Depletion of proteasome subunit PSMD1 induces cancer cell death via protein ubiquitination and DNA damage, irrespective of p53 status.

Hepatocellular carcinoma (HCC) is characterized by high incidence and fatality rates worldwide. In our exploration of prognostic factors in HCC, the 26s proteasome subunit, non-ATPase 1 (PSMD1) protein emerged as a significant contributor, demonstrating its potential as a therapeutic target in this aggressive cancer. PSMD1 is a subunit of the 19S regulatory particle in the 26S proteasome complex; the 19S particle controls the deubiquitination of ubiquitinated proteins, which are then degraded by the proteolytic activity of the complex. Proteasome-targeting in cancer therapy has received significant attention because of its practical application as an established anticancer agent. We investigated whether PSMD1 plays a critical role in cancer owing to its prognostic significance. PSMD1 depletion induced cell cycle arrest in G2/M phase, DNA damage and apoptosis of cancer cells, irrespective of the p53 status. PSMD1 depletion-mediated cell death was accompanied by an increase in overall protein ubiquitination. These phenotypes occurred exclusively in cancer cells, with no effects observed in normal cells. These findings indicate that PSMD1 depletion-mediated ubiquitination of cellular proteins induces cell cycle arrest and eventual death in cancer cells, emphasizing PSMD1 as a potential therapeutic target in HCC.

VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia.

Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given during four postnatal periods: P1-3, P8-10, P15-17, and P22-24. BAVM development was assessed at 2-3 months using latex dye perfusion. We examined the angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1-3), 86% (P8-10), and 55% (P15-17) of cases, with varying localization. Notably, the P22-24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the "second hit" theory, highlighting the role of early postnatal angiogenesis in initiating BAVM development in HHT type I mice.

A concept to detect a subgingival finish line using an intraoral optical coherence tomography system: A clinical report.

This clinical report introduces an approach for detecting the supragingival finish line by penetrating the teeth and gingival tissue using optical coherence tomography (OCT) technology. This approach was used in 3 patients who underwent tooth preparation with a subgingival finish line. Consequently, the subgingival finish line, typically challenging to discern clearly in intraoral scans, was identifiable in the OCT image.

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling.

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.

Heart rate and diastolic arterial pressure in cardiac arrest patients: A nationwide, multicenter prospective registry.

BACKGROUND: Guidelines have recommended monitoring mean arterial pressure (MAP) and systolic arterial pressure (SAP) in cardiac arrest patients, but there has been relatively little regard for diastolic arterial pressure (DAP) and heart rate (HR). We aimed to determine the prognostic significance of hemodynamic parameters at all time points during targeted temperature management (TTM). METHODS: We reviewed the SAP, DAP, MAP, and HR data in out-of-hospital cardiac arrest (OHCA) survivors from the prospective multicenter registry of 22 teaching hospitals. This study included 1371 patients who underwent TTM among 10,258 cardiac arrest patients. The hemodynamic parameters were recorded every 6 hours from the return of spontaneous circulation (ROSC) to 4 days. The risks of those according to time points during TTM were compared. RESULTS: Of the included patients, 943 (68.8%) had poor neurological outcomes. The predictive ability of DAP surpassed that of SAP and MAP at all time points, and among the hemodynamic variables HR/DAP was the best predictor of the poor outcome. The risks in patients with DAP < 55 to 70 mmHg and HR > 70 to 100 beats/min were steeply increased for 2 days after ROSC and correlated with the poor outcome at all time points. Bradycardia showed lower risks only at 6 hours to 24 hours after ROSC. CONCLUSION: Hemodynamic parameters should be intensively monitored especially for 2 days after ROSC because cardiac arrest patients may be vulnerable to hemodynamic instability during TTM. Monitoring HR/DAP can help access the risks in cardiac arrest patients.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice.

OBJECTIVE: Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. METHODS: Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. RESULTS: Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). CONCLUSIONS: Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

Txn2 haplodeficiency does not affect cochlear antioxidant defenses or accelerate the progression of cochlear cell loss or hearing loss across the lifespan.

Thioredoxin 2 (TXN2) is a small redox protein found in nearly all organisms. As a mitochondrial member of the thioredoxin antioxidant defense system, TXN2 interacts with peroxiredoxin 3 (PRDX3) to remove hydrogen peroxide. Accordingly, TXN2 is thought to play an important role in maintaining the appropriate mitochondrial redox environment and protecting the mitochondrial components against oxidative stress. In the current study, we investigated the effects of Txn2 haplodeficiency on cochlear antioxidant defenses, auditory function, and cochlear cell loss across the lifespan in wild-type (WT) and Txn2 heterozygous knockout (Txn2+/-) mice backcrossed onto CBA/CaJ mice, a well-established model of age-related hearing loss. Txn2+/- mice displayed a 58% decrease in TXN2 protein levels in the mitochondria of the inner ears compared to WT mice. However, Txn2 haplodeficiency did not affect the thioredoxin or glutathione antioxidant defense in both the mitochondria and cytosol of the inner ears of young mice. There were no differences in the levels of mitochondrial biogenesis markers, mitochondrial DNA content, or oxidative DNA and protein damage markers in the inner ears between young WT and Txn2+/- mice. In a mouse inner ear cell line, knockdown of Txn2 did not affect cell viability under hydrogen peroxide treatment. Consistent with the tissue and cell line results, there were no differences in hair cell loss or spiral ganglion neuron density between WT and Txn2+/- mice at 3-5 or 23-25 months of age. Furthermore, Txn2 haplodeficiency did not affect auditory brainstem response threshold, wave I latency, or wave I amplitude at 3-5, 15-16, or 23-25 months of age. Therefore, Txn2 haplodeficiency does not affect cochlear antioxidant defenses, accelerate degeneration of cochlear cells, or affect auditory function in mice across the lifespan.

Pressure-Sensitive Adhesive with Controllable Adhesion for Fabrication of Ultrathin Soft Devices.

As the interest in foldable smartphones recently launched onto the market shifts toward the next generation of flexible electronics, the development of ultrathin devices is gaining considerable attention. The strain formed on the surfaces of film-based devices approximates the film thickness divided by twice the radius of curvature; therefore, the use of an ultrathin substrate is the key for the development of next generation foldable devices. However, the stiffness of ultrathin films is extremely low; thus, it cannot be easily used directly as a substrate for device fabrication. Therefore, these films generally undergo device manufacturing processes while being attached to a rigid substrate such as glass and are peeled from the rigid substrate after the process is finished. Thus, the initial adhesion of the adhesive used to fix the film to the temporary substrate should be strong, and after the process is completed, the adhesion must be lessened to enable soft peeling. In this study, we succeeded in developing a novel pressure-sensitive adhesive (PSA) whose adhesive strength can be severely reduced by water treatment. Accordingly, considering that amphiphilic oligomers promote water absorption through hydrogen bonding to water, amphiphilic oligomers were mixed with an acrylic polymer to prepare the water-responsive PSA (wr-PSA). The adhesion strength of the wr-PSA in the early stage, which reached 382(±22) N/m, dramatically dropped to 9(±2) N/m after a water immersion test. Using the wr-PSA, a 1.4 µm-thick polyethylene terephthalate film coated with Ag nanowires was softly peeled off from the glass after being immersed in warm water. In addition, the adhesion reduced by the immersion in water was recovered again when the water absorbed by the adhesive was dried. This implies that the developed adhesive can be reusable.

Ultrafast Photoinduced Interconnection of Metal-Polymer Composites for Fabrication of Transparent and Stretchable Electronic Skins.

The high interest sparked by the foldable smartphones recently released on the market is gradually shifting to the next generation of flexible electronic devices, such as electronic skins in the form of stretchable thin films. To develop such devices, good mechanical flexibility of all components (including the substrate, electrode, and encapsulant) is critical. Various technologies have been developed to enhance the flexibility of these components; however, progress in developing interconnection methods for flexible and stretchable devices has been limited. Here, we developed an ultrafast photoinduced interconnection method that does not require any adhesive or surface treatment. This method is based on heating metal nanostructures using intense pulsed light (IPL) and the reversible cross-linking of polymers. First, we synthesized a stretchable, transparent, and free-standing polymer substrate that can be reversibly cross-linked, and then Ag nanowire (AgNW) networks were formed on its surface. This electrode was irradiated with IPL, which locally heated the AgNWs, followed by decomposition of the polymer via the retro-Diels-Alder reaction and recross-linking. Independently fabricated AgNW/polymer films were layered and irradiated three times with IPL to form a bonded sample with excellent joint quality and no increase in electrical resistance compared to a single electrode. Furthermore, the interconnected electrodes were stretchable and optically transparent. Even when more than 200% strain was applied in a peel test, no breakage at the joint was observed. This allowed us to successfully produce a stretchable, transparent, and bending-insensitive pressure sensor for various applications such as motion detectors or pressure sensor arrays.

Effects of Intense Pulsed Light (IPL) Rapid Annealing and Back-Channel Passivation on Solution-Processed In-Ga-Zn-O Thin Film Transistors Array.

We report on the effects of the intense pulsed light (IPL) rapid annealing process and back-channel passivation on the solution-processed In-Ga-Zn-O (IGZO) thin film transistors (TFTs) array. To improve the electrical properties, stability and uniformity of IGZO TFTs, the oxide channel layers were treated by IPL at atmospheric ambient and passivated by photo-sensitive polyimide (PSPI). When we treated the IGZO channel layer by the IPL rapid annealing process, saturation field effect mobility and subthreshold swing (S.S.) were improved. And, to protect the back-channel of oxide channel layers from oxygen and water molecules, we passivated TFT devices with photo-sensitive polyimide. The IGZO TFTs on glass substrate treated by IPL rapid annealing without PSPI passivation showed the field effect mobility (µFE) of 1.54 cm2/Vs and subthreshold swing (S.S.) of 0.708 V/decade. The PSPI-passivated IGZO TFTs showed higher µFE of 2.17 cm2/Vs than that of device without passivation process and improved S.S. of 0.225 V/decade. By using a simple and fast intense pulsed light treatment with an appropriate back-channel passivation layer, we could improve the electrical characteristics and hysteresis of IGZO-TFTs. We also showed the improved uniformity of electrical characteristics for IGZO TFT devices in the area of 10 × 40 mm2. Since this IPL rapid annealing process could be performed at a low temperature, it can be applied to flexible electronics on plastic substrates in the near future.

Innovative screening tests for COVID-19 in South Korea.

Recently, the number of Corona Virus Disease 2019 (COVID-19) cases has increased remarkably in South Korea, so the triage clinics and emergency departments (ED) are expected to be overcrowded with patients with presumed infection. As of March 21st, there was a total of 8,799 confirmed cases of COVID-19 and 102 related deaths in South Korea that was one of the top countries with high incidence rates [1]. This sharp increase in infection is associated with 1) outbreaks in individual provinces, 2) deployment of rapid and aggressive screening tests, 3) dedicated healthcare staffs for virus screening tests, 4) quarantine inspection data transparency and accurate data reporting, and 5) public health lessons from previous Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks. This commentary introduces innovative screening tests that are currently used in South Korea for COVID-19, e.g., Drive-Through and Walk-Through tests, and compare the advantages and disadvantages of both methods.

Self-Integratable, Healable, and Stretchable Electroluminescent Device Fabricated via Dynamic Urea Bonds Equipped in Polyurethane.

Reversible bonding between polymer chains has been used primarily to induce self-healing of damaged polymers. Inspired by the dynamic nature of such bonding, we have developed a polyurethane equipped with dynamic urea bonds (PEDUB) that has high strength sufficient to make it be freestanding and have a healing capability and self-bonding property. This allowed subsequent heterogeneous multicomponent device integration of electrodes/substrate and light-emitting pixels into a light-emitting device. We first used the PEDUB to individually fabricate a highly stretchable electrode containing Ag nanowires and stretchable composites with ZnS-based particles. They were successfully assembled into a stretchable, waterproof electroluminescent (EL) device even under mild conditions (60 °C for 10 min) owing to the reversible exchange of urea bonds and low glass transition temperature of PEDUB. The assembled device with an AC-driven EL architecture retained excellent EL characteristics even after stretching, submersion in water, and cutting owing to the robust solid-state bonding interfaces induced by the dynamic urea bonds. Consequently, various shapes of the illuminating elastomer and an illuminated picture were realized for the first time using the mosaic-like assembly method. This first demonstration of multicomponent assembly paves the way for future stretchable multifunctional devices.

Effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss in mice.

The glutathione transferase (GST) detoxification system converts exogenous and endogenous toxins into a less toxic form by conjugating the toxic compound to reduced glutathione (GSH) by a variety of GST enzymes. Of the ~20 GST isoforms, GSTA4 exhibits high catalytic efficiency toward 4-hydroxynonenal (4-HNE), one of the most abundant end products of lipid peroxidation that contributes to neurodegenerative diseases and age-related disorders. Conjugation to GSH by GSTA4 is thought to be a major route of 4-HNE elimination. In the current study, we investigated the effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss using young (3-5 months old) and old (24-25 months old) Gsta4+/+ and Gsta4-/- mice that were backcrossed onto the CBA/CaJ mouse strain, a well-established model of age-related hearing loss (AHL). At 3-5 months of age, loss of Gsta4 resulted in decreased total GSTA activity toward 4-HNE in the inner ears of young mice. However, there were no differences in the levels of 4-HNE in the inner ears between Gsta4+/+ and Gsta4-/- mice at 3-5 or 24-25 months of age. No histological abnormalities were observed in the cochlea and no hearing impairments were observed in young Gsta4-/- mice. At 24-25 months of age, both Gsta4+/+ and Gsta4-/- mice showed elevated ABR thresholds compared to 3-month-old mice, but there were no differences in ABR thresholds, cochlear spiral ganglion neuron densities, or stria vascularis thickness between Gsta4+/+ and Gsta4-/- mice. Together, these results suggest that under normal physiological conditions or during normal aging, GSTA4 is not essential for removal of 4-HNE in mouse inner ears.

Fabrication of a Bending-Insensitive In-Plane Strain Sensor from a Reversible Cross-Linker-Functionalized Silicone Polymer.

A reversibly cross-linkable and transparent polymer featuring stretchability and thermal healability is prepared by introducing Diels-Alder (DA)-reactive moieties into polydimethylsiloxane (PDMS), namely, a healable PDMS (h-PDMS). Inspired by the fact that retro-DA reactions occur even at low temperatures (albeit at a low rate), we maximize the effectiveness of small reactant products, demonstrating that self-healing and self-integration realized by 1-3 min exposure of cured h-PDMS to methyl ethyl ketone (MEK) vapor is more efficient than that achieved by direct sample heating at high temperatures. This technology is first used to uniformly transfer Ag nanowires (Ag NWs) formed on a temporary substrate to the h-PDMS surface, and further MEK vapor treatment allows the transferred NWs to be impregnated below the h-PDMS surface to afford an in-plane strain sensor. Most importantly, the developed method is used to perfectly integrate two identical Ag NW/h-PDMS films and thus place NWs on a neutral plane. Consequently, because of the unique structure in which a percolated network of AgNWs is formed on the interface where the two identical h-PDMS films are chemically integrated, the fabricated sensor is transparent, self-healable, stretchable, and insensitive to bending but sensitively responds to in-plane strain induced by lateral deformation.

"Passenger gene" problem in transgenic C57BL/6 mice used in hearing research.

Despite recent advances in genome engineering technologies, traditional transgenic mice generated on a mixed genetic background of C57BL/6 and 129/Sv mice remain widely used in age-related hearing loss (AHL) research, since C57BL/6 mice exhibit early onset and progression of AHL due to a mutation in cadherin 23-encoding gene (Cdh23753G>A). In these transgenic mice, backcrossing for more than 10 generations results in replacement of the donor background (129/Sv) with that of the recipient (C57BL/6), so that approximately 99.9% of genes are C57BL/6-derived and are considered congenic. However, the regions flanking the target gene may still be of 129/Sv origin, creating a so-called "passenger gene problem" where the normal 129/Sv-derived Cdh23753G allele can travel with the target gene. In this study, we investigated the role of fatty acid-binding protein 7 (Fabp7), which is important for cellular uptake and intracellular trafficking of fatty acids in the cochlea, using traditional Fabp7 knockout (KO) mice on the C57BL/6 background. We found that Fabp7 KO mice showed delayed AHL progression and milder cochlear degeneration. However, the genotype of the Cdh23 region flanking Fabp7 was still that of 129/Sv origin (Cdh23753GG). Our findings reveal the potential risk of contamination for traditional transgenic mice generated on the C57BL/6 background.

A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy.

BACKGROUND: Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment-related toxicity varies and has not been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area. METHODS: This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment-related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2-year local control, progression-free survival, and overall survival rates. RESULTS: In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation-induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively. CONCLUSIONS: With a median follow-up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.

Recent Advances in Basic Research for Brain Arteriovenous Malformation.

Arteriovenous malformations (AVMs) are abnormal connections of vessels that shunt blood directly from arteries into veins. Rupture of brain AVMs (bAVMs) can cause life-threatening intracranial bleeding. Even though the majority of bAVM cases are sporadic without a family history, some cases are familial. Most of the familial cases of bAVMs are associated with a genetic disorder called hereditary hemorrhagic telangiectasia (HHT). The mechanism of bAVM formation is not fully understood. The most important advances in bAVM basic science research is the identification of somatic mutations of genes in RAS-MAPK pathways. However, the mechanisms by which mutations of these genes lead to AVM formation are largely unknown. In this review, we summarized the latest advance in bAVM studies and discussed some pathways that play important roles in bAVM pathogenesis. We also discussed the therapeutic implications of these pathways.

GSTA4 mediates reduction of cisplatin ototoxicity in female mice.

Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4-/- mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4-/- mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.