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A reliable measurement of blood folate levels is necessary in the clinical field to prevent serious diseases such as cognitive impairment and neural tube defects. Herein, the certification of the low-content folic acid (FA) and 5-methyltetrahydrofolate (5-Me-THF) in human plasma certified reference material (KRISS CRM 111-01-018) was performed. A human plasma pool obtained from the Korean Red Cross was used as a CRM candidate. The certification of the human plasma CRM was performed by isotope dilution ultra-performance liquid chromatography/tandem mass spectrometry. Two-dimensional liquid chromatography was employed to confirm the validity of the analytical method for FA due to the susceptibility of FA to matrix effects because of its limited quantity. The CRM stability was evaluated at −20 °C for 2 months and at −70 °C for up to 12 months to determine the certified value of the CRM. The certified value of the CRM was (84.6 ± 4.3) ng kg−1and (5.80 ± 0.47) μg kg−1for FA and 5-Me-THF, respectively. The homogeneity of the CRM was 1.64% and 3.10% for FA and 5-Me-THF, respectively. Further long-term stability assessments were conducted, indicating that the CRM remains valid for at least 58 months at −70 °C for FA and 48 months for 5-Me-THF. Compared to other blood-based CRMs, this CRM has lower folate levels, making it helpful in establishing analytical methods for a broader range of folate levels.

The formation of an immunological synapse (IS) is essential for natural killer (NK) cells to eliminate target cells. Despite an advanced understanding of the characteristics of the IS and its formation processes, the mechanisms that regulate its stability via the cytoskeleton are unclear. Here, we show that Nogo receptor 1 (NgR1) has an important function in modulating NK cell-mediated killing by destabilization of IS formation. NgR1 deficiency or blockade resulted in improved tumor control of NK cells by enhancing NK-to-target cell contact stability and regulating F-actin dynamics during IS formation. Patients with tumors expressing abundant NgR1 ligand had poor prognosis despite high levels of NK cell infiltration. Thus, our study identifies NgR1 as an immune checkpoint in IS formation and indicates a potential approach to improve the cytolytic function of NK cells in cancer immunotherapy.

Introduction:Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods:We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5–97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results:We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8–11) and 21 months (CI: 17–26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p= 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p= 0.005) and receipt of L-RT (HR: 0.40; p= 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p< 0.001). Conclusion:For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Integrated evaluation of treatment response with CT and carbohydrate antigen 19-9 allowed more accurate survival stratification of patients with pancreatic ductal adenocarcinoma than did evaluation with Response Evaluation Criteria in Solid Tumors.

Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma.

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Natural protopanaxadiol ginsenosides exhibit low absorption in the human intestine. However, ginsenoside compound K (CK) with 1 conjugated glucose molecule exhibits favorable absorption. The purpose of this study was to compare the pharmacokinetics of ginsenoside CK from a CK fermentation product, CK‐30, and from a red ginseng extract. A randomized, open‐label, 2‐treatment, 2×2 crossover study was conducted. The volunteers were randomly divided into 2 groups. One group received CK‐30, and the other group received 2.94 g of a red ginseng extract. After a 7‐day washout period, the subjects received an alternative treatment for a single dose. The pharmacokinetic parameters, including the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to time of last measurable concentration, were calculated. The median time to reach Cmaxof ginsenoside CK after administration of CK‐30 was 3.0 hours, whereas the corresponding value of the red ginseng extract was 10.0 hours. Compared with the red ginseng extract, CK‐30 resulted in a higher systemic exposure to ginsenoside CK, with a 118.3‐fold increase in Cmaxand a 135.1‐fold increase in area under the plasma concentration–time curve from time 0 to time of last measurable concentration. The systemic exposure to ginsenoside CK was significantly higher after administration of CK‐30 than red ginseng extract.

Technological control over ultra-trace level contaminants is important for semiconductor development. Despite technological developments, defects remain in the single wafer wet cleaning process. In this paper, the source of the contamination is explained via trace analytical methods. Fluorine resin materials of polytetrafluoroethylene (PTFE) and ethylene tetrafluoroethylene (ETFE) are commonly used in semiconductor equipment. Isopropyl alcohol (IPA) oxidation reactions occur at high temperature below the boiling point due to impurities. IPA changed to different alcohol forms from gas chromatography (GCMS) analysis. The oxygen concentration in the X-ray photoelectron spectroscopy (XPS) results increased and formed new bonds in IPA with fluorine resin. These reactions confirmed that cations were a catalyst from the time-of-flight secondary ion mass spectrometry (TOF-SIMS) results. Representative ions were Fe+, K+, and Na+ with different concentrations for each material.

Introduction:There is no consensus regarding selection criteria on liver transplantation (LT) for hepatocellular carcinoma (HCC), especially for living donor liver transplantation, although emerging evidence has been found for the effectiveness of bridging or downstaging. Objective:We evaluated the long-term outcomes of patients who underwent LT with or without bridging or downstaging for HCC. Methods:This retrospective study included 896 LT recipients with HCC between June 2005 and May 2015. Recurrence-free survival (RFS), overall survival (OS), and their associated factors were evaluated. Results:The 5-year RFS in the full cohort of 896 patients was 82.4%, and the OS was 85.3%. In patients with initial Organ Procurement and Transplantation Network (OPTN) T1 and T2, the 5-year RFS and OS did not significantly differ between LT groups with and without bridging (all p≥ 0.05). The 5-year RFS and OS of OPTN T3 patients with successful downstaging were not significantly different from those of patients with OPTN T2 with primary LT (p= 0.070 and p= 0.185), but were significantly higher than in patients with OPTN T3 with downstaging failure and initial OPTN T1 or T2 with progression (all p< 0.001). In the multivariate analysis, last alpha-fetoprotein before LT ≥70 ng/mL (hazard ratio [HR]: 1.77, p= 0.001; HR: 1.72, p= 0.004), pretransplant HCC status exceeding the Milan criteria (HR: 5.12, p< 0.001; HR: 3.31, p< 0.001), and positron emission tomography positivity (HR: 2.57, p< 0.001; HR: 2.57, p< 0.001) were independent predictors for worse RFS and OS. Conclusions:The impact of bridging therapy on survival outcomes is limited in patients with early-stage HCC, whereas OPTN T1 or T2 with progression provides worse prognosis. OPTN T3 should undergo LT after successful downstaging, and OPTN T3 with successful downstaging allows for acceptable long-term posttransplant outcomes.

A mass balance method enables accurate determination of the purity of monosaccharides by incorporating the results obtained by various analytical techniques. High‐performance anion exchange chromatography with pulsed amperometric detection was used to quantify nonchromophoric impurities structurally related to the analyte. Organic acids as candidates of monosaccharide impurities were analyzed by ion chromatography with conductivity detection. Liquid chromatography with photodiode‐array UV detection was performed to detect other organic impurities. Karl‐Fischer coulometry with oven‐drying method was used to measure the water content in the samples. Finally, nonvolatile inorganic impurities were determined by thermal gravimetric analyses. The purities of the monosaccharides, glucose, galactose, fructose, and mannose, in kg/kg were (0.9983 ± 0.0004), (0.9962 ± 0.0005), (0.9999 ± 0.0004), and (0.9991 ± 0.0005), respectively. The mass balance method provides system of units (SI)‐traceable purity values, which can be applied to primary reference materials for assigning a certified value for the target monosaccharide in certified reference materials.

The approaching era of sustainable development and rapid increase in global energy demand necessitates the development of high-performance drilling fluids with low toxicity, sustainability, and in-siturheology controllability for complicated formation excavation. Herein, smart water-based drilling fluids (WDFs) with thermocontrollable rheological properties are developed using bentonite (BT) and dual-functionalized cellulose nanocrystals (fCNCs). The fCNCs are synthesized by surface grafting of poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PAMPS) and poly(N-isopropylacrylamide) (PNIPAM) through free-radical graft polymerization. The presence of PAMPS grafts with abundant amide and negatively charged sulfonate groups not only enables fCNCs to attach on the surface of BT platelets creating BT/fCNC clusters but also ensures the created BT/fCNC clusters to uniformly disperse through electrostatic repulsion. On the other hand, the introduction of thermoresponsive PNIPAM grafts induces the association of BT/fCNC clusters at elevated temperatures through enhanced hydrophobic attraction, resulting in promising thermothickening rheological performance of BT/fCNC-WDFs. Furthermore, the thermothickening rheological behavior can be maintained even after 10 heating/cooling cycles, albeit with a slight increase in the critical transition temperature. The developed BT/fCNC-WDFs with sustainability, in-siturheology controllability, and good cyclability have great potential in the smart drilling industry, making the exploration and production of oil and gas more safe, efficient, and environmentally friendly.

The Li-mediated artificial synapses with a vertical two-terminal configuration capable of various synaptic behaviors, including bio-plausible synaptic plasticity, were successfully demonstrated for the first time and thoroughly exploredSynaptic characteristics based on the progressive dearth of Li in LixCo2films are precisely controlled over the weight control spike, achieving extraordinary weight control functionality.In artificial neural network simulation, LixCoO2-based neuromorphic system showed excellent accuracy comparable to the theoretical maximum due to the low nonlinearity and programming error, suggesting feasibility of hardware neural network implementation.

Multivitamin tablet certified reference material (CRM, 108-10-019) was developed for the analysis of seven water-soluble vitamins, including thiamine, riboflavin, nicotinamide, pantothenic acid, pyridoxine, biotin, and folic acid. The CRM was prepared in powder form by grinding multivitamin tablets and then mixing, sieving, and bottling the powder. For the certification of each water-soluble vitamin, the isotope dilution mass spectrometry based on the liquid chromatography was applied. The methods for each analyte were validated by confirming the repeatability and reproducibility and by comparing with other CRMs. The property values and uncertainties for the vitamins were determined with 10 units from sample stored at − 20 °C. The homogeneity of each certified component was also examined in the range of 0.48–2.2%. All certified values for the seven water-soluble vitamins were stable for 3 or 6 years after the initial certification under storage conditions at − 20 °C. For fat-soluble vitamins, including retinol, α-tocopherol, cholecalciferol, and phylloquinone, two expert laboratories participated in analyses based on official methods, and the mean values of the reported results were assigned as reference values. The multivitamin tablet CRM (108-10-019) will be useful for validating analytical methods and for ensuring the quality of results for vitamin analysis in multivitamin tablets or similar products.

Osteoclasts are multinuclear bone-resorbing cells that differentiate from hematopoietic precursor cells. Prostate cancer cells frequently spread to bone and secrete soluble signaling factors to accelerate osteoclast differentiation and bone resorption. However, processes and mechanisms that govern the expression of osteoclastogenic soluble factors secreted by prostate cancer cells are largely unknown. MacroH2A (mH2A) is a histone variant that replaces canonical H2A at designated genomic loci and establishes functionally distinct chromatin regions. Here, we report that mH2A1.2, one of the mH2A isoforms, attenuates prostate cancer-induced osteoclastogenesis by maintaining the inactive state of genes encoding soluble factors in prostate cancer cells. Our functional analyses of soluble factors identify lymphotoxin beta (LTβ) as a major stimulator of osteoclastogenesis and an essential mH2A1.2 target for its anti-osteoclastogenic activity. Mechanistically, mH2A1.2 directly interacts with HP1α and H1.2 and requires them to inactivate LTβ gene in prostate cancer cells. Consistently, HP1α and H1.2 have an intrinsic ability to inhibit osteoclast differentiation in a mH2A1.2-dependent manner. Together, our data uncover a new and specific role for mH2A1.2 in modulating osteoclastogenic potential of prostate cancer cells and demonstrate how this signaling pathway can be exploited to treat osteolytic bone metastases at the molecular level.

Rim enhancement of pancreatic ductal adenocarcinoma identified at preoperative MR imaging is associated with worse prognosis than absence of rim enhancement for patients with attempted curative resection of pancreatic ductal adenocarcinoma.

Breast cancer cells relocate to bone and activate osteoclast-induced bone resorption. Soluble factors secreted by breast cancer cells trigger a cascade of events that stimulate osteoclast differentiation in the bone microenvironment. MacroH2A is a unique histone variant with a C-terminal non-histone domain and plays a crucial role in modulating chromatin organization and gene transcription. Here, we show that macroH2A1.2, one of the macroH2A isoforms, has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis. This repressive effect requires macroH2A1.2-dependent attenuation of expression and secretion of lysyl oxidase (LOX) in breast cancer cells. Furthermore, our mechanistic studies reveal that macroH2A1.2 physically and functionally interacts with the histone methyltransferase EZH2 and elevates H3K27me3 levels to keep LOX gene in a repressed state. Collectively, this study unravels a role for macroH2A1.2 in regulating osteoclastogenic potential of breast cancer cells, suggesting possibilities for developing therapeutic tools to treat osteolytic bone destruction.

A reservoir of HIV-1 is a major obstacle in eliminating HIV-1 in patients because it can reactivate in stopping antiretroviral therapy (ART). Histone modifications, such as acetylation and methylation, play a critical role in the organization of chromatin domains and the up- or downregulation of gene expression. Although many studies have reported that an epigenetic mechanism is strongly involved in the maintenance of HIV-1 transcriptional latency, neither the epigenetic control of viral replication nor how HIV-1 latency is maintained is not fully understood. We re-analyzed a high throughput parallel DNA sequencing (ChIP-seq) data from previous work to investigate the effect of histone modifications, H3K4me3 and H3K9ac, on HIV-1 latency in terms of chromosome distribution. The outputs of ChIP-seq from uninfected CD4+ T cell lines and HIV-1 latently infected cells were aligned to hg18 using bowtie and then analyzed using various software packages. Certain chromosomes (16, 17, 19, and 22) were significantly enriched for histone modifications in both decreased and increased islands. In the same chromosomes in HIV-1 latently infected cells, 38 decreased and 41 increased islands from common islands of H3K4me3 and H3K9ac were selected for functional annotation. In Gene Ontology analysis, the 38 genes associated with decreased islands were involved in the regulation of biological process, regulation of cellular process, biological regulation, and purinergic receptor signaling pathway, while the 41 genes associated with increased islands were involved in nucleic acid binding, calcium-activated cation channel activity, DNA binding, and zinc ion binding. In Pathway Commons analysis, the 38 genes were strongly involved in the p63 transcription factor network, while the 41 genes were involved in the RNA polymerase III transcription termination pathway. Several genes such as Nuclear factor I X (NFIX) and TNF receptor association factor 4 (TRAF4) were selected as candidate genes for HIV latency. Especially, NFIXwas highly expressed in HIV-1 latently infected cell lines and showed a dramatic reduction in expression after phorbol-13-myristate-12-acetate (PMA) treatment. These results show that the unique enrichment of histone modifications and its linked genes in specific chromosomes might play a critical role in the establishment and maintenance of HIV-1 latency.

In this meta-analysis, pooled percentages of malignancy for Ovarian-Adnexal Reporting and Data System (O-RADS) US categories 2–5 agreed with the probability of malignancy outlined in the O-RADS US risk stratification system.

BACKGROUND:The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mucosal subtypes, the efficacy of BRAF inhibitors for this subset of patients has not been extensively investigated. Acquired resistance generally appears 6 to 8 months after treatment with a BRAF inhibitor, and the mechanism of resistance is not well established. METHODS:We examined treatment outcomes for patients diagnosed with metastatic melanoma and treated with BRAF inhibitors at Samsung Medical Center between April 2013 and December 2015. We analyzed genomic alterations in selected patients using targeted sequencing. RESULTS:Twenty-seven patients with a median age of 49 years (range 23-82 years) with metastatic melanoma and treated with a BRAF inhibitor were identified. Of these patients, 19 (70.3%) had noncutaneous melanoma, including acral and mucosal melanoma. All patients had BRAFV600E mutations. The median progression-free survival of all patients was 9.2 months (95% confidence interval, 1.6-16.7), and the objective response rate was 78.9% in the mucosal/acral melanoma group and 75.0% in the cutaneous melanoma group. Three (11.1%) patients achieved complete response, and 19 (70.4%) showed a partial response. Targeted sequencing in five patients demonstrated NF1 mutations in three patients who did not respond to BRAF inhibitors. CONCLUSION:BRAF inhibitors were an effective therapeutic option for Korean patients with metastatic melanoma harboring a BRAF V600 mutation regardless of melanoma subtype (acral/mucosa versus cutaneous).

To improve the anticolitic efficacy of 5-aminosalicylic acid (5-ASA), a colon-specific mutual prodrug of 5-ASA was designed. 5-ASA was coupled to procainamide (PA), a local anesthetic, via an azo bond to prepare 5-(4-{[2-(diethylamino)ethyl]carbamoyl}phenylazo)salicylic acid (5-ASA-azo-PA). 5-ASA-azo-PA was cleaved to 5-ASA and PA up to about 76% at 10 h in the cecal contents while remaining stable in the small intestinal contents. Oral gavage of 5-ASA-azo-PA and sulfasalazine, a colon-specific prodrug currently used in clinic, to rats showed similar efficiency in delivery of 5-ASA to the large intestine, and PA was not detectable in the blood after 5-ASA-azo-PA administration. Oral gavage of 5-ASA-azo-PA alleviated 2,4,6-trinitrobenzenesulfonic acid-induced rat colitis. Moreover, combined intracolonic treatment with 5-ASA and PA elicited an additive ameliorative effect. Furthermore, combined treatment with 5-ASA and PA additively inhibited nuclear factor-kappaB (NFκB) activity in human colon carcinoma cells and inflamed colonic tissues. Finally, 5-ASA-azo-PA administered orally was able to reduce inflammatory mediators, NFκB target gene products, in the inflamed colon. 5-ASA-azo-PA may be a colon-specific mutual prodrug acting against colitis, and the mutual anticolitic effects occurred at least partly through the cooperative inhibition of NFκB activity.

Magnesium hydroxide, expandable graphite, and ammonium polyphosphate were used to enhance the thermal stability and fire retardant properties on wood flour/polypropylene composites. The thermal decompositions and flammability properties were investigated using modulated thermogravimetric analysis and cone calorimeter, and the activation energy of each decomposition process was also determined by modulated thermogravimetric analysis. The results showed that both expandable graphite and ammonium polyphosphate promoted thermal degradation of wood flour and char formulation, and magnesium hydroxide did not influence on the wood flour decomposition. Unlike in nitrogen atmosphere, magnesium hydroxide and ammonium polyphosphate increased the peak temperature of wood flour thermal degradation and diminished the decomposition peaks of polypropylene in air atmosphere. Cone calorimeter results showed that expandable graphite greatly reduced the heat and smoke release. A general activation energy range of 187–226 kJ mol−1(in nitrogen), 165–206 kJ mol−1(in air) at wood flour degradation stage, 237–262 kJ mol−1(in nitrogen), and 185–269 kJ mol−1(in air) at polypropylene degradation stage were proposed for wood flour/polypropylene composite with and without fire retardants.

The overall rate of hepatocellular carcinomas for each Liver Imaging Reporting and Data System diagnostic category was similar across three imaging modalities.

Wellbore instability and formation collapse caused by lost circulation are vital issues during well excavation in the oil industry. This study reports the novel utilization of soy protein isolate (SPI) as fluid loss additive in bentonite–water based drilling fluids (BT-WDFs) and describes how its particle size and concentration influence on the filtration property of SPI/BT-WDFs. It was found that high pressure homogenization (HPH)-treated SPI had superior filtration property over that of native SPI due to the improved ability for the plugging pore throat. HPH treatment also caused a significant change in the surface characteristic of SPI, leading to a considerable surface interaction with BT in aqueous solution. The concentration of SPI had a significant impact on the dispersion state of SPI/BT mixtures in aquesous solution. At low SPI concentrations, strong aggregations were created, resulting in the formation of thick, loose, high-porosity and high-permeability filter cakes and high fluid loss. At high SPI concentrations, intercatlated/exfoliated structures were generated, resulting in the formation of thin, compact, low-porosity and low-permeability filter cakes and low fluid loss. The SPI/BT-WDFs exhibited superior filtration property than pure BT-WDFs at the same solid concentraion, demonstrating the potential utilization of SPI as an effective, renewable, and biodegradable fluid loss reducer in well excavation applications.

Some tumors previously staged as N2 disease, using the Mountain-Dresler/American Thoracic Society (MD-ATS) map are staged as N1 per the new International Association for the Study of Lung Cancer (IASLC) lymph node (LN) map. We aimed to evaluate the effectiveness of the IASLC LN map in stratifying prognosis in patients with non-small cell lung cancer (NSCLC) and LN metastasis in nodal stations 4 or 10.

For more than a decade Montreal-based D & Q has been publishing highly literate comics and graphic novels that tackle subjects ranging from autobiography to urban romance to politics. Its [...]

The purpose of this study is to evaluate the dose reduction when using the stepwise collimation method for scoliosis patients undergoing full spine radiography. A Monte Carlo simulation was carried out to acquire dose vs. volume data for organs at risk (OAR) in the human body. While the effective doses in full spine radiography were reduced by 8, 15, 27 and 44% by using four different sizes of the collimation, the doses to the skin were reduced by 31, 44, 55 and 66%, indicating that the reduction of the dose to the skin is higher than that to organs inside the body. Although the reduction rates were low for the gonad, being 9, 14, 18 and 23%, there was more than a 30% reduction in the dose to the heart, suggesting that the dose reduction depends significantly on the location of the OARs in the human body. The reduction rate of the secondary cancer risk based on the excess absolute risk (EAR) varied from 0.6 to 3.4 per 10,000 persons, depending on the size of the collimation. Our results suggest that the stepwise collimation method in full spine radiography can effectively reduce the patient dose and the radiation-induced secondary cancer risk.

Numerous conjugated oligoacenes and polythiophenes are being heavily studied in the search for high-mobility organic semiconductors. Although many researchers have designed fused aromatic compounds as organic semiconductors for organic thin-film transistors (OTFTs), pyrene-based organic semiconductors with high mobilities and on–off current ratios have not yet been reported. Here, we introduce a new pyrene-based p-type organic semiconductor showing liquid crystal behavior. The thin film characteristics of this material are investigated by varying the substrate temperature during the deposition and the gate dielectric condition using the surface modification with a self-assembled monolayer, and systematically studied in correlation with the performances of transistor devices with this compound. OTFT fabricated under the optimum deposition conditions of this compound, namely, 1,6-bis(5′-octyl-2,2′-bithiophen-5-yl)pyrene (BOBTP) shows a high-performance transistor behavior with a field-effect mobility of 2.1 cm2V–1s–1and an on–off current ratio of 7.6 × 106and enhanced long-term stability compared to the pentacene thin-film transistor.

Aims and background Surgical resection remains the mainstay for the treatment of colorectal lung metastasis, but a group of patients who are medically inoperable or unsuitable for surgery are treated with radiotherapy. The purpose of this multi-institutional study was to evaluate the clinical outcome and investigate the prognostic factors affecting local control and survival in this subset of patients.Methods We retrospectively analyzed 30 patients with 43 lesions who underwent curative radiotherapy for isolated lung metastasis from colorectal cancer at nine institutions from 2003 and 2008. A total dose of 42–75 Gy at the peripheral planning target volume was administered in 3–35 fractions. The median biologically equivalent dose was 84 Gy (range, 58.5–180).Results Treatment response was complete in 10 (33.3%), partial in 13 (43.3%), stable in six (20.0%), and progressive in one patient (3.3%). The median follow-up period for all patients was 29.0 months (range, 5.0–93.8). Kaplan-Meier local control at 5 years was 44%. The median survival was 46.2 months, and the 5-year overall survival was 47%. Twenty-three patients (77%) experienced treatment failure, most of which were intrapulmonary failure. The intrapulmonary relapse-free survival and overall relapse-free survival at 5 years were 22% and 19%, respectively. Treatment response and pre-radiotherapy carcinoembryonic antigen level were significant prognostic factors for local control and survival. Grade 3–5 toxicity occurred in 7 patients. Three patients had grade 5 toxicity, including radiation pneumonitis, a tracheoesophageal fistula, and hemoptysis.Conclusions Curative radiotherapy for isolated lung metastasis from colorectal cancer in patients who are medially inoperable or unsuitable for surgery results in long-term survival, comparable to surgical resection. Curative radiotherapy could be an effective and noninvasive alternative if dose-limiting toxicity is carefully considered, particularly in patients with bilateral or central lesions.

Aims and background To report pain relief effect in patients with spinal metastases treated with Cyberknife®and to analyze the factors associated with pain relapse after initial pain relief.Methods and study design. We retrospectively analyzed patients with spinal metastasis treated with stereotactic body radiosurgery between April 2007 and June 2009. A total of 57 patients with 73 lesions were available for analysis with a median follow-up of 6.8 months (range, 1–30). Pain was assessed by a verbal/visual analogue scale at each visit: from 0 to 10. Pain relief was defined as a decrease of at least three levels of the pain score without an increase in analgesic use. Complete relief was defined as no analgesics or a score 0 or 1.Results Pain relief was achieved in 88% of the lesions, with complete relief in 51% within 7 days from the start of radiosurgery. The median duration of pain relief was 3.2 months (range, 1–30). Pain reappeared in 16 patients (27%). Spinal cord compression (P = 0.001) and performance status (P = 0.01) were predictive of pain relapse by multivariate Cox analysis. All 6 patients treated with solitary spinal metastasis experienced pain relief; 5 of them were alive without evidence of disease at a median of 16 months (range, 7–30).Conclusions As previous studies have shown, our study confirms that pain relief with spinal radiosurgery is around 90%. In particular, long-term pain relief and disease control was observed in patients with solitary spinal metastasis.

Breaking the aromaticity barrier: Nitrobenzene derivatives and other nitroarenes smoothly react at room temperature with an azomethine ylide to yield polycyclic adducts in high yields (see scheme; Bn=benzyl, TFA=trifluoroacetic acid). This unprecedented loss of aromaticity delivers scaffolds prone to a number of potentially interesting derivatizations.

To report the incidence of chemotherapy-related amenorrhea (CRA) from chemotherapy with/without adjuvant endocrine therapy in premenopausal women with breast cancer and to analyze the related factors.

Forced unbinding of complementary macromolecules such as ligand-receptor complexes can reveal energetic and kinetic details governing physiological processes ranging from cellular adhesion to drug metabolism. Although molecular-level experiments have enabled sampling of individual ligand-receptor complex dissociation events, disparities in measured unbinding force FRamong these methods lead to marked variation in inferred binding energetics and kinetics at equilibrium. These discrepancies are documented for even the ubiquitous ligand-receptor pair, biotin-streptavidin. We investigated these disparities and examined atomic-level unbinding trajectories via steered molecular dynamics simulations, as well as via molecular force spectroscopy experiments on biotin-streptavidin. In addition to the well-known loading rate dependence of FRpredicted by Bell's model, we find that experimentally accessible parameters such as the effective stiffness of the force transducer kcan significantly perturb the energy landscape and the apparent unbinding force of the complex for sufficiently stiff force transducers. Additionally, at least 20% variation in unbinding force can be attributed to minute differences in initial atomic positions among energetically and structurally comparable complexes. For force transducers typical of molecular force spectroscopy experiments and atomistic simulations, this energy barrier perturbation results in extrapolated energetic and kinetic parameters of the complex that depend strongly on k. We present a model that explicitly includes the effect of kon apparent unbinding force of the ligand-receptor complex, and demonstrate that this correction enables prediction of unbinding distances and dissociation rates that are decoupled from the stiffness of actual or simulated molecular linkers.

Parasitization by an endoparasitoid wasp, Cotesia plutellae, against diamondback moth (DBM), Plutella xylostella, is fostered by maternal and embryonic factors such as polydnavirus, venom, and teratocyte. Genome of C. plutellae bracovirus (‘CpBV’) possessed at least 19 DNA segments, which ranged from 6.8 to over 30 Kb in size and were not equimolar in abundance. Teratocytes began to release into hemolymph three days after parasitization. Their cell size increased more than two fold, but cell density was not changed until six days after parasitization. After six days, teratocytes began to disappear. With these parasitizing factors, proteomic analysis was conducted in non-parasitized and parasitized DBM every 24h after parasitization to find out parasitization-specific genes. About 2, 000 protein spots were resolved in two-dimensional gel. A clustering expression analysis indicated that 21 proteins of DBM were highly modulated in their expression level by the parasitization. Among such responsive proteins, 16 spots were specifically expressed in non-parasitized DBM, while five spots were only in parasitized DBM. The internal N-terminal amino acid sequences of five parasitization-specific proteins were identified by MALDI-TOF analysis and compared with those of the known proteins available in public databases. Sequence analysis revealed that the five parasitization-specific proteins shared slight homologies with several transcriptional factors or protein kinases. These five proteins were different in their expression profiles after parasitization. These proteomic analyses also reflect that parasitization by C. plutellae modulates various normal gene expressions of DBM probably by parasitization-specific factors.

An endoparasitic wasp, Cotesia plutellae, inhibits pupal metamorphosis of diamondback moth, Plutella xylostella. The parasitized larvae extended their larval stage about 2 days at 25°C and died after escape of wasp larvae for pupation. We set up a hypothesis that the wasp parasitization inhibits juvenile hormone (JH) degradation, which leads to extend larval stage and blocks metamorphosis. In this study, the activities of JH esterase (JHE), a major JH degrading enzyme in hemolymph, were analyzed by use of a surrogate substrate, HEPTAT (methyl 1-heptylthioacetothioate). Hemolymph JHE activities of P. xylostella showed a typical Michaelis-Menten enzyme kinetics in response to HEPTAT, where it exhibited KM at 19.7 μM and Vmax at 228.8 μM/min/μ 1. The parasitized C. plutellae did not exhibit decrease of the JHE activity, but rather kept high JHE activity during the extended larval period.

The absorbance spectra of individual methylene blue aggregates adsorbed by spin coating on a fused silica surface are resolved. Using singular value decomposition and a model incorporating Beer's Law and elemental conservation, a varied concentration family of UV–Vis spectra are fit. Results indicate that H-dimer formation occurs beginning at a surface concentration of 3×1013molecules/cm2, and further aggregate formation, including J-type dimers, is significant above 2×1014molecules/cm2. Based on our results, past assumptions that a spin-coated surface (using a millimolar coating solution) results in a monolayer of methylene blue monomers should be reexamined.

ABSTRACTTo investigate receptor-mediated Moloney murine leukemia virus (MoMuLV) entry, the green fluorescent protein (GFP)-tagged ecotropic receptor designated murine cationic amino acid transporter (MCAT-1) (MCAT-1-GFP) was constructed and expressed in 293 cells (293/MCAT-1-GFP). 293/MCAT-1-GFP cells displayed green fluorescence primarily at the cell membrane and supported wild-type levels of MoMuLV vector binding and transduction. Using immunofluorescence labeling and confocal microscopy, it was demonstrated that the surface envelope protein (SU) gp70 of MoMuLV virions began to appear inside cells 5 min after virus binding and was colocalized with MCAT-1-GFP. However, clathrin was not colocalized with MCAT-1-GFP, suggesting that MoMuLV entry, mediated by MCAT-1, does not involve clathrin. Double immunofluorescence labeling of SU and clathrin in 293 cells expressing untagged receptor (293/MCAT-1) gave the same results, i.e., SU and clathrin did not colocalize. In addition, we examined the transduction ability of MoMuLV vector on HeLa cells overexpressing the dominant-negative GTPase mutant of dynamin (K44A). HeLa cells overexpressing mutant dynamin have a severe block in endocytosis by the clathrin-coated-pit pathway. No significant titer difference was observed when MoMuLV vector was tranduced into HeLa cells overexpressing either wild-type or mutant dynamin, while the transduction ability of vesicular stomatitis virus glycoprotein pseudotyped vector into HeLa cells overexpressing mutant dynamin was decreased significantly. Taken together, these data suggest that MoMuLV entry does not occur through the clathrin-coated-pit-mediated endocytic pathway.

We have applied scanning moire fringe (SMF) imaging to the quantitative measurement of the strain introduced in n-type channel transistors with embedded SiC in the source and drain. The tensile strain parallel to the channels was reveal with a nano-meter scale spatial resolution. We investigated the strain field in transistors with various channel lengths scaled down to 25 nm, and found that the strain increases up to 0.7% as the channel length shrinks to 35 nm. However, the strain in the channel decreases to 0. 55% as the channel length is scaled from 35 nm down to 25 nm.

Abstract

ABSTRACTColitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy (“monotherapy”) or combined with ipilimumab (“combination therapy”) were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

The use of radiation therapy has been linked to an increased risk of cardiovascular disease. To understand the mechanisms underlying radiation-induced vascular dysfunction, we employed two models. First, we examined the effect of X-ray irradiation on vasodilation in rabbit carotid arteries. Carotid arterial rings were irradiated with 8 or 16 Gy using in vivo and ex vivo methods. We measured the effect of acetylcholine-induced relaxation after phenylephrine-induced contraction on the rings. In irradiated carotid arteries, vasodilation was significantly attenuated by both irradiation methods. The relaxation response was completely blocked by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a potent inhibitor of soluble guanylate cyclase. Residual relaxation persisted after treatment with L-Nω-nitroarginine (L-NA), a non-specific inhibitor of nitric oxide synthase (NOS), but disappeared following the addition of aminoguanidine (AG), a selective inhibitor of inducible NOS (iNOS). The relaxation response was also affected by tetraethylammonium, an inhibitor of endothelium-derived hyperpolarizing factor activity. In the second model, we investigated the biochemical events of nitrosative stress in human umbilical-vein endothelial cells (HUVECs). We measured iNOS and nitrotyrosine expression in HUVECs exposed to a dose of 4 Gy. The expression of iNOS and nitrotyrosine was greater in irradiated HUVECs than in untreated controls. Pretreatment with AG, L-N6-(1-iminoethyl) lysine hydrochloride (a selective inhibitor of iNOS), and L-NA attenuated nitrosative stress. While a selective target of radiation-induced vascular endothelial damage was not definitely determined, these results suggest that NO generated from iNOS could contribute to vasorelaxation. These studies highlight a potential role of iNOS inhibitors in ameliorating radiation-induced vascular endothelial damage.

The TFA‐catalyzed reaction of nitroarenes or heterocycles featuring a less pronounced aromatic character affords a variety of pyrrolo‐fused polycycles in a highly regioselective manner.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.