Hepatitis B virus X protein (HBx) and hepatic stellate cells (HSCs) are critical for liver fibrosis development. Anti-fibrosis occurs via reversion to quiescent-type HSCs or clearance of HSCs via ...apoptosis or ferroptosis. We aimed to elucidate the role of chrysophanol in rat HSC-T6 cells expressing HBx and investigate whether chrysophanol (isolated from Rheum palmatum rhizomes) influences cell death via ferroptosis in vitro. Analysis of lipid reactive oxygen species (ROS), Bip, CHOP, p-IRE1α, GPX4, SLC7A11, α-SMA, and CTGF showed that chrysophanol attenuated HBx-repressed cell death. Chrysophanol can impair HBx-induced activation of HSCs via endoplasmic reticulum stress (ER stress) and ferroptosis-dependent and GPX4-independent pathways.
The authors performed a study to review outcomes following Gamma Knife radiosurgery for cerebral arteriovenous malformations (AVMs) and to create a practical scale to predict long-term outcome.
...Outcomes were reviewed in 1012 patients who were followed up for more than 2 years. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent, symptomatic, radiation-induced complication. Preradiosurgery patient and AVM characteristics predictive of outcome in multivariate analysis were weighted according to their odds ratios to create the Virginia Radiosurgery AVM Scale.
The mean follow-up time was 8 years (range 2-20 years). Arteriovenous malformation obliteration occurred in 69% of patients. Postradiosurgery hemorrhage occurred in 88 patients, for a yearly incidence of 1.14%. Radiation-induced changes occurred in 387 patients (38.2%), symptoms in 100 (9.9%), and permanent deficits in 21 (2.1%). Favorable outcome was achieved in 649 patients (64.1%). The Virginia Radiosurgery AVM Scale was created such that patients were assigned 1 point each for having an AVM volume of 2-4 cm(3), eloquent AVM location, or a history of hemorrhage, and 2 points for having an AVM volume greater than 4 cm(3). Eighty percent of patients who had a score of 0-1 points had a favorable outcome, as did 70% who had a score of 2 points and 45% who had a score of 3-4 points. The Virginia Radiosurgery AVM Scale was still predictive of outcome after controlling for predictive Gamma Knife radiosurgery treatment parameters, including peripheral dose and number of isocenters, in a multivariate analysis. The Spetzler-Martin grading scale and the Radiosurgery-Based Grading Scale predicted favorable outcome, but the Virginia Radiosurgery AVM Scale provided the best assessment.
Gamma Knife radiosurgery can be used to achieve long-term AVM obliteration and neurological preservation in a predictable fashion based on patient and AVM characteristics.
Background and Aims
Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer‐specific survival in various BTC subtypes, including gallbladder ...cancer, ampulla of Vater cancer, and cholangiocarcinoma.
Approach and Results
Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose–response relationship. Cox’s proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow‐up of 1.59 years, the 5‐year survival rate was 27.4%. The multivariate‐adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC‐specific death. Adjusted HRs for BTC‐specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose–response trend (P < 0.001; nonusers as a reference). Cancer‐specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes.
Conclusions
The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC‐specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin’s efficacy in BTC.
The fabrication process and light extraction efficiency of AlGaInP-based flip-chip micro- light-emitting diode (<inline-formula> <tex-math notation="LaTeX">\mu </tex-math></inline-formula>-LED) array ...chips are improved by employing a wafer-bonding process, patterned metal contact, and sidewall passivation layers. The epilayers with indium tin oxide (ITO) can be successfully transferred from the GaAs substrate to the sapphire substrate and bound. Three types of patterned n-metal are employed in the <inline-formula> <tex-math notation="LaTeX">\mu </tex-math></inline-formula>-LED as a self-aligning mask and light reflection layer, where the n-GaAs layer can be partially removed by the wet etching process. The dry etching process of MESA has been optimized by applying the BCl 3 gas in the inductively coupled plasma (ICP) system, which can suppress the etching rate of the sidewall and improve the etching depth uniformity. Consequently, the leakage current of the <inline-formula> <tex-math notation="LaTeX">\mu </tex-math></inline-formula>-LED array chip is decreased from 85 to 7 nA under the bias of −5 V. Moreover, three configurations of the metal contact/n-GaAs structures with Omnidirectional reflector (ODR) have been designed to reduce the emission light absorption, passivating the sidewall of MESA, and enhance the output power. Finally, the 0.52-in red <inline-formula> <tex-math notation="LaTeX">\mu </tex-math></inline-formula>-LED array with a chip size of <inline-formula> <tex-math notation="LaTeX">100\,\,\mu \text{m}\,\,\times 100\,\,\mu \text{m} </tex-math></inline-formula> and resolution of 138 pixels/in is realized when bonded with the drive IC. Consequently, the <inline-formula> <tex-math notation="LaTeX">\mu </tex-math></inline-formula>-LED array chips with ODR and patterned contact show the highest external quantum efficiency of 51.1% and relative output power enhancement of 441% compared to the chip with SiO 2 passivation layer and nonpatterned n-metal contact.
Melatonin, a naturally biosynthesized molecule secreted by the pineal gland, exhibits antitumor activities against several different types of cancer. The mechanisms of action of melatonin against ...tumor progression involve cellular apoptosis, antimetastatic activity, antioxidant and mutagenic effects, antiangiogenic activity, and the restoration of cancer immune surveillance. Melatonin has anticancer activity when administered alone or in combination with standard chemotherapeutic agents, with measurable improvements seen in the clinical endpoints of tumor regression and patient survival. However, scant clinical evidence supports the use of melatonin in bladder cancer treatment. Our study has found that melatonin treatment suppresses the bladder cancer cell migratory ability by inhibiting the epithelial-mesenchymal transition (EMT) process, which appears to be linked to melatonin-induced decreases in bladder cancer cell autophagy. Finally, an evaluation of in vivo melatonin-induced antitumor effects in an orthotopic animal model of bladder cancer indicated that melatonin treatment slightly prolonged the survival of tumor-bearing mice. Our study offers novel insights into the use of melatonin in bladder cancer treatment.
Human placenta-derived multipotent cells (hPDMCs) are isolated from a source uncomplicated by ethical issues and are ideal for therapeutic applications because of their capacity for multilineage ...differentiation and proven immunosuppressive properties. It is known that heat shock preconditioning induces the upregulation of heat shock proteins (HSPs), which enhance survival and engraftment of embryonic stem cells (ESCs) during transplantation in live animal models, although whether heat shock preconditioning has the same effects in hPDMCs is unclear.
The hPDMCs were isolated from placenta of healthy donors. The cells were treated with heat shock (43 °C, 15 min), followed by evaluation of cell viability. Furthermore, the HSPs expression was assessed by Western blot, qPCR. The reactive oxygen species (ROS) production and signal pathway activation were determined by flow cytometry and Western blot, respectively. The regulatory pathways involved in HSPs expression were examined by pretreatment with chemical inhibitors, and siRNAs of MAPK, Akt, and heat shock factor 1 (HSF1), followed by determination of HSPs expression.
This study demonstrates that heat shock treatment induced ROS generation and HPSs expression in hPDMCs. Heat shock stimulation also increased p38 MAPK and Akt phosphorylation. These effects were reduced by inhibitors of ROS, p38 MAPK and Akt. Moreover, we found that heat shock treatment enhanced nuclear translocation of the HSF1 in hPDMCs, representing activation of HSF1. Pretreatment of hPDMCs with ROS scavengers, SB203580 and Akt inhibitors also reduced the translocation of HSF1 induced by heat shock.
Our data indicate that heat shock acts via ROS to activate p38 MAPK and Akt signaling, which subsequently activates HSF1, leading to HSP activation and contributing to the protective role of hPDMCs.
This study explores the seasonal sensitivity of tropical circulation responses to an idealized extratropical thermal forcing using the Community Atmosphere Model version 5 coupled to a slab ocean. ...The thermal heating over the Southern Ocean is held constant, and the tropical responses in each month of the year are investigated. An anomalous cross-equatorial cell and a southward tropical rain belt shift occur every month. The anomalous cross-equatorial cell has a strong influence on the strengths of the Hadley cell and the subtropical jet in the winter hemisphere; in contrast, it has nearly no impact on the Hadley cell and the subtropical jet strengths in the summer hemisphere. The seasonal variation of the anomalous cross-equatorial cell is small (≲30% of the annual mean change), and could be understood via the energetic and the sea surface temperature gradient perspectives. Both perspectives point to the seasonality of the anomalous ocean heat uptake within the deep tropics as the key factor explaining the weak seasonality of the anomalous cross-equatorial cell. We propose a hypothesis explaining about 75% of this seasonal variation via the climatological position of the ITCZ relative to the anomalous cross-equatorial cell. The results suggest a modest seasonality in tropical precipitation and circulation responses to extratropical forcing. Also, such seasonality may be partly predicted by the climatological seasonal cycle of the tropical circulations.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Object
The appropriate management of unruptured intracranial arteriovenous malformations (AVMs) remains controversial. In the present study, the authors evaluate the radiographic and clinical ...outcomes of radiosurgery for a large cohort of patients with unruptured AVMs.
Methods
From a prospective database of 1204 cases of AVMs involving patients treated with radiosurgery at their institution, the authors identified 444 patients without evidence of rupture prior to radiosurgery. The patients' mean age was 36.9 years, and 50% were male. The mean AVM nidus volume was 4.2 cm
3
, 13.5% of the AVMs were in a deep location, and 44.4% were at least Spetzler-Martin Grade III. The median radiosurgical prescription dose was 20 Gy. Univariate and multivariate Cox regression analyses were used to determine risk factors associated with obliteration, postradiosurgery hemorrhage, radiation-induced changes, and postradiosurgery cyst formation. The mean duration of radiological and clinical follow-up was 76 months and 86 months, respectively.
Results
The cumulative AVM obliteration rate was 62%, and the postradiosurgery annual hemorrhage rate was 1.6%. Radiation-induced changes were symptomatic in 13.7% and permanent in 2.0% of patients. The statistically significant independent positive predictors of obliteration were no preradiosurgery embolization (p < 0.001), increased prescription dose (p < 0.001), single draining vein (p < 0.001), radiological presence of radiation-induced changes (p = 0.004), and lower Spetzler-Martin grade (p = 0.016). Increased volume and higher Pittsburgh radiosurgery-based AVM score were predictors of postradiosurgery hemorrhage in the univariate analysis only. Clinical deterioration occurred in 30 patients (6.8%), more commonly in patients with postradiosurgery hemorrhage (p = 0.018).
Conclusions
Radiosurgery afforded a reasonable chance of obliteration of unruptured AVMs with relatively low rates of clinical and radiological complications.
Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Tau-tubulin kinase-2 (TTBK2) is genetically linked to spinocerebellar ataxia type 11, ...and its kinase activity is crucial for ciliogenesis. Although it has been shown that TTBK2 is recruited to the centriole by distal appendage protein CEP164, little is known about TTBK2 substrates associated with its role in ciliogenesis. Here, we perform superresolution microscopy and discover that serum starvation results in TTBK2 redistribution from the periphery toward the root of distal appendages. Our biochemical analyses uncover CEP83 as a bona fide TTBK2 substrate with four phosphorylation sites characterized. We also demonstrate that CEP164-dependent TTBK2 recruitment to distal appendages is required for subsequent CEP83 phosphorylation. Specifically, TTBK2-dependent CEP83 phosphorylation is important for early ciliogenesis steps, including ciliary vesicle docking and CP110 removal. In summary, our results reveal a molecular mechanism of kinase regulation in ciliogenesis and identify CEP83 as a key substrate of TTBK2 during cilia initiation.
BACKGROUND:Embolization before stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVM) has been shown to negatively affect obliteration rates, but its impact on the risks of ...radiosurgery-induced complications and latency period hemorrhage is poorly defined.
OBJECTIVE:To determine, in a case-control study, the effect of prior embolization on AVM SRS outcomes.
METHODS:We evaluated a database of AVM patients who underwent SRS. Propensity score analysis was used to match the case (embolized nidi) and control (nonembolized nidi) cohorts. AVM angioarchitectural complexity was defined as the sum of the number of major feeding arteries and draining veins to the nidus. Multivariate Cox proportional hazards regression analyses were performed on the overall study population to determine independent predictors of obliteration and radiation-induced changes.
RESULTS:The matching process yielded 242 patients in each cohort. The actuarial obliteration rates were significantly lower in the embolized (31%, 49% at 5, 10 years, respectively) compared with the nonembolized (48%, 64% at 5, 10 years, respectively) cohort (P = .003). In the multivariate analysis for obliteration, lower angioarchitectural complexity (P < .001) and radiologically evident radiation-induced changes (P = .016) were independent predictors, but embolization was not significant (P = .744). In the multivariate analysis for radiologic radiation-induced changes, lack of prior embolization (P = .009) and fewer draining veins (P = .011) were independent predictors.
CONCLUSION:The effect of prior embolization on AVM obliteration after SRS may be significantly confounded by nidus angioarchitectural complexity. Additionally, embolization could reduce the risk of radiation-induced changes. Thus, combined embolization and SRS may be warranted for appropriately selected nidi.
ABBREVIATIONS:AVM, arteriovenous malformationRBAS, radiosurgery-based AVM scoreSRS, stereotactic radiosurgeryVRAS, Virginia Radiosurgery AVM Scale
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