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Background and aims Proper measurement of expected risk is important for making rational decisions, and maladaptive decision making may underlie various psychiatric disorders. However, differentially expressed genetic profiling involved in this process is still largely unknown. A rodent version of the gambling task (rGT) has been developed to measure decision-making by adopting the same principle of Iowa Gambling Task in humans. In the present study, we examined using next-generation sequencing (NGS) technique whether there are differences in gene expression profiles in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) when rats make different choices toward risk in rGT. Methods Rats were trained in a touch screen chamber to learn the relationships between 4 different light signals on the window of the screen and accompanied reward outcomes or punishments set up with different magnitudes and probabilities. Once they showed a stabilized pattern of preference upon free choice, rats were classified into risk-averse or risk-seeking groups. After performing the rGT, rats were decapitated, the mPFC and the NAc was dissected out, and NGS was performed with the total RNA extracted. Results We found that 477 and 36 genes were differentially expressed (approximately 75 and 83% out of them were downregulated) in the mPFC and the NAc, respectively, in risk-seeking compared to risk-averse rats. Among those, we suggested a few top ranked genes that may contribute to promoting risky choices. Discussion and conclusions Our findings provide insights into transcriptional components underlying risky choices in rats.

To determine whether imaging-based risk stratification enables prognostication in diffuse glioma, NOS (not otherwise specified).Data from 220 patients classified as diffuse glioma, NOS, between January 2011 and December 2020 were retrospectively included. Two neuroradiologists analyzed pre-surgical CT and MRI to assign gliomas to the three imaging-based risk types considering well-known imaging phenotypes (e.g., T2/FLAIR mismatch). According to the 2021 World Health Organization classification, the three risk types included (1) low-risk, expecting oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, and 1p/19q-codeleted; (2) intermediate-risk, expecting astrocytoma, IDH-mutant; and (3) high-risk, expecting glioblastoma, IDH-wildtype. Progression-free survival (PFS) and overall survival (OS) were estimated for each risk type. Time-dependent receiver operating characteristic analysis using 10-fold cross-validation with 100-fold bootstrapping was used to compare the performance of an imaging-based survival model with that of a historical molecular-based survival model published in 2015, created using The Cancer Genome Archive data.Prognostication according to the three imaging-based risk types was achieved for both PFS and OS (log-rank test, p0.001). The imaging-based survival model showed high prognostic value, with areas under the curves (AUCs) of 0.772 and 0.650 for 1-year PFS and OS, respectively, similar to the historical molecular-based survival model (AUC = 0.74 for PFS and 0.87 for OS). The imaging-based survival model achieved high long-term performance in both 3-year PFS (AUC = 0.806) and 5-year OS (AUC = 0.812).Imaging-based risk stratification achieved histomolecular-level prognostication in diffuse glioma, NOS, and could aid in guiding patient referral for insufficient or unsuccessful molecular diagnosis.• Three imaging-based risk types enable distinct prognostication in diffuse glioma, NOS (not otherwise specified). • The imaging-based survival model achieved similar prognostic performance as a historical molecular-based survival model. • For long-term prognostication of 3 and 5 years, the imaging-based survival model showed high performance.

PurposeThe KNOG-1101 study showed improved 2-year PFS with temozolomide during and after radiotherapy compared to radiotherapy alone for patients with anaplastic gliomas. This trial investigates the effect of concurrent and adjuvant temozolomide on health-related quality of life (HRQoL).Materials and MethodsIn this randomized, open-label, phase II trial, 90 patients with World Health Organization grade III glioma were enrolled across multiple centers in South Korea between March 2012 to February 2015 and followed up through 2017. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and 20-item EORTC QLQ-Brain Neoplasm (QLQ-BN20) were used to compare HRQoL between patients assigned to concurrent chemoradiotherapy with temozolomide followed by 6 cycles of adjuvant temozolomide (arm A) and radiotherapy (RT) alone (arm B).ResultsOf the 90 patients in the study, 84 patients (93.3%) completed the baseline HRQoL questionnaire. Emotional functioning, fatigue, nausea and vomiting, dyspnea, constipation, appetite loss, diarrhea, seizures, itchy skin, drowsiness, hair loss, and bladder control were not affected by the addition of temozolomide. All other items did not differ significantly between arm A and arm B throughout treatment. Global health status particularly stayed consistent at the end of adjuvant temozolomide (p=0.47) and at the end of RT (p=0.33).ConclusionThe addition of concurrent and adjuvant temozolomide did not show negative influence on HRQoL with improvement of progression-free survival for patients with anaplastic gliomas. The absence of systematic and clinically relevant changes in HRQoL suggests that an overall long-term net clinical benefit exists for concurrent and adjuvant temozolomide.

Objective : Intracranial atypical meningiomas have a poor prognosis and high rates of recurrence. Moreover, up to one-third of the recurrences undergo high-grade transformation into malignant meningiomas. We aimed to investigate the clinical factors that can predict the propensity of malignant transformation from atypical to anaplastic meningiomas.Methods : Between 2001 and 2018, all patients with atypical meningioma, in whom the tumors had undergone malignant transformation to anaplastic meningioma, were included. The patients’ medical records documenting the diagnosis of atypical meningioma prior to malignant transformation were reviewed to identify the predictors of transformation. The control group comprised 56 patients with atypical meningiomas who were first diagnosed between January 2017 and December 2018 and had no malignant transformation.Results : Nine patients in whom the atypical meningiomas underwent malignant transformation were included. The median time interval from diagnosis of atypical meningioma to malignant transformation was 19 months (range, 7–78). The study group showed a significant difference in heterogeneous enhancement (77.8% vs. 33.9%), bone invasion (55.6% vs. 12.5%), mitotic index (MI; 14.8±4.9 vs. 3.5±3.9), and Ki-67 index (20.7±13.9 vs. 9.5±7.1) compared with the control group. In multivariate analysis, increased MI (odds ratio, 1.436; 95% confidence interval, 1.127–1.900; p=0.004) was the only significant factor for predicting malignant transformation.Conclusion : An increased MI within atypical meningiomas might be used as a predictor of malignant transformation. Tumors at high risk for malignant transformation might require more attentive surveillance and management than other atypical meningiomas.

Repeated injections of psychomotor stimulants like amphetamine (AMPH) to rodents can induce behavioral sensitization, which represents a long-lasting craving that is usually observed in human addicts. Behavioral sensitization is characteristically maintained for a long duration, accompanied by structural plasticity in some brain areas involved in reward circuitry. For example, it increased dendritic spine densities in the nucleus accumbens (NAcc), which is considered to reflect neurophysiological changes at this site, leading to addictive behaviors. The ezrin, radixin, and moesin (ERM) proteins regulate spine maturity by modifying their phosphorylation at the C-terminal region. We previously showed that ERM phosphorylation is reduced by AMPH in the NAcc core, suggesting that ERM-mediated spine changes at this site might be associated with AMPH sensitization. To test this hypothesis, we administered AMPH to rats according to a sensitization development schedule, with lentivirus encoding a phosphomimetic pseudo-active mutant of radixin (Rdx T564D) in the NAcc core, and examined dendritic spines at this site. We found that compared to acute AMPH, AMPH sensitization increased thin spine density with a similar ratio of filopodia-like to mature thin spines. However, with Rdx T564D, the density of thin spines increased, with augmented filopodia-like thin spines, resulting in no AMPH sensitization. These results indicate that Rdx T564D forces thin spines to immaturity and thereby inhibits AMPH sensitization, for which an increase in mature thin spines is normally necessary. These findings provide significant clues to our understanding of the role of dendritic spines in mediating the development of psychomotor stimulant addiction.

It is important to impose a persistent stochastic factor on the underlying asset model to obtain the fair value of financial derivatives with long time-to-maturities. Our empirical study, including the Covid-19 pandemic crisis period, indicates the presence of both fast and slow-scale in the elasticity of variance of S&P 500. This paper extends the elasticity in terms of multiscale stochastic process and obtains a closed form analytic pricing formula for European options and then derive the fair value of Equity-Linked-Annuity (ELA). The Mellin transform method for solving the relevant partial differential equations provides a computationally-efficient pricing formula for the options and the ELA. The prices can be easily calculated simply by taking derivatives of the Black–Scholes option price. Our results reveal the sensitivity of the ELA term structure to the fast-scale or slow-scale related group parameters.

GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gαi/o and Gαq/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca2+ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of pre-existing compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs.

Phosphorylation levels of glycogen synthase kinase 3β (GSK3β) negatively correlated with psychomotor stimulant-induced locomotor activity. Locomotor sensitization induced by psychomotor stimulants was previously shown to selectively accompany the decrease of GSK3β phosphorylation in the nucleus accumbens (NAcc) core, suggesting that intact GSK3β activity in this region is necessary for psychomotor stimulants to produce locomotor sensitization. Similarly, GSK3β in the NAcc was also implicated in mediating the conditioned effects formed by the associations of psychomotor stimulants. However, it remains undetermined whether GSK3β plays a differential role in the two sub-regions (core and shell) of the NAcc in the expression of drug-conditioned behaviors. In the present study, we found that GSK3β phosphorylation was significantly lower in the NAcc shell obtained from rats expressing amphetamine (AMPH)-induced conditioned locomotor activity. Further, we demonstrated that these effects were normalized by treatment with lithium chloride, a GSK3β inhibitor. These results suggest that the behavior produced by AMPH itself and a conditioned behavior formed by associations with AMPH are differentially mediated by the two sub-regions of the NAcc.

Apoptosis plays an essential role in maintaining cellular homeostasis and preventing cancer progression. Bcl-xL, an anti-apoptotic protein, is an important modulator of the mitochondrial apoptosis pathway and is a promising target for anticancer therapy. In this study, we identified octenidine as a novel Bcl-xL inhibitor through structural feature-based deep learning and molecular docking from a library of approved drugs. The NMR experiments demonstrated that octenidine binds to the Bcl-2 homology 3 (BH3) domain-binding hydrophobic region that consists of the BH1, BH2, and BH3 domains in Bcl-xL. A structural model of the Bcl-xL/octenidine complex revealed that octenidine binds to Bcl-xL in a similar manner to that of the well-known Bcl-2 family protein antagonist ABT-737. Using the NanoBiT protein-protein interaction system, we confirmed that the interaction between Bcl-xL and Bak-BH3 domains within cells was inhibited by octenidine. Furthermore, octenidine inhibited the proliferation of MCF-7 breast and H1299 lung cancer cells by promoting apoptosis. Taken together, our results shed light on a novel mechanism in which octenidine directly targets anti-apoptotic Bcl-xL to trigger mitochondrial apoptosis in cancer cells.

Malignant glioma is the most common central nervous system tumor of adults and is associated with a significant degree of morbidity and mortality. Gliomas are highly invasive and respond poorly to conventional treatments. Gliomas, like other tumor types, arise from a complex and poorly understood sequence of genetic and epigenetic alterations. Epigenetic alterations leading to gene silencing, in the form of aberrant CpG island promoter hypermethylation and histone deacetylation, have not been thoroughly investigated in brain tumors, and elucidating such changes is likely to enhance our understanding of their etiology and provide new treatment options. We used a combined approach of pharmacologic inhibition of DNA methylation and histone deacetylation, coupled with expression microarrays, to identify novel targets of epigenetic silencing in glioma cell lines. From this analysis, we identified >160 genes up-regulated by 5-aza-2′-deoxycytidine and trichostatin A treatment. Further characterization of 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, revealed that they are frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppress glioma cell growth in culture. Furthermore, we show that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant promoter hypermethylation events. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in gliomas and how they may be exploited for therapeutic purposes. (Cancer Res 2006; 66(15): 7490-501)

Supplementary Figures 1-3, Table 1 from Epigenomic Profiling Reveals Novel and Frequent Targets of Aberrant DNA Methylation-Mediated Silencing in Malignant Glioma

Background Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. Methods We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC–MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC–MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. Results In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. Conclusions The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Purpose We aim to evaluate efficacy of immediate post-concurrent chemoradiotherapy (CCRT) advanced MRI in patients with glioblastoma to guide treatment decisions and improve survival outcomes. Methods This retrospective study included 168 patients with IDH wild-type glioblastoma who showed measurable enlarging enhancing lesion on MRI within 12 weeks after CCRT between January 2013 and August 2021. Patients were classified with positive MRI group when early progression was suspected on advanced MRI. The rate of switching to second-line treatment was compared between patients with positive and negative findings. Overall survival (OS) after adjustment with propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) was compared between patients continuing primary treatment and those switched to second-line treatment. Multivariable Cox proportional hazards analysis was performed on PSM patients. Results Among 168 patients, 110 exhibited positive findings and 58 showed negative findings on advanced MRI. The positive MRI group showed higher rate of switching to second-line treatment than negative MRI group (49% [54/110] vs. 2% [1/58]; p

Background An open‐label single‐arm phase 2 study was conducted to evaluate the role of levetiracetam as a sensitizer of concurrent chemoradiotherapy (CCRT) for patients with newly diagnosed glioblastoma. This study aimed to determine the survival benefit of levetiracetam in conjunction with the standard treatment for glioblastoma. Methods Major eligibility requirements included histologically proven glioblastoma in the supratentorial region, patients 18 years or older, and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Levetiracetam was given at 1,000–2,000 mg daily in two divided doses during CCRT and adjuvant chemotherapy thereafter. The primary and the secondary endpoints were 6‐month progression‐free survival (6mo‐PFS) and 24‐month overall survival (24mo‐OS), respectively. Outcomes of the study group were compared to those of an external control group. Results Between July 2016 and January 2019, 76 patients were enrolled, and 73 patients were included in the final analysis. The primary and secondary outcomes were improved in the study population compared to the external control (6mo‐PFS, 84.9% vs. 72.3%, p = 0.038; 24mo‐OS, 58.0% vs. 39.9%, p = 0.018), but the differences were less prominent in a propensity score‐matched analysis (6mo‐PFS, 88.0% vs. 76.9%, p = 0.071; 24mo‐OS, 57.1% vs. 38.8%, p = 0.054). In exploratory subgroup analyses, some results suggested that patients with ages under 65 years or unmethylated MGMT promoter might have a greater survival benefit from the use of levetiracetam. Conclusions The use of levetiracetam during CCRT in patients with newly diagnosed glioblastoma may result in improved outcomes, but further investigations are warranted., Patients aged less than 65 years exhibited better outcomes with levetiracetam. Patients with unmethylated MGMT promoter possibly have greater benefits from levetiracetam.

INTRODUCTION This study investigated the role of natural polymers as moisturizers with low toxicity and biodegradability in the cosmetic and pharmaceutical industries. We isolated a polysaccharide extract from Dendrobium candidum (D. candidum) and determined its efficacy in skin hydration when used as an active cosmetic ingredient. METHODS The molecular weight distribution of D. candidum polysaccharides was analyzed via gel permeation chromatography (GPC). We performed real-time reverse transcription PCR (RT-PCR) and western blotting assays to investigate the physiological mechanism of the polysaccharides extracted from D. candidum (PDC). Based on in vitro data, the efficacy of PDC in improving skin condition was tested on the face of 21 volunteers. RESULTS The expression of filaggrin (FLG), caspase-14, and bleomycin hydrolase, which are the major components contributing to skin hydration, was significantly increased in the PDC-treated group. Further, the PDC upregulated the mRNA expression of occludin and claudin-1, which play a key role in epidermal barrier function. In addition, a topical application of PDC markedly increased skin hydration and improved trans-epidermal water loss (TEWL) and skin elasticity after 2 weeks. CONCLUSIONS It is the first study reporting the efficacy of PDC-mediated FLG mechanism associated with positive skin hydration. PDC can be used as an active ingredient in moisturizers. Long-term application of PDC-based moisturizers may result in significant improvement in elasticity and barrier function.

Brown Skuas (Stercorarius lonnbergi) are known to feed on other birds or eggs during the breeding season. In some cases, however, a few pairs monopolize a penguin colony, and the other skuas mainly forage in the sea. We installed automatic camera traps to monitor two groups of breeding Brown Skua pairs on King George Island: the nests of Group A were located near a Gentoo Penguin (Pygoscelis papua) colony, while those of Group B were relatively far away. From the resulting photographs, we were able to distinguish the food items that parents brought to the nest and could confirm the egg hatching date. Overall, 97.1% of the food items that group A brought to the nest were from the penguin colonies, while 94.1% of the prey items of group B were fish. Group A had a hatching date at least 8 days earlier than Group B. Our results show that a few Brown Skua pairs that bred near the penguin colony fed primarily on penguin nest contents such as eggs or chicks within their feeding territory and had earlier hatching dates. The Brown Skuas that nested close to penguin nests may have had advantages in foraging and breeding performance.

As is well known, multi-factor stochastic volatility models are necessary to capture the market accurately in pricing financial derivatives. However, the multi-factor models usually require too many parameters to be calibrated efficiently and they do not lead to an analytic pricing formula. The double Heston model is one of them. The approach of this paper for this difficulty is to rescale the double Heston model to reduce the number of the model parameters and obtain a closed form analytic solution formula for variance swaps explicitly. We show that the rescaled double Heston model is as effective as the original double Heston model in terms of fitting to the VIX market data in a stable condition and yet the computing time is much less than that under the double Heston model. However, in a turbulent situation after the start of the COVID-19 pandemic in 2020, we acknowledge that even the double Heston model fails to capture the market accurately.

A key function of multitarget tracking (MTT) is the state estimation of unknown targets. In this paper, we propose a new state estimator, the probabilistic data association finite impulse response filter (PDAFIRF), which is designed to overcome the drawbacks of the existing state estimators used for MTT. Because the existing state estimation methods used for MTT employ all past measurements, they may exhibit poor performance because of the accumulated errors caused by modeling uncertainties and numerical errors. To overcome the weaknesses of the existing methods, the proposed PDAFIRF uses recent finite measurements, and therefore, can prevent accumulated errors. The proposed PDAFIRF requires recent finite measurements from lidar and stereo vision and processes data in a probabilistic manner. Owing to its FIR-type structure, the PDAFIRF overcomes the structural and conditional defects of the existing stochastic filters. An MTT algorithm employing the PDAFIRF and lidar and stereo vision data is developed for multi-object tracking and target information estimation with high accuracy. The fusion of lidar and stereo vision sensor data is provided for the PDAFIRF. For verifying the high accuracy of the PDAFIRF-based MTT, a simulation of tracking eight objects under fast-varying conditions is conducted. An experimental test is performed using lidar and stereo vision for tracking three pedestrians. It is demonstrated that the proposed PDAFIRF-based MTT considerably enhances the tracking performance compared to the existing Kalman filter-, unscented Kalman filter-, and particle filter-based algorithms.

Background We aimed to investigate the detection rate of body CT or PET/CT for sites of extracranial disease in patients with a new pathological diagnosis of CNS DLBCL and to identify factors associated with sites of extracranial disease. Methods An international multicenter cohort study of consecutive immunocompetent patients with a new diagnosis of CNS DLBCL confirmed by brain biopsy who underwent CT and/or PET/CT to evaluate for sites of extracranial disease between 1998 and 2019. The primary outcome was the detection rate of extracranial lymphoma by CT or PET/CT. Subgroup analyses according to age and EBV status were also performed. Logistic regression analyses were performed to determine factors related to sites of extracranial disease. Detection rates of CT and PET/CT were compared. Results One thousand and forty-three patients were included. The overall detection rate of CT or PET/CT was 2.6% (27/1043). The treatment approach was adjusted in 74% of these patients. Multivariable analysis demonstrated that age >61 years (OR, 3.10; P = .016) and EBV positivity (OR, 3.78; P = .045) were associated with greater odds of extracranial lymphoma. There was no statistically significant difference in detection rate between CT and PET/CT (P = .802). In patients ≤61 years old, the false-referral rates were significantly higher than the detection rates (P < .001). Conclusion Our results showed increased odds of extracranial lymphoma in patients with older age or EBV-positive lymphoma. Treatment was adjusted in a majority of patients diagnosed with extracranial lymphoma, thereby supporting the current guidelines for the use of contrast-enhanced body CT or PET/CT in patients with newly diagnosed CNS DLBCL.

Microinjection of cocaine- and amphetamine-regulated transcript (CART) peptide 55–102 into the nucleus accumbens (NAcc) core significantly attenuates psychostimulant-induced locomotor activity. However, the molecular mechanism remains poorly understood. We examined the phosphorylation levels of Akt, glycogen synthase kinase 3β (GSK3β), and glutamate receptor 1 (GluA1) in NAcc core tissues obtained 60 min after microinjection of CART peptide 55–102 into this site, followed by systemic injection of amphetamine (AMPH). Phosphorylation levels of Akt at Thr308 and GSK3β at Ser9 were decreased, while those of GluA1 at Ser845 were increased, by AMPH treatment. These effects returned to basal levels following treatment with CART peptide 55–102. Furthermore, the negative regulatory effects of the CART peptide on AMPH-induced changes in phosphorylation levels and locomotor activity were all abolished by pretreatment with the S9 peptide, an artificially synthesized indirect GSK3β activator. These results suggest that the CART peptide 55–102 in the NAcc core plays a negative regulatory role in AMPH-induced locomotor activity by normalizing the changes in phosphorylation levels of Akt-GSK3β, and subsequently GluA1 modified by AMPH at this site. The present findings are the first to reveal GSK3β as a key regulator of the inhibitory role of the CART peptide in psychomotor stimulant-induced locomotor activity.

Brain metastasis from thyroid cancer (TCBM) is extremely rare; thus, despite a good treatment outcome for thyroid cancer, TCBM has shown poor clinical outcomes. Considering the short survival and poor general condition of patients with TCBM, stereotactic radiosurgery may be preferred to achieve local control.A total of 25 patients with TCBM who underwent Gamma Knife radiosurgery (GKS) were initially included in this study; however, 3 patients were excluded because of a lack of data.There were 7 men (31.8%) and 15 women (68.2%) and the mean age was 63.7 years. The most common type of thyroid cancer histology was papillary carcinoma. Fourteen patients (63.6%) harbored single brain metastatic tumor and 8 (36.3%) had multiple brain metastatic tumors. The mean duration from thyroid cancer diagnosis to detection of brain metastasis was 7.7 years (range, 0-23 years). The median dose of radiation of GKS was 22 Gy (range, 18-25 Gy). There was no radiation-induced complication after GKS. The median overall survival (OS) was 15 months and the 1-year OS of patients with TCBM was 63%, the 2-year OS was 38%, and the 5-year OS was 28%. The 6-month progression-free survival (PFS) for local recurrence of TCBM was 90.4%, the 1-year PFS was 84%, and the 3-year PFS was 84%.GKS showed favorable local control for TCBM. However, the rate of distant brain metastasis was high and median survival of patients with TCBM was only 15 months.

The double-mean-reverting model, introduced by Gatheral [(2008). Consistent modeling of SPX and VIX options. In The Fifth World Congress of the Bachelier Finance Society London, July 18], is known to be a successful three-factor model that can be calibrated to both CBOE Volatility Index (VIX) and S&P 500 Index (SPX) options. However, the calibration of this model may be slow because there is no closed-form solution formula for European options. In this paper, we use a rescaled version of the model developed by Huh et al. [(2018). A scaled version of the double-mean-reverting model for VIX derivatives. Mathematics and Financial Economics 12: 495–515] and obtain explicitly a closed-form pricing formula for European option prices. Our formulas for the first and second-order approximations do not require any complicated calculation of integral. We demonstrate that a faster calibration result of the double-mean revering model is available and yet the practical implied volatility surface of SPX options can be produced. In particular, not only the usual convex behavior of the implied volatility surface but also the unusual concave down behavior as shown in the COVID-19 market can be captured by our formula.

Although rats with melanin-pigmentated retinal pigment epithelial (RPE) cells are physiologically more appropriate models for human eye research than their albino counterparts, reliable models from the former strain are not available to study retinal degeneration. Here, we describe the development of a novel Pde6b-knockout Long–Evans (LE Pde6b KO) rat model that recapitulates key features of human retinitis pigmentosa (RP). After the generation of the Pde6b-knockout Sprague–Dawley rats with the CRISPR-Cpf1 system, the LE rat was back-crossed over 5 generations to develop the pigmented LE Pde6b KO strain. Interestingly, LE Pde6b KO displayed well-developed bone-spicule pigmentation; a hallmark of fundus in patients with RP which cannot be observed in non-pigmented albino rats. Moreover, the rat model showed progressive thinning of the retina, which was evident by intravital imaging with optical coherence tomography. Histologically, significant atrophy was observed in the outer nuclear layer. Functionally, LE Pde6b KO presented a marked decrease of amplitude level during electroretinogram testing, demonstrating significant loss of visual function. Therefore, these findings suggest that the LE Pde6b KO model robustly recapitulates the hallmark phenotype of RP. We believe that the LE Pde6b KO model may be used effectively for preclinical translational research to further study retinal degeneration.

ObjectiveA lack of understanding of the clinical course of neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS) often complicates the decision-making in terms of optimal timing and mode of treatment. We investigated the outcomes of stereotactic radiosurgery (SRS) in this population.MethodsWe retrospectively analyzed NF2 patients treated with Gamma-Knife SRS for VS in our tertiary referral center. A total of 41 treated lesions from 33 patients were collected with a follow-up period of 69.1 (45.0-104.8) months. We reviewed the treatment history, hearing function, and other treatment-related morbidities in individual cases. We also analyzed pre- and post-treatment tumor volumes via imaging studies. Longitudinal volumetric analyses were conducted for the tumor volume response of the 41 treated lesions following SRS. The growth pattern of 22 unirradiated lesions during an observation period of 83.4 (61.1-120.4) months was separately evaluated.ResultsMost treated lesions showed effective tumor control up to 85% at 60 months after SRS, whereas unirradiated lesions progressed with a relative volume increase of 14.0% (7.8-27.0) per year during the observation period. Twelve (29%) cases showed pseudoprogression with significant volume expansion in the early follow-up period, which practically reduced the rate of tumor control to 57% at 24 months. Among the patients with serviceable hearing, two (20%) cases lost the hearing function on the treated side during the early follow-up period within 24 months.ConclusionsProgressive NF2-associated VS can be adequately controlled by SRS but the short-term effects of this treatment are not highly advantageous in terms of preserving hearing function. SRS treatment candidates should therefore be carefully selected.

Diffuse midline glioma (DMG) which occurs in midline structures and characterized by harboring K27M mutation in genes encoding the histone 3 protein is classified as World Health Organization (WHO) grade IV regardless of histological findings and has a poor prognosis. Nevertheless, because of its relatively rare incidence compared with other high-grade gliomas, a comprehensive description encompassing clinical features and genomic profiles of DMG is still lacking.In this study, we analyzed data of 24 patients who were diagnosed as DMG which was confirmed by surgical specimens in both pediatric and adult patients. We described the clinical outcomes of patients with DMG and their genomic profiles through a retrospective analysis of 24 patients with DMG.The clinical characteristics of the 24 patients with DMG were analyzed. Ten patients (41%) underwent tumor resection and 14 patients (59%) underwent tumor biopsy. The median overall survival was 10.4 months (95% confidence interval [CI], 8.4 to 12.5) and progression free survival was 3.9 months (95% CI, 2.6 to 5.2). Fifteen patients (62%) were accompanied by hydrocephalus. None of the patient, tumor, or treatment factors had any significant associated with survival. In both immunohistochemistry staining (n=24) and targeted next generation sequencing (n=15), TP53 mutation was the most common genetic mutation (25% and 46%, respectively) found in the patients except alterations in histone 3 protein.Although surgical treatment of patient with DMG does not affect the overall survival prognosis, it can help improve the patient's accompanying neurological symptoms in some limited cases. Hydrocephalus is often accompanied with DMG and treatment for hydrocephalus is often also required. Multidisciplinary therapeutic approach is needed.

Anaplastic meningioma is very rare and is generally known to have a poor prognosis. However, due to its rarity, the relationship between clinical prognosis and prognostic factors is not clear. We analyzed the prognostic factors influencing survival outcomes of patients with anaplastic meningioma. Moreover, we analyzed on the progression pattern and the response to treatment about anaplastic meningioma.Retrospective review of 48 patients with diagnosis of World Health Organization (WHO) grade 3 meningioma was performed. According to diagnosis type, primary anaplastic meningioma was included in 28 cases and secondary anaplastic meningioma in 20 cases. Gross total resection was performed in 36 patients (75.0%), and 32 patients (66.7%) received adjuvant radiotherapy after tumor resection with confirmed WHO grade 3 meningioma. Kaplan-Meier survival curve and Cox proportional hazards modeling were used for outcome analysis.The median progression-free survival (PFS) and overall survival (OS) were 13.9 months (95% confidence interval [CI], 8.8 to 19.1) and 56.9 months (95% CI, 24.1 to 89.7), respectively. Adjuvant radiotherapy was a robust prognostic factor for PFS and OS. Extent of resection and diagnosis type which appeared to be significant prognostic factors in univariate analysis were failed to prove statistical significance in multivariate analysis.Adjuvant radiotherapy is an essential treatment arm in patients with anaplastic meningiomas. Stereotactic radiosurgery seems to play an important role as a salvage treatment. But chemotherapy seems to have limited efficacy. Because of the disseminated nature of the disease, further investigations to improve survival outcome are needed.

Cereblon (CRBN) is a multi-functional protein that acts as a substrate receptor of the E3 ligase complex and a molecular chaperone. While CRBN is proposed to function in mitochondria, its specific roles are yet to be established. Here, we showed that knockdown of CRBN triggers oxidative stress and calcium overload in mitochondria, leading to disruption of mitochondrial membrane potential. Notably, long-term CRBN depletion using PROteolysis TArgeting Chimera (PROTAC) induced irreversible mitochondrial dysfunction, resulting in cell death. Our collective findings indicate that CRBN is required for mitochondrial homeostasis in cells. [BMB Reports 2021; 54(6): 305-310].