Transient Superhydrophilic Surface Modification of Polyimide by Metal Ion Beam Irradiation.

Polyimide is commonly used as a substrate for flexible electronic devices because of its excellent thermal, physical, and electrical properties. To enhance the adhesion between substrates and electrodes, it is necessary to improve the hydrophilic properties of the polyimide. Various surface treatments, such as plasma treatment, laser ablation, and ultraviolet treatments, have been applied for this purpose. In this study, we demonstrated that Cu and Ti ion beam irradiation can temporarily create a superhydrophilic surface on polyimide after irradiation. When Cu or Ti ions bombarded the polyimide, the contact angle changed systematically with the beam current density and over time. We present atomic force microscopy (AFM) data for polyimide irradiated with Cu and Ti ions at different beam current densities and discuss the possible mechanisms behind the changes in the contact angle.

Studies on the selective synthesis of diorganyl diselenides using potassium hydroxide and mechanistic investigations of the reaction pathway.

Methods of selectively synthesizing diorganyl diselenides (R-Se-Se-R) without using harmful reducing agents are presented. We optimized the reaction conditions for the selective formation of the diselenide dianion (Se22-) and the corresponding diorganyl diselenides using basic reagents (e.g., KOH), while suppressing the formation of side products, such as diorganyl selenides (R-Se-R) or multiselenides (R-Sen-R; n ≥ 3). Furthermore, we have suggested and examined the reaction pathways responsible for the formation of the desired diorganyl diselenides 1 and side products 2 and 3. Consequently, the selective synthesis of diverse diorganyl diselenides was achieved with modest to excellent yields (33-99%) using various organyl halides under optimized conditions. The results provide a practical and efficient synthetic method for diorganyl diselenides as a representative class of organoselenium compounds.

CX-4945 (Silmitasertib) Induces Cell Death by Impairing Lysosomal Utilization in KRAS Mutant Cholangiocarcinoma Cell Lines.

BACKGROUND/AIM: Macropinocytosis is a non-selective form of endocytosis that facilitates the uptake of extracellular substances, such as nutrients and macromolecules, into the cells. In KRAS-driven cancers, including pancreatic ductal adenocarcinoma, macropinocytosis and subsequent lysosomal utilization are known to be enhanced to overcome metabolic stress. In this study, we investigated the role of Casein Kinase 2 (CK2) inhibition in macropinocytosis and subsequent metabolic processes in KRAS mutant cholangiocarcinoma (CCA) cell lines. MATERIALS AND METHODS: The bovine serum albumin (BSA) uptake indicating macropinocytosis was performed by flow cytometry using the HuCCT1 KRAS mutant CCA cell line. To validate macropinosome, the Rab7 and LAMP2 were labeled and analyzed via immunocytochemistry and western blot. The CX-4945 (Silmitasertib), CK2 inhibitor, was used to investigate the role of CK2 in macropinocytosis and subsequent lysosomal metabolism. RESULTS: The TFK-1, a KRAS wild-type CCA cell line, showed only apoptotic morphological changes. However, the HuCCT1 cell line showed macropinocytosis. Although CX-4945 induced morphological changes accompanied by the accumulation of intracellular vacuoles and cell death, the level of macropinocytosis did not change. These intracellular vacuoles were identified as late macropinosomes, representing Rab7+ vesicles before fusion with lysosomes. In addition, CX-4945 suppressed LAMP2 expression following the inhibition of the Akt-mTOR signaling pathway, which interrupts mature macropinosome and lysosomal metabolic utilization. CONCLUSION: Macropinocytosis is used as an energy source in the KRAS mutant CCA cell line HuCCT1. The inhibition of CK2 by CX-4945 leads to cell death in HuCCT1 cells through alteration of the lysosome-dependent metabolism.

Associations of Night Shift Status During Pregnancy With Small for Gestational Age and Preterm Births.

BACKGROUND: Shift work, including night shift work, during pregnancy has been associated with adverse birth outcomes such as small for gestational age (SGA) infants and preterm births. This study, conducted in South Korea using the Korean CHildren's ENvironmental health Study (Ko-CHENS) cohort, aimed to investigate the association between shift work and night shift status during pregnancy and adverse birth outcomes. METHODS: The Korean Ko-CHENS is a nationwide prospective birth cohort study of children's environmental diseases, conducted by the Ministry of Environment and the National Institute of Environmental Research. This study included pregnant women recruited from 2015 to 2020 for Ko-CHENS Core Cohorts, and 4,944 out of a total of 5,213 pregnant women were selected as final subjects. A logistic regression model was used to identify the risk factors affecting SGA births, preterm births, and low-birth-weight infants, and the odds ratio (OR) was adjusted. This was confirmed by calculating ORs. Maternal age, infant sex, maternal educational status, body mass index, smoking status, alcohol consumption status, parity, gestational diabetes mellitus, preeclampsia, and abortion history were used as adjusted variables. RESULTS: No statistically significant differences were observed in the birth outcomes or maternal working patterns. There were no significant differences in the adjusted odds ratios (aORs) of SGA and preterm births between the non-worker, day worker, and shift worker. However, there was a significant difference in the aORs of SGA between non-workers and night shift workers. (aORs [95% confidence interval], 2.643 [1.193-5.859]). CONCLUSION: Working during pregnancy did not increase the risk of SGA or preterm birth, and night shift work did not increase the risk of preterm birth. However, night-shift work increases the risk of SGA.

PARP Inhibitor Sensitizes BRCA-mutant Pancreatic Cancer to Oxaliplatin by Suppressing the CDK1/BRCA1 Axis.

BACKGROUND/AIM: Currently, olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has been approved as maintenance therapy for patients with germline BRCA mutations and metastatic pancreatic cancer. However, platinum-based chemotherapy, which induces synthetic lethality with PARP inhibitor treatment, is still controversial. Hence, we aimed to examine a platinum-based drug in combination with a PARP inhibitor and generate data regarding the use of a PARP inhibitor in the overall treatment of pancreatic cancer. MATERIALS AND METHODS: Using the Capan-1 cell line (BRCA2-mutant pancreatic cancer cell line), we evaluated the combinatorial effects of olaparib, a PARP inhibitor, and oxaliplatin by cell viability, combination index, western blotting, immunocytochemistry, flow cytometry, apoptosis assays and in vivo experiments. RESULTS: Capan-1 cells showed high sensitivity to olaparib due to the alteration in PARP activity, which led to cell death through the accumulation of oxaliplatin-induced DNA damage. Beyond DNA damage, oxaliplatin also suppressed the CDK1/BRCA1 signaling axis, which induced defects in homologous recombination repair. Additionally, inhibition of CDK1, a biomarker for oxaliplatin efficacy, induced cell death regardless of the BRCA mutation profile. CONCLUSION: Oxaliplatin may be used in combination with olaparib in PDAC patients with DNA damage repair mutations. Our findings highlight CDK1 as a potential therapeutic target for pancreatic cancer.

Changes in the Review Period of Drug Application and a Drug Lag from the FDA and the EMA: An Industry Survey in South Korea Between 2011 and 2020.

BACKGROUND: The Korean regulatory authority has enacted legislation to expedite the new drug approval (NDA) process. However, the effectiveness of such efforts in reducing review time and drug approval delays between Korea and the USA/EU remains to be evaluated. METHODS: We investigated NDA trends in Korea from 2011 to 2020 using approval information from pharmaceutical companies. We compared the changes in the actual review duration according to active ingredient (chemical vs. biological), orphan status, therapeutic class, and NDA review process. We estimated the submission and approval gaps of new drugs between Korea and the US and EU across the study period. RESULTS: For 235 new drugs, the median NDA review time was 315 days, with a significant increase in the delay (average 15.4 days) over time. Biological drugs had a 43.2-day delay for approval than the time taken for approving chemical drugs. The median NDA review time for orphan drugs was 130.4 days faster than that for others, although the difference diminished after 2016. Good manufacturing practice reviews played a crucial role in delaying review time. The median submission and approval gaps in Korea were 493 and 551 days, respectively, compared to those of the US and EU. CONCLUSIONS: Despite recent legislative initiatives, the delay in the NDA review timeline has steadily increased over 10 years in Korea. Delays in orphan drugs reviews increased after the enactment of the 'Rare Disease Management Act' in 2016. Careful enforcement of relevant laws and supplementary actions is required to increase new drug accessibility.

Studies on the Selective Syntheses of Sodium Ditelluride and Dialkyl Ditellurides.

Studies on the selective synthetic method for dialkyl ditellurides 1, a representative class of organyl tellurium compounds, were presented. Considering the difficulty in conducting previous harsh reactions and in suppressing the formation of dialkyl tellurides 2 as side products, we optimized reaction conditions for selective syntheses of sodium ditelluride and the corresponding dialkyl ditellurides 1. We reduced tellurium to sodium ditelluride by using NaBH4 and subsequently, treated the obtained sodium ditelluride with alkyl halides (RX) to give the target compounds 1. Consequently, by applying various alkyl halides (RX) we achieved the selective syntheses of dialkyl ditellurides 1 (13 examples with 4 new compounds) in modest to good yields. We also suggested the mechanistic pathways to dialkyl ditellurides 1.

Syntheses of New Multisubstituted 1-Acyloxyindole Compounds.

The syntheses of novel 1-acyloxyindole compounds 1 and the investigations on reaction pathways are presented. Nitro ketoester substrate 2, obtained in a two-step synthetic process, underwent reduction, intramolecular addition, nucleophilic 1,5-addition, and acylation to afford 1-acyloxyindoles 1 in one pot. Based on the systematic studies, we established the optimized reaction conditions for 1 focusing on the final acylation step of the intermediate 1-hydroxyindole 8. With the optimized conditions, we succeeded in synthesizing 21 examples of new 1-acyloxyindole derivatives 1 in modest yields (Y = 24 - 35%). Among the 1-acyloxyindole compounds, 1-acetoxyindole compounds 1x were generally unstable, and their yields were relatively lower than the other 1-acyloxyindoles. We expect that a bulkier alkyl or aromatic group on R2 could stabilize the 1-acyloxyindole compounds. Significantly, one-pot reactions of a four-step sequence successfully generated compounds 1 that are all new and might be difficult to be synthesized otherwise.

An Efficient Method for Selective Syntheses of Sodium Selenide and Dialkyl Selenides.

The studies on the selective synthesis of dialkyl selenide compounds 1 were presented. Overcoming the complexity and difficulty of selenides (R-Se-R) and/or multiselenides (R-Sen-R; n ≥ 2), we aimed to optimize the reaction condition for the tolerable preparation of sodium selenide (Na2Se) by reducing Se with NaBH4, and then to achieve selective syntheses of dialkyl selenides 1 by subsequently treating the obtained sodium selenide with alkyl halides (RX). Consequently, various dialkyl selenides 1 were efficiently synthesized in good-to-moderate yields. The investigations on reaction pathways and solvent studies were also described.

The Casein Kinase 2 Inhibitor CX-4945 Promotes Cholangiocarcinoma Cell Death Through PLK1.

BACKGROUND/AIM: Casein Kinase 2 (CK2) is a prosurvival protein kinase involved in cell growth/proliferation through the regulation of the cell cycle and apoptosis. CK2 is over-expressed in various cancers, which correlates with a poor prognosis. This study examined the anti-cancer effects of silmitasertib (CX-4945), a CK2 inhibitor, on cholangiocarcinoma (CCA) cells. MATERIALS AND METHODS: The effects of CX-4945 on cell viability, cell cycle arrest, and apoptosis in the human cholangiocarcinoma cell lines TFK-1 and SSP-25 were evaluated. Alterations in posttranslational modifications and the levels of cell cycle regulators including p21, Polo-like kinase 1 (PLK1), andp53 were assessed by western blotting. Apoptotic responses were examined using Propidium iodine/Annexin V staining. RESULTS: TFK-1 and SSP-25 cells exposed to CX-4945 showed morphologic changes and a more than 50% decrease in cell viability (p<0.05). Cell cycle arrest at the G2 phase was detected following an increase in phosphorylated PLK1 and p21. Furthermore, phospho-PLK1 induced the degradation of p53, which led to the dissociation of Bax from Bcl-xL. The cleavage of Caspase3 and PARP were also induced by CX-4945 treatment. CONCLUSION: CX-4945 induces cell cycle arrest and cell death in cholangiocarcinoma cells via the regulation of PLK1 and p53. This may provide a novel therapeutic strategy for advanced cholangiocarcinoma.

Removal of Hexavalent Chromium(VI) from Wastewater Using Chitosan-Coated Iron Oxide Nanocomposite Membranes.

Chromium is a toxic and carcinogenic heavy metal that originates from various human activities. Therefore, the effective removal of chromium from aqueous solutions is an extremely important global challenge. Herein, we report a chitosan-coated iron oxide nanoparticle immobilized hydrophilic poly(vinylidene) fluoride membrane (Chi@Fe2O3-PVDF) which can potentially be used for efficient removal of hexavalent chromium(VI) by a simple filtration process. Membrane filtration is an easy and efficient method for treating large volumes of water in a short duration. The adsorption experiments were conducted by batch and continuous in-flow systems. The experimental data showed rapid capture of hexavalent chromium (Cr(VI)) which can be explained by the pseudo-second-order kinetic and Langmuir isotherm model. The nanocomposite membrane exhibited high adsorption capacity for Cr(VI) (14.451 mg/g in batch system, 14.104 mg/g in continuous in-flow system). Moreover, its removal efficiency was not changed significantly in the presence of several competing ions, i.e., Cl-, NO3-, SO42-, and PO43-. Consequently, the Chi@Fe2O3-PVDF-based filtration process is expected to show a promising direction and be developed as a practical method for wastewater treatment.

Blockade of GRP78 Translocation to the Cell Surface by HDAC6 Inhibition Suppresses Proliferation of Cholangiocarcinoma Cells.

BACKGROUND/AIM: HDAC6, a cytoplasmic localized deacetylase, is a positive regulator of cancer progression via modification of various substrates. We evaluated how the interaction between HDAC6 and glucose regulatory protein 78 (GRP78) affects the growth of cholangiocarcinoma (CCA). MATERIALS AND METHODS: The anti-tumor effects of ACY-1215, an HDAC6 specific inhibitor, in CCA cell lines were analyzed by cell viability assay, western blotting, flow cytometry, co-immunoprecipitation, and biotinylation assays. In vivo effects of ACY-1215 were evaluated in a xenograft model using CCA cell line TFK-1. RESULTS: ACY-1215 increased the acetyl-form of GRP78 by approximately 50% compared to control, which impaired the translocation of GRP78 to the plasma membrane by 50% through alteration of cellular proliferative signaling via PI3K/AKT. Furthermore, ACY-1215 suppressed tumor growth by 50% compared to vehicle control in a CCA xenograft model. CONCLUSION: Increase in GRP78 acetylation by HDAC6 inhibition suppressed GRP78 translocation to the cell surface, which inhibited proliferation and promoted apoptosis in CCA.

Enhanced anomalous magnetization in carbonyl iron by Ni+ ion beam irradiation.

We investigate the magnetic properties in carbonyl iron (CI) particles before and after Ni[Formula: see text] and H[Formula: see text] ion beam irradiation. Upon increasing temperatures, the saturation magnetization ([Formula: see text]) in hysteresis loops exhibits an anomalous increase at a high temperature for the unirradiated and the Ni[Formula: see text]-beam-irradiated samples, unlike in H[Formula: see text]-beam-irradiated sample. Moreover, the magnetization values at low and high temperatures are more intense after Ni[Formula: see text] beam irradiation, whereas after H[Formula: see text] beam irradiation those are remarkably suppressed. Hematite ([Formula: see text]-Fe[Formula: see text]O[Formula: see text]) phase introduced on the surface of our CI particles undergoes the Morin transition that was observed in our magnetization-temperature curves. The Morin transition causing canted antiferromagnetism above the Morin temperature was found in the unirradiated and Ni[Formula: see text]-beam-irradiated samples, but not in H[Formula: see text]-beam-irradiated sample. It is thus revealed that the CI particles undergoing the Morin transition cause the anomalous increase in [Formula: see text]. We may suggest that Ni[Formula: see text] ion beam increases uncompensated surface spins on the CI particles resulting in a more steep Morin transition and the intensified [Formula: see text]. Ion-beam irradiation may thus be a good tool for controlling the magnetic properties of CI particles, tailoring our work for future applications.

Metastatic gallbladder cancer to the ovary presenting as primary ovarian cancer: a case report.

BACKGROUND: Krukenberg tumors are uncommon and are indicative of an ovarian metastatic carcinoma that originates from another site of primary malignancy. The majority of metastases to ovaries are derived from the stomach and colon. We present a rare case of a metastatic ovarian malignant tumor that originated from gallbladder adenocarcinoma. CASE PRESENTATION: A 45-year-old premenopausal Korean woman presented with abdominal distension. Bilateral multiseptated ovarian tumors and a wall-thickened gallbladder were found on abdominal computed tomography. The patient was diagnosed with metastatic ovarian carcinoma arising from gallbladder adenocarcinoma and was treated with adjuvant chemotherapy. CONCLUSIONS: Metastases to the ovaries from other sites, including the gallbladder, are rare and usually resemble primary ovarian tumors. Therefore, potential metastatic ovarian tumors of newly diagnosed pelvic masses should be considered in differential diagnoses.

Spontaneous Rupture of Ovarian Artery Aneurysm in a Postmenopausal Woman: A Case Report and Literature Review.

Spontaneous rupture of an ovarian artery aneurysm is an extremely rare, life-threatening disease and has been reported to be most highly associated with pregnancy. The current study presents a case of intraperitoneal and retroperitoneal hematoma caused by spontaneous rupture of a right ovarian artery aneurysm in a 56-year-old woman. A 56-year-old woman visited the emergency room with right lower quadrant abdominal pain. Contrast-enhanced computed tomography showed a large retroperitoneal and intraperitoneal hematoma and active extravasation of contrast medium in the right retroperitoneum. Consequently, transcatheter arterial embolization was successfully performed. Spontaneous rupture of an ovarian artery aneurysm should be suspected in multiparous women with abdominal or flank pain even if it is unrelated to pregnancy. Suspicion of this entity is needed for earlier diagnosis and management.

One-Pot Synthesis of Novel Multisubstituted 1-Alkoxyindoles.

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent three consecutive reactions of nitro reduction, intramolecular condensation, and nucleophilic 1,5-addition to provide the intermediates, 1-hydroxyindoles 8, which then were alkylated in situ with alkyl halide to afford the novel target products 1. We optimized the reaction conditions for 1 focusing on the alkylation step, along with the consideration of formation of intermediates 8. The optimized condition was SnCl2·2H2O (3.3 eq) and alcohols (R1OH, 2.0 eq) for 1-2 h at 40 °C and then, base (10 eq) and alkyl halides (R2Y, 2.0 eq) for 1-4 h at 25-50 °C. Notably, all four step reactions were performed in one-pot to give 1 in good to modest yields. Furthermore, the mechanistic aspects were also discussed regarding the reaction pathways and the formation of side products. The significance lies in development of efficient one-pot reactions and in generation of new 1-alkoxyindoles.

Simultaneous selective removal of cesium and cobalt from water using calcium alginate-zinc ferrocyanide-Cyanex 272 composite beads.

Composite beads consisting of Ca alginate mixed with zinc ferrocyanide (ZnFC) and Cyanex 272 were synthesized in order to selectively adsorb Cs+ and Co2+ from water. Their physicochemical properties of the synthesized composite beads were characterized using various techniques, including FESEM, EDX, FTIR, and TGA. The ZnFC/Cyanex 272/alginate (ZCA) composite beads were then tested as an adsorbent for the selective removal of Cs+ and Co2+ from an aqueous solution. The adsorption capacity increased with increasing ZnFC and Cyanex 272 contents. The adsorption process followed the Langmuir model and pseudo-second-order kinetics. The ZCA composite beads exhibited excellent selectivity toward Cs+ and Co2+ even in the presence of competitive cations (K+, Na+, Fe2+, and Ni2+). The adsorption capacity of the ZCA composite beads for Cs+ and Co2+ was almost maintained after three times of adsorption-desorption process.

A mechanism of surface hardness enhancement for H+ irradiated polycarbonate.

H+ irradiation increases the surface hardness of polycarbonate. Nano indentation measurement shows that the hardness increases up to 3.7 GPa at the dose of 5 × 1016 # cm-2 and at the irradiation energy of 150 keV. In addition, the hardness increases with the dose and the energy of H+ irradiation. In accordance with the nano indentation measurement, the Fourier-transform infrared spectroscopy (FTIR) depends on the dose and energy of H+ irradiation. The peak at ∼1500 cm-1 for the aromatic ring and the peak at ∼1770 cm-1 for the C[double bond, length as m-dash]O stretch decrease with increasing dose and energy, while the increase of the dose and energy develops a new C[double bond, length as m-dash]O stretch vibration at ∼1700 cm-1 and forms aromatic hydrocarbons at ∼1600 cm-1. X-ray diffraction experiments are also consistent with the nano indentation measurement and FTIR spectra. Based on the experiments, we discuss a possible mechanism of the surface hardness enhancements by ion beam irradiation.

Changes in Fecal Calprotectin After Rifaximin Treatment in Patients With Nonconstipated Irritable Bowel Syndrome.

BACKGROUND: Fecal calprotectin, an indicator of colonic inflammation, is associated with nonconstipated irritable bowel syndrome. Rifaximin is an antibiotic used to treat nonconstipated irritable bowel syndrome. We performed a retrospective review of patient charts to investigate the changes in fecal calprotectin levels and intestinal symptoms following treatment with rifaximin in patients with nonconstipated irritable bowel syndrome with elevated fecal calprotectin. METHODS: This study included 198 patients presenting with gastrointestinal complaints consistent with Rome III criteria for irritable bowel syndrome. We treated them with rifaximin for 4-12 weeks, until fecal calprotectin levels were normalized, and divided these into 4-, 8-, and 12-week groups according to the treatment period. Fecal calprotectin levels and gastrointestinal symptoms were assessed following rifaximin therapy. RESULTS: A total of 162 subjects achieved normalized fecal calprotectin values. Of these, most patients who used rifaximin for 8 or 12 weeks showed a significant improvement in gastrointestinal symptoms by the fourth week of treatment, and gradually improved symptoms after 4 weeks. Fecal calprotectin levels were reduced with concomitant improvement of clinical symptoms. In addition, 36 patients who had elevated fecal calprotectin even after 12 weeks of rifaximin treatment showed a gradual reduction in gastrointestinal symptoms and fecal calprotectin during the course of treatment for 12 weeks. CONCLUSIONS: These findings suggest that fecal calprotectin might be a useful biomarker for measuring the effect of rifaximin therapy in nonconstipated irritable bowel syndrome patients with elevated fecal calprotectin values.

Erratum: Socio-demographic factors and diet-related characteristics of community-dwelling elderly individuals with dysphagia risk in South Korea.

[This corrects the article on p. 406 in vol. 12, PMID: 30323908.].