Mechanistic analyses indicated that TINCR could bind to STAU1 (staufen1) protein, and influence KLF2 mRNA stability and expression, then KLF2 regulated cyclin-dependent kinase genes CDKN1A/P21 and CDKN2B/P15 transcription and expression, thereby affecting the proliferation and apoptosis of GC cells. Together, our findings suggest that TINCR contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.
Epithelial-mesenchymal transition (EMT) and endothelial-mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in ...pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.
High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
Peptide/protein-polymer conjugates make up a new class of soft matter comprising natural and synthetic building blocks. They have the potential to combine the advantages of proteins and synthetic ...polymers (i.e., the precise chemical structure and diverse functionalities of biomolecules and the stability and processability of synthetic polymers) to generate hybrid materials with properties yet to be realized with either component alone. Here we briefly discuss recent developments in the design, fundamental understanding, and self-assembly of various peptide-polymer conjugates, as well as emerging biological and nonbiological applications that range from nanomedicine, to separation, and beyond.
Reverse osmosis and nanofiltration are highly adopted, growing technologies that are used to remove salts and other small molecules in water treatment. Both of these technologies primarily use ...cross-linked polyamide membranes to achieve the desired separation. Many novel nanoporous materials are being developed as alternatives or complements to polyamides, including graphene, graphene oxide, block copolymers, liquid crystals, aquaporins, and other biologically inspired molecular channels. This article evaluates each of these technologies by (i) reviewing the current progress in each area, (ii) identifying key needs for immediate research, and (iii) evaluating considerations for commercial development. The economic benefits of these technologies in reverse osmosis applications are further reviewed to help frame the expected commercial value proposition.
Power harvesting refers to the practice of acquiring energy from the environment which would be otherwise wasted and converting it into usable electric energy. Much work has been done on studying the ...optimal AC power output, while little has considered the AC-DC output. This article investigates the optimal AC-DC power generation for a rectified piezoelectric device. In contrast with estimates based on various degrees of approximation in the recent literature, an analytic expression for the AC-DC power output is derived under steady-state operation. It shows that the harvested power depends on the input vibration characteristics (frequency and acceleration), the mass of the generator, the electrical load, the natural frequency, the mechanical damping ratio and the electromechanical coupling coefficient of the system. An effective power normalization scheme is provided to compare the relative performance and efficiency of devices. The theoretical predictions are validated and found to be in good agreement with both experimental observations and numerical simulations. Finally, several design guidelines are suggested for devices with large coupling coefficient and quality factor.
This article proposes to use the idea of equivalent impedance to investigate the electrical response of an array of piezoelectric oscillators endowed with distinct energy harvesting circuits. Three ...interface electronics systems are considered including standard AC/DC and parallel/series-SSHI (synchronized switch harvesting on inductor) circuits. Various forms of equivalent load impedance are analytically obtained for different interfaces. The steady-state response of an array system is then shown to be determined by the matrix formulation of generalized Ohm's law whose impedance matrix is explicitly expressed in terms of the load impedance. A model problem is proposed for evaluating the ability of power harvesting under various conditions. It is shown first that harvested power is increased dramatically for the case of small deviation in the system parameters. On the other hand, if the deviation in mass is relatively large, the result is changed from the power-boosting mode to wideband mode. In particular, the parallel-SSHI array system exhibits much more significant bandwidth improvement than the other two cases. Surprisingly, the series-SSHI array system shows the worst electrical response. Such an observation is opposed to our previous finding that an SSHI technique avails against the standard technique in the case based on a single piezoelectric energy harvester and the explanation is under investigation.
This paper studies the energy conversion efficiency for a rectified piezoelectric power harvester. An analytical model is proposed, and an expression of efficiency is derived under steady-state ...operation. In addition, the relationship among the conversion efficiency, electrically induced damping and ac-dc power output is established explicitly. It is shown that the optimization criteria are different depending on the relative strength of the coupling. For the weak electromechanical coupling system, the optimal power transfer is attained when the efficiency and induced damping achieve their maximum values. This result is consistent with that observed in the recent literature. However, a new finding shows that they are not simultaneously maximized in the strongly coupled electromechanical system.
This paper provides an analysis for the performance evaluation of a piezoelectric energy harvesting system using the synchronized switch harvesting on inductor (SSHI) electronic interface. In ...contrast with estimates based on a variety of approximations in the literature, an analytic expression of harvested power is derived explicitly and validated numerically for the SSHI system. It is shown that the electrical response using an ideal SSHI interface is similar to that using the standard interface in a strongly coupled electromechanical system operated at short circuit resonance. On the other hand, if the SSHI circuit is not ideal, the performance degradation is evaluated and classified according to the relative strength of coupling. It is found that the best use of the SSHI harvesting circuit is for systems in the mid-range of electromechanical coupling. The degradation in harvested power due to the non-perfect voltage inversion is not pronounced in this case, and a new finding shows that the reduction in power is much less sensitive to frequency deviations than that using the standard technique.
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