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Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of 'eye movements of the blind.' It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration. [ABSTRACT FROM AUTHOR]

Overall, more than 50% of marginal zone lymphoma (MZL) patients experience a relapse within 10 years. This phase II trial was conductedto assess the efficacy and safety of oxaliplatin-prednisone (Ox-P) chemotherapy for patients with relapsed or refractory MZL. Patients received oxaliplatin 130 mg/m2on day 1 and prednisone 100 mg/day on days 1–5 of each cycle. A total of 38 patients were enrolled. The median age of the 34 (16 males, 18 females) evaluated patients was 53 (range = 27–74) years. There were seven complete responses (20.6%) and 15 partial responses (44.1%) (Overall response rate = 64.7%). No treatment-related deaths occurred. The median progression-free survival was 14.2 months (95% CI = 2.1–26.3 months); 3-year overall survival rate was 77.7%. Thus, salvage Ox-P chemotherapy for patients with relapsed or refractory MZL at the stated dosage and schedule showed moderate clinical activity and was considerable in very few selected patients (NCT01068392). [ABSTRACT FROM AUTHOR]

Purpose: Mantle cell lymphoma (MCL) is a disease that frequently relapses and primarily affects elderly people. We performed an open-label, multi-center, phase II study to investigate the effect and quality of life (QoL) of treatment with vorinostat in combination with fludarabine, mitoxantrone and dexamethasone (V-FND) for relapsed or refractory MCL.Methods: The treatment schedule was composed of four cycles of induction treatment with V-FND and subsequent consolidation therapy involving autologous hematopoietic stem cell transplantation or six cycles of vorinostat maintenance. QoL was assessed using EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) every 2 cycles.Results: Data from a total of 20 patients were collected for an interim analysis. The median age was 67 years (range 49-75), and 14 or the patients (70 %) were male. The full course of V-FND induction treatment was completed in 11 patients, but only three completed all six cycles of maintenance therapy. Response to V-FND was not available in two patients. Among the other 18 patients, the objective response rate was 77.8 % (complete response in five patients + partial response in nine patients). Median progression-free survival was 9.3 months [95 % confidence interval (CI) 4.0-12.3]. Fifteen patients (75 %) experienced grade 3/4 toxicities. Analysis of QoL demonstrated significant deterioration of social functioning (p = 0.01), and significant aggravation of fatigue and nausea/vomiting (p = 0.04 and 0.01, respectively) after two cycles of V-FND induction.Conclusions: V-FND is effective in patients with relapsed or refractory MCL. However, significant toxicities were hurdles to sustained V-FND therapy. [ABSTRACT FROM AUTHOR]

Background: Because many physicians seem reluctant to recommend splenectomy for elderly patients with immune thrombocytopenia (ITP), we investigated the safety and efficacy of splenectomy and the predictive factors for response in these patients. Methods: 184 patients with primary ITP were retrospectively analyzed based on age at splenectomy: an elderly group (≥ 60 years, n = 52) and a younger group (<60 years, n = 132). Results: There was no difference in the response rate of elderly versus younger patients (80.7 vs. 80.3%, p = 0.466). Relapse (45.2 vs. 22.6%, p = 0.006), complications, and median postoperative stay (9.5 vs. 7 days, p = 0.019) were significantly higher in the elderly group. The 5-year relapse-free survival of responders was 51.8% in the elderly group and 76.3% in the younger group (p = 0.002). Response to any treatment before splenectomy (HR 2.9, 95% CI: 1.24-6.80, p = 0.014) and platelet count on postoperative day 14 ≥ 200 × 109/l (HR 31.43, 95% CI: 4.15-238.28, p = 0.001) were independent factors for a favorable response. Conclusions: Age ≥ 60 years did not influence the response to splenectomy but was associated with increased relapse and postoperative complications. Splenectomy could provide a durable longterm response for elderly ITP patients. [ABSTRACT FROM AUTHOR]

Tunable and selective areal polymer chain alignment method is developed for spin-cast blend films of poly(3-hexylthiophene)(P3HT):[6,6]-phenyl-C61-butlyric methyl ester (PCBM) system by a femtosecond laser process. The chain alignment, phase separation, and molecular structure of the laser exposed P3HT:PCBM films are investigated by grazing incidence wide angle X-ray scattering and micro-Raman analysis. The alkyl chains of P3HT polymer become highly ordered along the polarization axis of the laser. Thus, the amount of desirable face-on configuration for solar cell application is largely enhanced with a subsequent postannealing process. Vertically expanded morphology up to 200 nm on P3HT:PCBM films is also prompted by the laser irradiation without deteriorating intramolecular structure and changing chemical composition. Simultaneously, vertical phase separation of PCBM toward surface is induced at exposed region. [ABSTRACT FROM AUTHOR]

The structure of P3HT in P3HT:PCBM films is examined on a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) substrate subjected to cryo-cooling to low temperature (−143 °C) followed by gradual heating to 50 °C. The behavior of these systems is examined in the absence and presence of an Al electrode on top of the P3HT:PCBM film. At temperatures below −10 °C, only the type-I phase of P3HT is observed. However, the type-II phase of P3HT starts to form near −10 °C, in both the presence and absence of the Al layer. In the system without an Al layer, the type-II phase disappears at 30 °C, but this phase persists to 50 °C in the presence of the Al layer. Concomitant with the formation of the type-II phase, a 1:3 ordered P3HT type-II (1/3,0,0) superlattice peak emerged. The type-II domains tend to form near the Al electrode layer and show a higher degree of alignment than the type-I crystals. [ABSTRACT FROM AUTHOR]

Purpose Triweekly delivery of cisplatin concurrent with a course of radiation therapy (RT) has been the standard regimen for treatment of locally advanced nasopharyngeal carcinoma (NPC) despite a high level of concern regarding treatment-related complications. We conducted a randomized phase II study to compare weekly and triweekly cisplatin delivery during RT with respect to efficacy and toxicity profiles. Material and methods Patients with locally advanced NPC (stage II–IVb) were randomly assigned to a regimen of either seven doses of cisplatin (40 mg/m 2 ) given once a week or three doses of cisplatin (100 mg/m 2 ) given every 3 weeks concurrently during RT. Results Of 109 eligible patients, 53 were assigned to the weekly regimen and 56 to the triweekly regimen. The two groups were comparable with respect to demographic and clinical characteristics. There were no significant differences in mean RT dose (68.3 Gy vs. 67.3 Gy, p = 0.559) and mean cisplatin dose (248.9 mg/m 2 vs. 256.6 mg/m 2 , p = 0.433) between the two regimens. The primary endpoint was 3-year progression-free survival, which was not different between the regimens (64.9% vs. 63.8%, p = 0.074). Overall, the occurrence of grade 3–4 toxicities was similar between the two arms (47.2% vs. 39.3%, p = 0.443). Quality of life (QoL) related to functional outcomes 3 weeks after treatment completion was better for the weekly regimen. Conclusions Although no definitive conclusions can be made, a once-weekly cisplatin regimen appears to be associated with improved QoL and is not inferior to the standard triweekly regimen with respect to efficacy and toxicity profiles. [ABSTRACT FROM AUTHOR]

Glucocorticoids effectively mediate the resolution of inflammation, but long-term use of glucocorticoids inevitably causes metabolic side effects. However, it is unknown if metabolic effectors such as Dexras1, a dexamethasone-stimulated protein, play a role in the anti-inflammatory outcome of dexamethasone. Here, we demonstrate that Dexras1 is required for the dexamethasone-induced upregulation ofannexin A1expression, but is not involved in the reduction of inflammation as evidenced by decreased pro-inflammatory parameters. In the absence of Dexras1, lipopolysaccharide (LPS)-induced interleukin-6 expression was suppressed when murine macrophage RAW264.7 cells were treated with dexamethasone. Similar observations were made in the blood of Dexras1 knockout mice. Furthermore, dexamethasone suppressed the LPS-stimulated increase of NFκB-p65 in both control and Dexras1-absent RAW264.7 cells. Interestingly, depletion of Dexras1 resulted in the loss of pERK production. These results suggest that Dexras1 is involved primarily in the metabolic side effects and its inhibition preserves the anti-inflammatory action of glucocorticoids. Thus, the inhibition of Dexras1 will be an excellent target for reducing steroid-induced side effects. [ABSTRACT FROM AUTHOR]

Polymers using 6-(2-thienyl)-4 H -thieno[3,2- b ]indole (TTI) with high planarity were synthesized and utilized for the photovoltaics. Push-pull types of conjugated polymers ( PTTICN, PTTICNR and PTTIFR ) containing TTI as electron pushing unit and 2-pyriminecarbonitrile or 2-fluoropyrimidine as electron pulling unit were synthesized. We designed pyrimidine derivatives with strong electron-withdrawing group (C N or fluorine) for the generation of strong electron pulling property. By the combination with the electron pushing unit, the pyrimidines with strong electron pulling units will provide low highest occupied molecular orbital (HOMO) energy levels for higher open-circuit voltages ( V OC ). For the syntheses of the polymers, the electron pushing and the electron pulling units were combined by Stille coupling reaction with Pd(0)-catalyst. The polymers of PTTICN and PTTICNR with CN unit show higher V OC than the polymer with fluorine unit. The device comprising PTTICNR and PCBM (1:4) with diiodooctane (DIO) additive showed a V OC of 0.82 V, a J SC of 6.38 mA/cm 2 , and a fill factor ( FF ) of 0.53, giving a power conversion efficiency of 2.81%. [ABSTRACT FROM AUTHOR]

R4358 --> 653.2 --> Alzheimer's disease (AD), a neurodegenerative disorder, has been known to be mostly commonly diagnosed in people over the age of 65. However, there is no drug that can cure AD. This study aimed to investigate if wasp venom (WV) can mitigate phenotypes of AD using a 5xFAD transgenic mouse model. The mice were administered intraperitoneally with WV obtained from Vespa velutina at a concentration of 250 or 400 μg/kg body weight (BW) once a week for a total of 14 weeks. WV treatment was shown to alleviate memory impairments in 5xFAD mice in behavioral tasks, including passive avoidance, Y‐maze and Morris water maze tests. In addition, we found that WV treatment decreased the level of 8‐hydroxy‐2′‐deoxyguanosine, a biomarker of oxidative DNA damage, in mouse plasma and the level of malondialdehyde, an indicative of lipid peroxidation, in liver and cerebral cortex, indicating that WV prevents oxidative damage. In particular, WV treatment increased expression of antioxidant‐associated proteins, a nuclear factor erythroid‐derived 2‐related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), in the cerebral cortex and decreased inflammation‐associated protein, cyclooxygenase‐2 (COX‐2), amyloid beta (Aβ) plaque‐associated proteins, C‐terminal fragment (C99), and beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1, β‐secretase) in the hippocampal tissue homogenates. Furthermore, we confirmed that WV treatment reduced the accumulation of Aβ plaque in the hippocampal area via thioflavin S staining. Taken together, these findings suggest that WV could ameliorate AD symptoms and delay AD onset and progression. [ABSTRACT FROM AUTHOR]

Despite extensive progress in organic field-effect transistors, there are still far fewer reliable, high-mobility n-type polymers than p-type polymers. It is demonstrated that by using dopants at a critical doping molar ratio ( MR), performance of n-type polymer poly[[ N, N9-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,59-(2,29-bithiophene)] (P(NDI2DO-T2)) field-effect transistors (FETs) can be significantly improved and simultaneously optimized in mobility, on-off ratio, crystallinity, injection, and reliability. In particular, when using the organic dopant bis(cyclopentadienyl)-cobalt(II) (cobaltocene, CoCp2) at a low concentration (0.05 wt%), the FET mobility is increased from 0.34 to 0.72 cm2 V-1 s-1, and the threshold voltage was decreased from 32.7 to 8.8 V. The relationship between the MR of dopants and electrical characteristics as well as the evolution in polymer crystallinity revealed by synchrotron X-ray diffractions are systematically investigated. Deviating from previous discoveries, it is found that mobility increases first and then decreases drastically beyond a critical value of MR. Meanwhile, the intensity and width of the main peak of in-plane X-ray diffraction start to decrease at the same critical MR. Thus, the mobility decrease is correlated with the disturbed in-plane crystallinity of the conjugated polymer, for both organic and inorganic dopants. The method provides a simple and efficient approach to employing dopants to optimize the electrical performance and microstructure of P(NDI2DO-T2). [ABSTRACT FROM AUTHOR]

The effects of the temperature and the presence of an interfacial buffer layer on the nanostructure of organic bulk heterojunctions (BHJs) based on copper phthalocyanine (CuPc) and fullerene (C60) systems were examined using real-time in situ X-ray measurements. The CuPc:C60 BHJ structures prepared without a buffer layer formed a standing-on configured γ-CuPc phase. Once formed, the γ-phase could be rendered thermally stable by post-annealing at 180°C. The insertion of a CuI buffer layer prior to the deposition of a CuPc:C60 BHJ layer induced the formation of a lying-down configured CuPc phase in the BHJ layer. The CuPc peak intensity and lattice parameters gradually increased upon thermal annealing. This increase in intensity appeared to be related to the strain at the interface between the CuPc:C60 and CuI layers. [ABSTRACT FROM AUTHOR]

Diagnosis of central vestibulopathy remains a challenge when it is associated with peripheral vestibular dysfunction because neurotological findings from peripheral vestibulopathy may overshadow those from central vestibular involvements. To define the characteristics of disorders involving both peripheral and central vestibular structures, we classified the combined vestibulopathies into four types according to their vestibular manifestations, and describe a typical case in each subtype. Infarction involving the territory of anterior inferior cerebellar artery is the most common cause of acute unilateral cases, whereas tumors involving the cerebellopontine angle should be of prime suspicion in patients with chronic unilateral ones. Wernicke encephalopathy was most common in patients with acute bilateral combined vestibulopathy while degenerative disorders should be considered in chronic bilateral ones. Since the head impulse test (HIT) is mostly positive in combined vestibulopathy, signs of central vestibular dysfunction other than negative HIT should be sought carefully even in patients with obvious clinical or laboratory features of peripheral vestibulopathy. [ABSTRACT FROM AUTHOR]

Abstract: Total body irradiation (TBI) has traditionally been used in the conditioning regimen for allogenetic hematopoietic stem cell transplantation (alloHCT) from an unrelated donor (u-HCT). However, patients are increasingly receiving a fludarabine-based conditioning regimen without TBI, as it seemed less toxic than TBI. We need to know the clinical results of non-TBI u-HCT treatments. We retrospectively investigated the clinical outcomes of allogenetic hematopoietic cell transplantation (alloHCT) from an unrelated donor without TBI (non-TBI u-HCT) and compared the clinical outcomes of fludarabine-based (FLU group) and cyclophosphamide-ATG (Cy-ATG group) conditioning regimens. Sixty-one patients received the non-TBI conditioning regimen for u-HCT (32 in the FLU group and 29 in the Cy-ATG group). The cumulative incidence of neutrophil engraftment at 30 days, platelet>20K/μL at 30 days, acute graft-versus host disease (aGvHD) at 100 days, and chronic GvHD (cGvHD) at 2 years were 87.01%, 65.57%, 35.20%, and 26.64%, respectively. However, transplantation outcomes and overall survival rates did not differ between the FLU and Cy-ATG groups. Only infused CD34+ cells >3×106 kg−1 was identified as a favorable factor for survival in the multivariate analysis. In conclusion, non-TBI u-HCT was feasible and there was no difference between the FLU and Cy-ATG groups in terms of transplantation outcomes. [Copyright &y& Elsevier]

The oculomotor abnormalities with isolated infarction of the cerebellar tonsil are unknown. In a patient with acute infarction of the right tonsil, we found (1) nearly completely abolished ipsilateral smooth pursuit and impaired contralateral pursuit, (2) a low-amplitude ipsilesional right-beating nystagmus without fixation, (3) gaze-holding deficits, and (4) normal vestibulo-ocular reflex. These findings contrast with striking vestibular abnormalities reported with unilateral flocculus and anterior tonsil infarction. Taken together, these findings allow more diagnostic certainty in cerebellar patients, help resolve controversies about interpretation of experimental findings in monkeys, and clarify homologies between the monkey and human cerebellum. [ABSTRACT FROM AUTHOR]

The oculomotor abnormalities with isolated infarction of the cerebellar tonsil are unknown. In a patient with acute infarction of the right tonsil, we found (1) nearly completely abolished ipsilateral smooth pursuit and impaired contralateral pursuit, (2) a low-amplitude ipsilesional right-beating nystagmus without fixation, (3) gaze-holding deficits, and (4) normal vestibulo-ocular reflex. These findings contrast with striking vestibular abnormalities reported with unilateral flocculus and anterior tonsil infarction. Taken together, these findings allow more diagnostic certainty in cerebellar patients, help resolve controversies about interpretation of experimental findings in monkeys, and clarify homologies between the monkey and human cerebellum. Ann Neurol 2014;75:429-434 [ABSTRACT FROM AUTHOR]

[Display omitted] • Dimple nanostructures are formed on PEN films using a one-step IBS. • Nanotip size, geometry controllable by varying ion-irradiation energy density. • Nanotips with spacing under 10 nm effectively enhanced SERS signal. • IBS process has potential for use in roll-to-roll manufacture of SERS substrates. Surface-enhanced Raman spectroscopy (SERS) utilizes metal nanostructures to enhance the intensity of Raman signals. Although many methods have been developed for fabricating SERS nanostructures, most involve multiple steps. Herein, we employed oxygen ion beam sputtering (IBS), a one-step technique suitable for processing flexible substrates in roll-to-roll processes for mass production, Specifically, one-step oxygen IBS was used to fabricate self-organized dimple nanostructures, whose area and roughness could be controlled using the ion irradiation energy density, on the surfaces of polyethylene naphthalate films. Gold nano-tips for SERS were subsequently obtained by evaporating gold onto the dimple nanostructures. Finite-difference time-domain (FDTD) simulations revealed that nano-tip structures with spacings of less than 10 nm increased the localized E-field enhancement, which improved the SERS signal. Fabrication at a low energy density (5.8 J/cm2) produced more nano-tips with spacings of less than 10 nm, corresponding to a density of 61.4 nano-tips/μm2. SERS analysis conducted with methylene blue at 638 nm and 785 nm demonstrated that the Raman signal intensity was stronger for SERS substrates fabricated with low energy density (5.8 J/cm2) than for substrates fabricated with high energy density (17.3 J/cm2), because of the high density of nano-tips on the former substrate. [ABSTRACT FROM AUTHOR]

Defoliation (DF) on peach (Prunus persica L.) and Japanese apricot (Prunus mume Sieb. et Zucc.) trees caused by a hailstorm in 2017, year 1, was investigated for its effects on growth and fruit yield in South Korea over four years, comparing with recovery effects of the DF trees treated with repeated immediate pruning (IP) right after the storm. Treatments included 0–10, 10–40, 40–70, and 70–100% of DF trees, with 0–10, 10–40, 40–70, and 70–100% of DF + IP trees. The hailstorms increased the damages to shoots for peaches and to shoots and scaffold for Japanese apricot trees in year 1, with fruit yield reduced more than 80% observed on 10–100 DF of both fruit species. The IP treatment increased the number of new shoots in years 2–4 but reduced shoot length and diameter of peach and Japanese apricot trees. Tree canopy in years 2–4 was reduced on 40–100 DF of peach trees and on 70–100 of DF and DF + IP of Japanese apricot trees. The 40–100 DF Japanese apricot trees resulted in a fruit yield index of less than 90% for years 2–4, which was observed on 40–100 DF+IP trees only in year 2 due to balanced tree vegetative and reproductive growth. [ABSTRACT FROM AUTHOR]

Abstract: The Wnt/β-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells (HNSCC). Increased β-catenin predisposes HNSCC patients to poor prognosis and survival. This study was conducted to determine the mechanism by which β-catenin regulates the viability of HNSCC. AMC-HN-3, -HN-8, UM-SCC-38, and -SCC-47 cells, which were established from human head and neck cancer specimens, and underwent cell death following β-catenin silencing. β-Catenin silencing significantly induced G1 arrest and increased the expression of Bax and active caspase-3, which demonstrates the sequential activation of apoptotic cascades following treatment of HNSCC with targeted siRNA. Intriguingly, β-catenin silencing also induced autophagy. Here, we confirm that the number of autophagic vacuoles and the expression of type II light chain 3 were increased in cells that were treated with β-catenin siRNA. These cell death modes are most likely due to the activation of LKB1-dependent AMPK following β-catenin silencing. The activated LKB1/AMPK pathway in AMC-HN-3 cells caused G1 arrest by phosphorylating p53 and suppressing mTOR signaling. In addition, treating AMC-HN-3 cells with LKB1 siRNA preserved cell viability against β-catenin silencing-induced cytotoxicity. Taken together, these results imply that following β-catenin silencing, HNSCC undergo both apoptotic and autophagic cell death that are under the control of LKB1/AMPK. To the best of our knowledge, these results suggest for the first time that novel crosstalk between β-catenin and the LKB1/AMPK pathway regulates the viability of HNSCC. This study thus presents new insights into our understanding of the cellular and molecular mechanisms involved in β-catenin silencing-induced cell death. [Copyright &y& Elsevier]

Abstract: Background: We performed a phase II study to evaluate the efficacy of bortezomib in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas (PTCLs) based on our phase I study results. Methods: Patients received bortezomib on days 1 and 8 at a dose of 1.6mg/m2 in addition to CHOP every 3weeks for a total of six cycles. Results: Forty-six patients were enrolled: PTCL, not otherwise specified (PTCL-NOS, n =16), extranodal NK/T-cell lymphoma, nasal type (ENKTL, n =10), angioimmunoblastic T-cell lymphoma (AITL, n =8), ALK-negative anaplastic large-cell lymphoma (ALCL, n =6), cutaneous T-cell lymphoma (CTCL, n =5) and hepatosplenic T-cell lymphoma (n =1). Thirty patients achieved complete response (CR, 65%) and the overall response rate was 76% (35/46). Although the CR rate of ENKTL was only 30% (3/10), three subtypes of PTCLs (PTCL-NOS, AITL and ALCL) showed 87% of overall response rate (ORR) (26/30) and 73% of CR rate (22/30). However, the 3-year overall survival and progression-free survival were 47% and 35%, respectively due to frequent relapse after remission. Grade 3/4 leucopenia was the most frequent toxicity whereas neurotoxicity was tolerable: grade 1 or 2 of peripheral neuropathy. Conclusions: The combined treatment of bortezomib and CHOP is an effective and feasible regimen for advanced-stage PTCLs other than ENKTL, with acceptable toxicity. However, future studies exploring new drug combinations are warranted to overcome relapse after remission. [Copyright &y& Elsevier]

Angiotensin II (Ang II)-mediated modification of the redox milieu of vascular smooth muscle cells (VSMCs) has been implicated in several pathophysiological processes, including cell proliferation, migration and differentiation. In this study, we demonstrate that the peroxisome proliferator-activated receptor (PPAR) δ counteracts Ang II-induced production of reactive oxygen species (ROS) in VSMCs. Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly reduced Ang II-induced ROS generation in VSMCs. This effect was, however, reversed in the presence of small interfering (si)RNA against PPARδ. The marked increase in ROS levels induced by Ang II was also eliminated by the inhibition of phosphatidylinositol 3-kinase (PI3K) but not of protein kinase C, suggesting the involvement of the PI3K/Akt signalling pathway in this process. Accordingly, ablation of Akt with siRNA further enhanced the inhibitory effects of GW501516 in Ang II-induced superoxide production. Ligand-activated PPARδ also blocked Ang II-induced translocation of Rac1 to the cell membrane, inhibiting the activation of NADPH oxidases and consequently ROS generation. These results indicate that ligand-activated PPARδ plays an important role in the cellular response to oxidative stress by decreasing ROS generated by Ang II in vascular cells. [ABSTRACT FROM AUTHOR]

Abstract: The issue of whether aberrant expression of β1-integrin is associated with cancer progression and development of resistance to cytotoxic therapy is of considerable interest. Studies to date have shown that the anchorage-independent survival of cancer is attributed, in part, to epithelial-to-mesenchymal transition (EMT). Here, we have reported a novel alternative mechanism of anchorage-independent survival of cancer cells. Cell lines derived from head and neck cancer patients (AMC-HN-3 and AMC-HN-9) and the well-known EMT cancer cell line, MDA-MB231, were examined. The EMT features of AMC-HN-9 cells were comparable to those of MDA-MB231, whereas AMC-HN-3 cells showed no EMT characteristics. Although the pattern and degree of β1-integrin expression were similar in all three cell lines, sensitivities of the cells to β1-integrin knockdown with small interfering RNA (siRNA) were different. Cancer cells with no EMT features underwent cell death to a more significant extent following β1-integrin silencing than those with EMT. Intriguingly, we observed reactive activation of the p53–p21 pathway after β1-integrin silencing in AMC-HN-9 cells lacking an apparent cell death response. Simultaneous knockdown of wild-type p53 and β1-integrin in this cell line promoted cell death. Our data collectively indicate that β1-integrin-related cell death is closely associated with EMT phenotypes and activation of the p53–p21 pathway is partly involved in the acquisition of resistance to apoptosis induced by β1-integrin silencing. Further clarification of the mechanisms underlying p53 integration with β1-integrin signaling may facilitate the development of novel anti-cancer strategies. [Copyright &y& Elsevier]

Abstract: Objective: Our previous in vitro study demonstrated that glyceollins help normalize glucose homeostasis by potentiating β-cell function and survival in insulinoma cells as well as improving glucose utilization in adipocytes. Here, we investigated whether fermented soybeans containing glyceollins had an antidiabetic action in type 2 diabetic animals. Methods: The diabetic mice, their diabetes induced by intraperitoneal injections of streptozotocin (20 mg/kg bw), were administered a high fat diet with no soybeans (control), 10% unfermented soybeans and 10% fermented soybeans containing glyceollins, respectively, (FSG) for 8 weeks. As positive controls, rosiglitazone (20 mg/kg/bw) was given to diabetic mice fed a no soybean diet and non-diabetic mice were also placed on the same diet. Results: Among the diabetic mice, FSG-treated mice exhibited the lowest peak for blood glucose levels with an elevation of serum insulin levels during the first part of oral glucose tolerance testing. FSG also made blood glucose levels drop quickly after the peak and it decreased blood glucose levels more than the control during insulin tolerance testing. This improvement was associated with increased hepatic glycogen accumulation and decreased triglyceride storage. The phosphorylation of Akt, AMP-kinase, and acetyl-CoA carboxylase in the liver was potentiated by FSG, whereas phosphoenolpyruvate carboxykinase expression decreased. The enhancement of glucose homeostasis was comparable to the effect induced by rosiglitazone, a commercial peroxisome proliferator-activated receptor-γ agonist, but it did not match the level of glucose homeostasis in the non-diabetic mice. Conclusion: Glyceollin-containing FSG improves glucose homeostasis, partly by enhancing hepatic insulin sensitivity in type 2 diabetic mice. [Copyright &y& Elsevier]

Purpose: Primary thyroid marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type (pTY-MZL) is an extremely uncommon form of lymphoma. Due to its rarity, the natural history and optimal treatment modality for this disease have yet to be clearly established. Methods: A total of 27 patients with histologically confirmed pTY-MZL were retrospectively analyzed. Results: The median age of our subjects was 53 years (range 25-82). This study involved 17 females (63.0%) and 10 males (37.0%). Twenty-four out of 27 patients (88.9%) initially presented with localized disease, defined by Ann Arbor stage I/II. Bone marrow involvement was detected in 8.3% of the patients (2 patients), and 91.7% of the patients (25 of 27) were categorized into the low or low-intermediate risk group, according to the International Prognostic Index criteria. Accompanying Hashimoto's thyroiditis was detected in 72% of the patients, whereas thyroglobulin antibody levels were elevated in 70% of the patients. Twenty-six patients were treated with surgery, radiotherapy or chemotherapy, and 25 patients achieved complete remission. During the follow-up period, only 2 patients evidenced progression, and no deaths occurred over the course of the study. Conclusion: pTY-MZL tends to be an indolent disease. However, unlike other mucosa-associated lymphoid tissue site MZLs, pTY-MZL was well controlled via several treatment modalities, and the patients' responses were sustained for a prolonged period. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML [ABSTRACT FROM AUTHOR]

Abstract: The better understanding of polymeric nanoparticles as a drug delivery carrier is a decisive factor to get more efficient therapeutic response in vivo. Here, we report the non-invasive imaging of bare polymeric nanoparticles and drug-loaded polymeric nanoparticles to evaluate biodistribution in tumor bearing mice. To make nano-sized drug delivery carrier, glycol chitosan was modified with different degrees of hydrophobic N-acetyl histidine (NAcHis-GC-1, -2, and -3). The biodistribution of polymeric nanoparticles and drug was confirmed by using gamma camera with 131I-labeled NAcHis-GC and 131I-labeled doxorubicin (DOX) and by using in vivo live animal imaging with near-infrared fluorescence Cy5.5-labeled NAcHis-GC. Among bare nanoparticles, NAcHis-GC3 (7.8% NAcHis content) showed much higher tumor targeting efficiency than NAcHis-GC1 (3.3% NAcHis content) and NAcHis-GC2 (6.8% NAcHis content). In contrast, for drug-loaded nanoparticles, DOX-NAcHis-GC1 displayed two-fold higher tumor targeting property than DOX-NAcHis-GC3. These data imply that the biodistribution and tumor targeting efficiency between bare and drug-loaded nanoparticles may be greatly different. Therapeutic responses for NAcHis-GC nanoparticles after drug loading were also evaluated. In xenograft animal model, we could find out that DOX-NAcHis-GC1 with higher tumor targeting of DOX has more excellent therapeutic effect than DOX-NAcHis-GC3 and free DOX. These results mean that the hydrophobic core stability might be a critical factor for tumor targeting efficiency of nanoparticles. The present study indicates that by using molecular imaging, we can select more appropriate nanoparticles with the highest tumor targeting properties, leading to exerting more excellent therapeutic results in cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although platinum-based doublet chemotherapy is considered as standard of care for patients with advanced non-small cell lung cancer (NSCLC), most of them are eventually supposed to experience disease progression. Pemetrexed, docetaxel, erlotinib, and gefitinib have been shown to be active as monotherapy for pretreated patients. In this study, the efficacy of pemetrexed and carboplatin as a salvage therapy for patients with advanced NSCLC is evaluated. Patients and methods: From March 2007 to February 2009, 32 patients who were diagnosed with inoperable NSCLC and treated with one or more prior cisplatin-based chemotherapies were enrolled. Treatment consisted of pemetrexed 500mg/m2 over a 10-min intravenous infusion and carboplatin at an AUC 5mg/mL/min over a 30-min intravenous infusion on Day 1 of a 21-day cycle. All patients were supplemented with folic acid and vitamin B12 to reduce the hematological toxicity of pemetrexed. Results: There were one (3.1%) complete response and five partial (15.6%) responses. The overall response rate was 18.8% and the median response duration was 4.4 months. Among the responders, four patients had adenocarcinoma and two had squamous cell carcinoma. Nine patients had stable disease, and the disease control rate was 46.9%. With a median follow up duration of 9.4 months, the median time to progression was 2.3 months and the median OS was 9.4 months. Seven patients (21.9%) experienced grade 3 and 4 hematologic toxicities; one anemia (3.1%), six neutropenia (18.8%), and six thrombocytopenia (18.8%). Two patients experienced grade 4 febrile neutropenia with infection. Four patients (12.5%) experienced grade 3 non-hematologic toxicities; four asthenia (12.5%), two anorexia (6.3%), and one stomatitis (3.1%). Grade 1–2 peripheral neuropathy developed in 13 patients (40.6%). Conclusion: The combination of pemetrexed and carboplatin showed favorable toxicity profiles and activity in the pretreated patients with advanced NSCLC. It is suggested that this regimen can be a good chemotherapeutic option as a salvage therapy for patients with NSCLC. [Copyright &y& Elsevier]

Abstract: To compare the molecular cytogenetic characteristics between Waldenström macroglobulinemia (WM) and multiple myeloma (MM), we performed interphase fluorescent in situ hybridization (FISH) in Korean patients with WM and MM. Forty patients with WM and 132 patients with MM were enrolled onto the study. FISH was performed with seven different probes: 6q21, 6q23, CEP4, CEP9, immunoglobulin (IgH) breakapart, RB1 gene, and 1q25. Out of 22 WM patients, 4 (18%) had abnormal karyotypes, mainly structural changes on conventional karyotyping. After performing FISH for the available 29 cases, deletions of 6q23 and 6q21 were newly detected in 3 cases (10%). There was no other anomaly, including trisomy 4 in WM. No 6q deletion was observed in MM patients, but RB1 deletion was the most common change (45%), followed by IgH translocation (42%) and gain of 1q (38%). In conclusion, Korean WM patients had a low rate of 6q deletion (10%) and no trisomy 4. [Copyright &y& Elsevier]

Abstract: Background: Brain metastases (BMs) are found in about 10% of patients with newly diagnosed non-small cell lung cancer (NSCLC). This retrospective study was conducted to assess the clinical outcomes and prognostic factors of patients who received chemotherapy after cranial irradiation for NSCLC with synchronous BMs. Materials and methods: From January 2000 through July 2007, we reviewed the medical records of patients who received systemic chemotherapy following cranial irradiation for BMs from newly diagnosed NSCLC. Results: A total of 40 patients were included in this review. As the first-line chemotherapy, a total of 114 cycles were administered, for a median number of 2 cycles per patient (range, 0.5–8 cycles). Thirty-four patients (85%) received platinum-based combination regimen and the remaining 6 received chemotherapy with a single agent. Sixteen (40%) patients, 11 of whom had ECOG of 2, only received 1 cycle or less of chemotherapy due to early death, rapid progression, clinical impairment, or toxicity. For 28 patients who were evaluable for response, the extracranial overall response rate was 43%. The median overall survival for all patients was 7 months (range, 0.9–25.3 months) and an estimated 1-year survival rate was 23%. Multivariate analysis revealed that ECOG status (P =0.018) and number of BM (P =0.038) were independent prognostic factors. Conclusion: Our results suggest that chemotherapy can be used to increase survival of patients treated with cranial irradiation for newly diagnosed NSCLC with synchronous BM. However, systemic chemotherapy should be carefully considered according to the patient''s prognostic condition. Especially, patients with good performance status and limited number of BM may be good candidates for systemic chemotherapy after cranial irradiation. [Copyright &y& Elsevier]

Aldose reductase (AR) is abundantly expressed in a variety of cell lineages and has been implicated in the cellular response against oxidative stress. However, the exact functional role of AR against oxidative stress remains relatively unclear. This study investigated the role of AR in acrolein- or hydrogen peroxide-induced apoptosis using the J774.A.1 macrophage cell line. Ablation of AR with a small interference RNA or inhibition of AR activity significantly enhanced the acrolein- or hydrogen peroxide-induced generation of reactive oxygen species and aldehydes, leading to increased apoptotic cell death. Blockade of AR activity in J774A.1 cells markedly augmented the acrolein- or hydrogen peroxide-induced translocation of Bax to mitochondria along with reduced Bcl-2 and increased release of cytochrome c from the mitochodria. Taken together, these findings indicate that AR plays an important role in the cellular response against oxidative stress, by sequestering the reactive molecules generated in cells exposed to toxic substances. [ABSTRACT FROM AUTHOR]

Mountain ginseng (Panax ginseng) has been used for cancer patient therapy in Northeast Asia. Although it is well known that cancer cells are able to induce angiogenesis, the effect of mountain ginseng on angiogenesis is still unknown. In the present study, we investigated whether ethanolic extract of mountain ginseng (MGE) could inhibit angiogenesis in in vitro and in vivo models. In comparison with farm-cultivated ginseng extract (FGE), MGE more strongly inhibited cell migration and formation of capillary-like network within non-cytotoxic ranges in SVEC4-10 cells. In addition, MGE dose-dependently suppressed Transwell cell migration of the cells. Moreover, MGE reduced the phosphorylation and expression of VEGF-R2 as well as the phosphorylation of FAK, Src, Akt and ERK, the intermediate proteins in the VEGF-R2 signaling cascade, in the cells. As expected, MGE dramatically decreased hemoglobin content in Matrigel plugs in mice. In conclusion, MGE possesses stronger anti-angiogenic properties than FGE in vascular endothelial cells. Such effect of MGE is correlated with inhibition of activation of the VEGF-R2 signaling pathway. Therefore, the novel features of MGE may be helpful for understanding its anticancer mechanism for the treatment of cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Double saccadic pulses (DSP) are saccadic intrusions that consist of an initial saccade away from a fixation followed immediately by a return saccade back to the fixation. DSP have been reported in patients with presumed multiple sclerosis and metabolic encephalopathy. However, DSP have not been described in a circumscribed brain lesion. We report a man who developed almost continuous DSP with intervening macrosaccadic oscillations from a circumscribed lesion in the dorsal pontine tegmentum which extended up to the midbrain level and spared the nucleus raphe interpositus where the pause cells reside. Damage to the projections from the superior colliculus to omnipause neurons and resultant dysfunction of omnipause neuron may be a mechanism of saccadic intrusions and oscillations observed in our patient with a circumscribed brainstem lesion. [Copyright &y& Elsevier]

Abstract: We investigated whether increased heme oxygenase (HO)-1 activity by NS-398 is responsible for protection against hypoxia-induced damage in C6 cells. The expression of HO-1 was analyzed by Western blot and cell viability was analyzed by lactate dehydroxygease (LDH) activity. NS-398 increased HO-1 expression in a concentration- and time-dependent manner during both normoxia and hypoxia (95% N2/5% CO2), but the latter was much more sensitive. Because induction of HO-1 occurred due to hypoxia itself, NS-398 seemed to potentiate the expression of HO-1. The reduced cell viability due to hypoxia was significantly reversed by either NS-398 or [Ru(CO)3(Cl)2]2, a CO-donor. Zinc protophorphrin (ZnPPIX), a HO-1 inhibitor, inhibited the protective effect of NS-398 against hypoxia. Treatment with glucose oxidase (GOX, 20mU/ml) increased ROS production and caused apoptotic death, as assayed by DCFH-DA and TUNEL, respectively. NS-398 significantly reduced GOX-induced cell death and ROS production; these effects were reversed by pre-treatment with oxyhemoglobin (HbO2), a CO/NO scavenger, or ZnPPIX. Finally, NS-398 increased PPAR-γ luciferase activity in transiently PPAR-γ transfected C6 cells, which was antagonized by ZnPPIX. NS-398 increased phosphorylation of Akt, and LY-294002, a specific PI3 kinase inhibitor, inhibited NS-398-induced HO-1 expression. Taken together, we conclude that therapeutic use of NS-398 in the treatment of oxidative stress-oriented neuronal disorders would be beneficial through dual actions: HO-1 induction and COX-2 inhibition. [Copyright &y& Elsevier]

Summary: Background: The combination of gemcitabine and cisplatin is among the most active regimens for the treatment of NSCLC. However, the optimal dose and schedule for administration of the two drugs has not yet been determined. We investigated the activity and toxicity of a gemcitabine and split-dose cisplatin regimen in an outpatient setting for patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: From June 2004 to May 2005 patients with stage IIIB or IV who had not had prior chemotherapy entered the study. Treatment consisted of gemcitabine 1250mg/m2 and cisplatin 35mg/m2, both given intravenously on days 1 and 8 every 21 days. Results: Forty-five patients were entered this study. Patient characteristics were as follows: male/female, 34/11; median age (range), 62 (30–76) years; ECOG PS 0/1/2, 7/30/8; stage IIIB/IV, 18/27. A total of 168 cycles were delivered, with a median of 4 cycles (range, 1–6). All patients were evaluable for toxicity. Grade 3 and 4 toxicities according to the NCI toxicity criteria included neutropenia in 8 patients (18%), anemia in 4 (9%), thrombocytopenia in 7 (15%), and emesis in 1 (2%). Of 42 patients assessable for response, 23 patients showed a partial remission. On intent-to-treat basis, the overall response rate was 51% (95% CI, 37–65%). Median time to progression was 6.0 months (range, 1.2–12.0 months) and median overall survival was 13.1 months (range, 1.4–17 months). Conclusions: This regimen with gemcitabine and split-dose cisplatin using a 21-day schedule appears to be active and very well-tolerated in an outpatients setting for patients with advanced NSCLC. [Copyright &y& Elsevier]

Abstract: Deltamethrin (DLM), [(S)-α-cyano-d-phenoxybenzyl-(1R,3R)-e-(2,2 dibromovinyl)-2,2-dimethylcyclo-propane-1-carboxylate], is a pyrethroid insecticide widely used in agriculture and households. There are several methods for analysis of DLM in biological fluids and tissues, but these methods are time consuming. They generally involve the extraction of DLM with lipid-soluble solvents such as n-pentane, n-hexane, diethylether or acetone, and subsequent evaporation of the solvent. A more rapid and sensitive high-performance liquid chromatography (HPLC) method to analyze DLM in plasma and tissues (liver, kidney, and brain) was developed and validated according to U.S. Food and Drug Administration (U.S. FDA) and International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. The limit of detection (S/N of 3/1) for DLM was 0.01μg/ml for plasma, liver, kidney and brain. The method performances were shown to be selective for DLM and linear over the concentration range 0.01–20.0μg/ml. For five replications of samples at 0.05, 0.1, 0.2, 1.5 and 4.0μg/ml, intraday precision and accuracy values were in the range of 0.7–13.1% relative standard deviation (%R.S.D.) and 1.8–14.1%Error, respectively. Interday (n =15) precision and accuracy values at 0.05, 0.1, 0.2, 1.5, and 4.0μg/ml were in the range of 3.2–15.2% (%R.S.D.) and 3.7–14.8%Error, respectively. The absolute recoveries of DLM ranged from 93 to 103% for plasma, 95 to 114% for liver, 97 to 108% for kidney, and 95 to 108% for brain. This method can be quite useful for DLM pharmacokinetic and tissue distribution studies, for which multiple plasma and tissue samples have to be analyzed quickly with high reproducibility. [Copyright &y& Elsevier]

Abstract: To elucidate the molecular mechanisms underlying the up-regulation of aldose reductase observed in many cancer cells, we investigated the signal transduction pathways mediating induction of aldose reductase gene expression by 12-O-tetradecanoylphorbol-13-acetate, a potent tumor promoter. A maximum of four-fold induction in aldose reductase mRNA was demonstrated in HeLa cells treated with 12-O-tetradecanoylphorbol-13-acetate. The increased level of aldose reductase transcript was accompanied by the elevated level of enzyme activity, and completely abolished in the presence of actinomycin D. Inhibitors of protein kinase C, bisindolylmaleimide I and calphostin C, as well as inhibitors of tyrosine kinase, genistein and tyrphostin A23, significantly attenuated 12-O-tetradecanoylphorbol-13-acetate-induced increase in aldose reductase mRNA. Blockade of the p38 mitogen-activated protein kinase pathway by SB203580 also suppressed 12-O-tetradecanoylphorbol-13-acetate-induced aldose reductase expression. The promoter activity of aldose reductase gene was significantly augmented in the cells treated with 12-O-tetradecanoylphorbol-13-acetate, but attenuated in the presence of bisindolylmaleimide I, tyrphostin A23 or SB203580. Pyrrolidinedithiocarbamate, a nuclear factor κB inhibitor, dose-dependently suppressed 12-O-tetradecanoylphorbol-13-acetate-induced increase in aldose reductase mRNA. 12-O-tetradecanoylphorbol-13-acetate augmented the DNA binding activity of nuclear factor κB and nuclear factor κB-dependent gene transcription, and these effects were attenuated by bisindolylmaleimide I or tyrphostin A23, but not by SB203580. Taken together, activation of protein kinase C and tyrosine kinase by 12-O-tetradecanoylphorbol-13-acetate elicits increased promoter activity of aldose reductase gene via nuclear factor κB. A p38 mitogen-activated protein kinase pathway, distinct from the tyrosine kinase pathway, may also take part in 12-O-tetradecanoylphorbol-13-acetate-induced increase in aldose reductase gene expression. [Copyright &y& Elsevier]

Abstract: Astragali radix, which has tonifying and circulatory effect as well as immune response, is one of the oldest and most frequently used crude drug for oriental medicine in many Asian countries. The present study was conducted to evaluate the effect of aqueous extract of Astragali radix (ARE) on the functions of murine macrophage cell line, RAW 264.7 macrophage cells. In the cell proliferation assay, methotrexate (MTX), an agent of immune suppression, decreased the cell proliferation of RAW 264.7 macrophage cells (IC50: 100μg/ml), but the suppression of cell proliferation was significantly protected by ARE treatment in RAW 264.7 macrophage cells. The expressions of cytokine gene by ARE were investigated using reverse transcription polymerase chain reaction (RT-PCR). In RT-PCR, IL-1α, IL-1β and IL-6 mRNA expressions was induced in ARE-treated RAW 264.7 macrophage cells. We also investigated the effect of the nitric oxide (NO) synthesis and inducible nitric oxide synthase (iNOS) mRNA expression by ARE. ARE alone had no effect on NO synthesis and iNOS mRNA expression in RAW 264.7 cells. In the case of lipopolysaccharide (LPS) stimulation, NO production and iNOS mRNA expression were detected in RAW 264.7 cells. However, NO production and iNOS mRNA expression which is induced by LPS decreased after treatment of ARE. These data demonstrate that ARE can reduce the suppression of macrophage cell proliferation induced by MTX, and induce IL-1α, IL-1β and IL-6 mRNA expressions in RAW 264.7 macrophage cells. Also, ARE inhibit NO production in LPS-stimulated RAW 264.7 macrophage cells, and the inhibition of NO production may be associated with the inhibition of iNOS mRNA expression. [Copyright &y& Elsevier]

The present study was conducted to evaluate the immunomodulatory effect of aqueous-extracted Astragali radix (ARE) in methotrexate (MTX)-treated mouse spleen cells. In spleen cell proliferation assay, ARE enhanced mitogenic activity in the dose–response manner. We also investigated the effect of ARE on the reducing of immune suppression caused by MTX in mouse spleen cells. MTX decreased the spleen cell proliferation (IC50:800 μg/ml). However, ARE significantly reduced the suppression of cell proliferation by MTX in mouse spleen cells. Immunomodulatory effect of ARE were further investigated using reverse transcription polymerase chain reaction (RT-PCR). In RT-PCR, we examined the expressions of various cytokines such as IL-6, IL-1α, IL-1β, IL-12p40, GM-CSF and TNF. Enhancement of IL-1α and IL-12p40 mRNA expressions were shown in mouse spleen cells by ARE. In spite of MTX treatment, the expressions of IL-1α and IL-12p40 mRNA sustained in spleen cells. These data indicate that (1) ARE has a protective effect of immune suppression, and (2) the immunomodulatory effects of ARE may be, in part, associated with the expressions of IL-1α and IL-12p40 mRNA as well as the mitogenic effect on spleen cells. [Copyright &y& Elsevier]

This work reports the self-organization of dimple nanostructures on a polyethylene naphthalate (PEN) surface where an Ar ion beam was irradiated at an ion energy of 600 eV. The peak-to-peak roughness and diameter of dimple nanostructures were 29.1~53.4 nm and 63.4~77.6 nm, respectively. The electron energy loss spectrum at the peaks and troughs of dimples showed similar C=C, C=O, and O=CH bonding statuses. In addition, wide-angle X-ray scattering showed that Ar ion beam irradiation did not induce crystallization of the PEN surface. That meant that the self-organization on the PEN surface could be due to the ion-induced surface instability of the amorphous layer and not due to the partial crystallinity differences of the peaks and valleys. A nonlinear continuum model described surface instability due to Ar ion-induced sputtering. The Kuramoto–Sivashinsky model reproduced the dimple morphologies numerically, which was similar to the experimentally observed dimple patterns. This preliminary validation showed the possibility that the continuum equation used for metal and semiconductor surfaces could be applied to polymer surfaces where ion beam sputtering occurred. [ABSTRACT FROM AUTHOR]

Face masks will be used to prevent pandemic recurrence and outbreaks of mutant SARS-CoV-2 strains until mass immunity is confirmed. The polypropylene (PP) filter is a representative disposable mask material that traps virus-containing bioaerosols, preventing secondary transmission. In this study, a copper thin film (20 nm) was deposited via vacuum coating on a spunbond PP filter surrounding a KF94 face mask to provide additional protection and lower the risk of secondary transmission. Film adhesion was improved using oxygen ion beam pretreatment, resulting in cuprous oxide formation on the PP fiber without structural deformation. The copper-coated mask exhibited filtration efficiencies of 95.1 ± 1.32% and 91.6 ± 0.83% for NaCl and paraffin oil particles, respectively. SARS-CoV-2 inactivation was evaluated by transferring virus-containing media onto the copper-coated PP filters and subsequently adding Vero cells. Infection was verified using real-time polymerase chain reaction and immunochemical staining. Vero cells added after contact with the copper-coated mask did not express the RNA-dependent RNA polymerase and envelope genes of SARS-CoV-2. The SARS-CoV-2 nucleocapsid immunofluorescence results indicated a reduction in the amount of virus of more than 75%. Therefore, copper-coated antiviral PP filters could be key materials in personal protective equipment, as well as in air-conditioning systems. [ABSTRACT FROM AUTHOR]

Mountain ginseng (Panax ginseng C.A. Meyer) is a medicinal herb with immune effects, muscle damage protection and energy metabolism effects. However, the pharmacological role of mountain ginseng in dexamethasone (DEXA)-induced muscle atrophy through the forkhead box O (FOXO) family is not understood. Therefore, we hypothesized that mountain ginseng inhibits skeletal muscle atrophy by decreasing muscle RING finger protein-1 (MuRF1) and atrogin1 through FOXO3 in L6 myotubes. Rat myoblast (L6) cells or Sprague-Dawley (SD) rats were exposed to DEXA and mountain ginseng. The expressions of muscle atrophy targets such as MuRF1, atrogin1, MyHC (myosin heavy chain), HSP90, p-Akt, Akt, p-ERK1/2, ERK, FOXO3a, FOXO1, myostatin, and follistatin were analyzed by using Western blot analysis or real-time PCR. The diameter of myotubes was measured. Recruitment of glucocorticoid receptor (GR) or FOXO3a was analyzed by performing a chromatin immunoprecipitation (ChIP) assay. Mountain ginseng treatment reduced muscle weight loss and collagen deposition in DEXA-induced rats. Mountain ginseng treatment led to decreases in MuRF1, atrogin1, p-ERK1/2, FOXO3a, FOXO1, and myostatin. Also, mountain ginseng treatment led to increases in the diameter of myotubes, MyHC, HSP90, p-Akt, and follistatin. Treatment with mountain ginseng reduced enrichment of GR, FOXO3a, and RNA polymerase II on the promoters. These results suggest that mountain ginseng inhibits skeletal muscle atrophy by decreasing MuRF1 and atrogin1 through FOXO3a in L6 myotubes. Image 1 • Mountain ginseng increased myotube in skeletal muscle. • Mountain ginseng inhibited MuRF1/atrogin1/FOXO3a/myostatin. [ABSTRACT FROM AUTHOR]

Cicadae Periostracum (CP), derived from the slough of Cryptotympana pustulata, has been used as traditional medicine in Korea and China because of its diaphoretic, antipyretic, anti-inflammatory, antioxidant, and antianaphylactic activities. The major bioactive compounds include oleic acid (OA), palmitic acid, and linoleic acid. However, the precise therapeutic mechanisms underlying its action in asthma remain unclear. The objective of this study was to determine the antiasthmatic effects of CP in an ovalbumin (OVA)-induced asthmatic mouse model. CP and OA inhibited the inflammatory cell infiltration, airway hyperresponsiveness (AHR), and production of interleukin (IL)7 and Th2 cytokines (IL-5) in the bronchoalveolar lavage fluid and OVA-specific imunoglobin E (IgE) in the serum. The gene expression of IL-5, IL-13, CCR3, MUC5AC, and COX-2 was attenuated in lung tissues. CP and OA might inhibit the nuclear translocation of GATA-binding protein 3 (GATA-3) and retinoic acid receptor-related orphan receptor γt (RORγt) via the upregulation of forkhead box p3 (Foxp3), thereby preventing the activation of GATA-3 and RORγt. In the in vitro experiment, a similar result was observed for Th2 and GATA-3. These results suggest that CP has the potential for the treatment of asthma via the inhibition of the GATA-3/Th2 and IL-17/RORγt signaling pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: As the population of the yellow-legged hornet (Vespa velutina) spreads, this study investigated ways to utilize this resource of abundant invasive wasp species. Hymenoptera venoms, including bee venom and wasp venom, have therapeutic potential. Although the venoms are toxic to humans, the elucidation of their composition and working mechanisms has led to discoveries about their potential applications in treatment modalities for a variety of disorders. Therefore, we examined the anti-inflammatory effect of wasp venom from V. velutina in comparison with that of bee venom from honey bee on BV-2 murine microglial cells. Treatment with wasp venom reduced the secretion of nitric oxide and pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor alpha, from BV-2 cells activated by lipopolysaccharide (LPS). Western blot analysis revealed that wasp venom and bee venom decreased the expression levels of inflammation markers, including inducible nitric oxide synthase and cyclooxygenase-2. In addition, wasp venom decreased the nuclear translocation of nuclear factor κB (NF-κB), which is a key transcription factor in the regulation of cellular inflammatory response. Overall, the findings demonstrated that wasp venom inhibited LPS-induced inflammation in microglial cells by suppressing the NF-κB-mediated signaling pathway, which warrants further studies to confirm its therapeutic potential for neurodegenerative diseases. The aim of this study was to compare the anti-inflammatory effect of wasp venom (WV) from the yellow-legged hornet (Vespa velutina) with that of bee venom (BV) on BV-2 murine microglial cells. WV was collected from the venom sac, freeze-dried, and used for in vitro examinations. WV and BV were non-toxic to BV-2 cells at concentrations of 160 and 12 µg/mL or lower, respectively. Treatment with WV reduced the secretion of nitric oxide and proinflammatory cytokines, including interleukin-6 and tumor necrosis factor alpha, from BV-2 cells activated by lipopolysaccharide (LPS). Western blot analysis revealed that WV and BV decreased the expression levels of inflammation markers, including inducible nitric oxide synthase and cyclooxygenase-2. In addition, WV decreased the nuclear translocation of nuclear factor κB (NF-κB), which is a key transcription factor in the regulation of cellular inflammatory response. Cumulatively, the results demonstrated that WV inhibited LPS-induced neuroinflammation in microglial cells by suppressing the NF-κB-mediated signaling pathway, which warrants further studies to confirm its therapeutic potential for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Arbitrary upfront dose reduction (UDR) of palliative chemotherapy has often been performed according to the judgement of the physician of older adults with metastatic solid cancer in current practice. UDR might decrease treatment efficacy in older adults but may be helpful for palliation, so selecting older adults who benefit from UDR and the identification of predictors of UDR are required. The authors investigated the prevalence and predictors of UDR through variables of geriatric assessment (GA). Chemotherapy compliance between the UDR and standard dose patient groups was also compared. The results of this study demonstrated that approximately 60% of older adults with metastatic solid cancer received UDR. Poor performance status (PS) and living without a spouse were predictive factors of UDR of first-line palliative chemotherapy, and patients with UDR better-tolerated chemotherapy compared with patients with standard doses. Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (≥70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4–47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3–5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose. [ABSTRACT FROM AUTHOR]

Metastasis is the main cause of cancer-related deaths. Anoikis is a type of apoptosis caused by cell detachment, and cancer cells become anoikis resistant such that they survive during circulation and can successfully metastasize. Therefore, sensitization of cancer cells to anoikis could prevent metastasis. Here, by screening for anoikis sensitizer using natural compounds, we found that pygenic acid A (PA), a natural compound from Prunella vulgaris, not only induced apoptosis but also sensitized the metastatic triple-negative breast cancer cell lines, MDA-MB-231 cells (human) and 4T1 cells (mouse), to anoikis. Apoptosis protein array and immunoblotting analysis revealed that PA downregulated the pro-survival proteins, including cIAP1, cIAP2, and survivin, leading to cell death of both attached and suspended cells. Interestingly, PA decreased the levels of proteins associated with anoikis resistance, including p21, cyclin D1, p-STAT3, and HO-1. Ectopic expression of active STAT3 attenuated PA-induced anoikis sensitivity. Although PA activated ER stress and autophagy, as determined by increases in the levels of characteristic markers, such as IRE1α, p-elF2α, LC3B I, and LC3B II, PA treatment resulted in p62 accumulation, which could be due to PA-induced defects in autophagy flux. PA also decreased metastatic characteristics, such as cell invasion, migration, wound closure, and 3D growth. Finally, lung metastasis of luciferase-labeled 4T1 cells decreased following PA treatment in a syngeneic mouse model when compared with the control. These data suggest that PA sensitizes metastatic breast cancer cells to anoikis via multiple pathways, such as inhibition of pro-survival pathways and activation of ER stress and autophagy, leading to the inhibition of metastasis. These findings suggest that sensitization to anoikis by PA could be used as a new therapeutic strategy to control the metastasis of breast cancer. [ABSTRACT FROM AUTHOR]

There are limited data from prospective controlled trials regarding optimal treatment strategies in patients with primary breast diffuse large B-cell lymphoma (DLBCL). In this phase 2 study (NCT01448096), we examined the efficacy and safety of standard immunochemotherapy and central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX). Thirty-three patients with newly diagnosed primary breast DLBCL received six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and four fixed doses of IT-MTX (12 mg). The median age was 50 years (range, 29–75), and all patients were females. According to the CNS-International Prognostic Index, most patients (n = 28) were categorized as the low-risk group. Among the 33 patients, 32 completed R-CHOP, and 31 completed IT-MTX as planned. With a median follow-up of 46.1 months (interquartile range (IQR), 31.1–66.8), the 2-year progression-free and overall survival rates were 81.3% and 93.5%, respectively. Six patients experienced treatment failures, which included the CNS in four patients (two parenchyma and two leptomeninges) and breast in two patients (one ipsilateral and one contralateral). The 2-year cumulative incidence of CNS relapse was 12.5%. Although standard R-CHOP and IT-MTX without routine radiotherapy show clinically meaningful survival outcomes, this strategy may not be optimal for reducing CNS relapse and warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Gefitinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase is an effective agent used in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Adverse drug reactions were frequently observed in the skin, gastrointestinal tract, and liver, but they were generally mild in severity and reversible. Therefore, gefitinib has been regarded as a relatively safe agent. As a serious adverse effect, however, acute lung injury has been reported. The present report describes a patient with NSCLC who developed bilateral subdural hemorrhage as a possible adverse drug reaction after gefitinib therapy. We expect that this case may provide a reference for clinicians being involved in the treatment with gefitinib. [Copyright &y& Elsevier]

Mechanisms of CML-induced DN via CPT2 downregulation. • CML reduces CPT-2 production in streptozotocin-induced diabetic mice kidney. • CPT2 is associated with fatty acid oxidation and mitochondrial dysfunction. • CML-induced CPT2 down regulation causes mitochondrial FAO damage, leading to renal fibrosis and diabetic nephropathy. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in the world. Advanced glycation end products (AGEs) are thought to be involved in the pathogenesis of DN via multifactorial mechanisms including the generation of oxidative stress and overproduction of various growth factors and cytokines. AGEs are heterogeneous cross-linked sugar-derived proteins, and N ε-(carboxymethyl)-lysine (CML)-conjugated BSA is a major component of AGEs. However, the proteins involved in DN induction by CML have never been reported. Herein, we investigated specific protein regulators of AGE-mediated DN via proteomic analysis of streptozotocin (STZ)-induced diabetic mice kidneys. We identified 937, 976, and 870 proteins in control, STZ, and STZ + CML-BSA samples, respectively. Bioinformatics analysis identified several CML-mediated proteins potentially involved in kidney damage, activation of fatty acid oxidation (FAO), and mitochondrial dysfunction. Furthermore, we identified the CML-specific differential protein carnitine palmitoyltransferase 2 (CPT2), related to FAO. To confirm the effect of CPT2 and the CML-mediated mechanism, human renal tubular HK-2 cells were treated with CML-BSA and cpt2 siRNA, and examined for FAO-mediated fibrosis and mitochondrial dysfunction. CML-BSA and CPT2 knockdown induced fibrosis-related gene expression and damage to mitochondrial membrane potential. Moreover, CPT2 overexpression recovered CML-induced fibrosis-related gene expression. Based on these results, a decrease in CML-induced CPT2 expression causes mitochondrial FAO damage, leading to renal fibrosis and DN. [ABSTRACT FROM AUTHOR]