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Controlling the assembly of 2D materials such as graphene oxides (GO) has a significant impact on their properties and performance. One of the critical issues on the processing and handling of GO is that they need to be in dilution solution (0.5 to 2.5 wt%) to maintain their high degree of exfoliation and dispersion. As a result, the shipment of GO in large quantity involves a huge volume of solvent (water) and thus the transportation costs for large sales volume would become extremely high. Through cross-sectional scanning electron microscopy and polarized optical microscopy together with x-ray diffraction and small-angle x-ray scattering studies, we demonstrated that the assembly and structure of GO microsheets can be preserved without restacking, when assembled GO via water-based wet spinning are re-dispersed into solution. A couple of alkyl ammonium bromides, CTAB and TBAB, as well as NaOH, were examined as coagulants and the resulting fibers were redispersed in an aqueous solution. The redispersed solution of fibers that were wet-spun into the commonly used CTAB and TBAB coagulation baths, maintained their physico-chemical properties (similar to the original GO dispersion) however, did not reveal preservation of liquid crystallinity. Meanwhile, the redispersed fibers that were initially spun into NaOH coagulation bath were able to maintain their liquid crystallinity if the lateral size of the GO sheets was large. Based on these findings, a cost-effective solid handling approach is devised which involves (i) processing GO microsheets in solution into folded layers in solid-state, (ii) transporting assembled GO to the customers, and (iii) redispersion of folded GO into a solution for their use. The proposed solid handling of GO followed by redispersion into solution can greatly reduce the transportation costs of graphene oxide materials by reducing the transportation volume by more than 90%., (© 2021 IOP Publishing Ltd.)

The structures and phase transitions of [NH 3 (CH 2 ) n NH 3 ]MnCl 4 ( n = 2, 3, and 4) crystals were confirmed through X-ray diffraction and differential scanning calorimetry (DSC) experiments. Thermodynamic properties, ferroelastic properties, and molecular dynamics of three crystals were studied as a function of the number ( n ) of CH 2 groups in the alkylene chains. The loss in molecular weight due to a decrease in n marked the onset of the partial thermal decomposition. The thermal decomposition temperature, T d , increased with increasing length of the CH 2 chain. While the ferroelastic twin domain walls for n = 2 and 4 were in the same direction at all temperatures, the domain walls for n = 3 were rotated by 45°, and the direction of extinction in phase II was rotated by 45° with respect to phases I and III. The 1 H and 13 C MAS NMR spectra of the three crystals were recorded as a function of temperature. With increasing length of the CH 2 chain, the 1 H spin relaxation time decreased, indicating that molecular motions were activated. These results provide insights into the thermodynamic properties and structural dynamics of the [NH 3 (CH 2 ) n NH 3 ]MnCl 4 crystals and are expected to facilitate their potential applications., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Hybrid perovskites have potential applications in several electrochemical devices such as supercapacitors, batteries, and fuel cells. Therefore, we studied the thermal behavior and structural dynamics of organic-inorganic hybrid perovskite [(NH 3 )(CH 2 ) 3 (NH 3 )]CdBr 4 crystals near phase transition temperatures, T C2 (=328 K) and T C1 (=363 K), which are correlated to the structural dynamics of cations and anions. The structural geometry and molecular dynamics with emphasis on the role of the [(NH 3 )(CH 2 ) 3 (NH 3 )] cation and CdBr 6 anion were discussed in terms of MAS 1 H NMR, MAS 13 C NMR, 14 N NMR, and 113 Cd NMR as a function of the temperature. The environments surrounding 1 H, 13 C, 14 N, and 113 Cd are investigated near T C1 and T C2 using these results. Spin-lattice relaxation times T 1ρ were discussed in terms of the change in temperature. The discontinuous changes of 1 H T 1ρ and 13 C T 1ρ near T C1 are consistent with the change of the lattice constant. Shorter T 1ρ values at high temperature indicate that 1 H and 13 C in the organic chains are more flexible at these temperatures. Based on these results, the physicochemical properties of the cation and anion during the III-II-I phase transitions were discussed. This study was conducted to improve the relatively weak thermal stability compared to the high efficiency for a variety of applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The physical properties of the organic-inorganic hybrid crystals having the formula [NH 3 (CH 2 ) 3 NH 3 ]ZnX 4 (X = Cl, Br) were investigated. The phase transition temperatures (T C ; 268K for Cl and 272K for Br) of the two crystals bearing different halogen atoms in their skeletons were determined through differential scanning calorimetry. The thermodynamic properties of the two crystals were investigated through thermogravimetric analysis. The structural dynamics, particularly the role of the [NH 3 (CH 2 ) 3 NH 3 ] cation, were probed through 1 H and 13 C magic-angle spinning nuclear magnetic resonance spectroscopy as a function of temperature. The 1 H and 13 C NMR chemical shifts did not show any changes near T C . In addition, the 1 H spin-lattice relaxation time (T 1ρ ) varied with temperature, whereas the 13 C T 1ρ values remained nearly constant at different temperatures. The T 1ρ values of the atoms in [NH 3 (CH 2 ) 3 NH 3 ]ZnCl 4 were higher than those in [NH 3 (CH 2 ) 3 NH 3 ]ZnBr 4 . The observed differences in the structural dynamics obtained from the chemical shifts and T 1ρ values of the two compounds can be attributed to the differences in the bond lengths and halogen atoms. These findings can provide important insights or potential applications of these crystals.

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05-5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

Purpose: Next-generation sequencing (NGS) can facilitate precision medicine approaches in metastatic colorectal cancer (mCRC) patients. We investigated the molecular profiling of Korean mCRC patients under the K-MASTER project which was initiated in June 2017 as a nationwide precision medicine oncology clinical trial platform which used NGS assay to screen actionable mutations., Materials and Methods: As of 22 January 2020, total of 994 mCRC patients were registered in K-MASTER project. Targeted sequencing was performed using three platforms which were composed of the K-MASTER cancer panel v1.1 and the SNUH FIRST Cancer Panel v3.01. If tumor tissue was not available, cell-free DNA was extracted and the targeted sequencing was performed by Axen Cancer Panel as a liquid biopsy., Results: In 994 mCRC patients, we found 1,564 clinically meaningful pathogenic variants which mutated in 71 genes. Anti-EGFR therapy candidates were 467 patients (47.0%) and BRAF V600E mutation (n=47, 4.7%), deficient mismatch repair/microsatellite instability-high (n=15, 1.5%), HER2 amplifications (n=10, 1.0%) could be incorporated with recently approved drugs. The patients with high tumor mutation burden (n=101, 12.7%) and DNA damaging response and repair defect pathway alteration (n=42, 4.2%) could be enrolled clinical trials with immune checkpoint inhibitors. There were more colorectal cancer molecular alterations such as PIK3CA, KRAS G12C, atypical BRAF, and HER2 mutations and even rarer but actionable genes that approved or ongoing clinical trials in other solid tumors., Conclusion: K-MASTER project provides an intriguing background to investigate new clinical trials with biomarkers and give therapeutic opportunity for mCRC patients.

The structural characterization of the [(CH 2 ] 3 (NH 3 ) 2 ] + cation in the perovskite [(CH 2 ) 3 (NH 3 ) 2 ]CuCl 4 crystal was performed by solid-state 1 H nuclear magnetic resonance (NMR) spectroscopy. The 1 H NMR chemical shifts for NH 3 changed more significantly with temperature than those for CH 2 . This change in cationic motion is enhanced at the N-end of the organic cation, which is fixed to the inorganic layer by N-H···Cl hydrogen bonds. The 13 C chemical shifts for CH 2 -1 increase slowly without any anomalous change, while those for CH 2 -2 move abruptly compared to CH 2 -1 with increasing temperature. The four peaks of two groups in the 14 N NMR spectra, indicating the presence of a ferroelastic multidomain, were reduced to two peaks of one group near T C2 (= 333 K); the 14 N NMR data clearly indicated changes in atomic configuration at this temperature. In addition, 1 H and 13 C spin-lattice have shorter relaxation times (T 1ρ ), in the order of milliseconds because T 1ρ is inversely proportional to the square of the magnetic moment of paramagnetic ions. The T 1ρ values for CH 2 and NH 3 protons were almost independent of temperature, but the CH 2 moiety located in the middle of the N-C-C-C-N bond undergoes tumbling motion according to the Bloembergen-Purcell-Pound theory. Ferroelasticity is the main cause for the phase transition near T C2 .

In this study, we investigated the structural dynamic features of the [NH 3 (CH 2 ) 2 NH 3 ]ZnCl 4 crystal as a function of temperature through magic angle spinning (MAS) 1 H nuclear magnetic resonance (NMR), MAS 13 C NMR, and static 14 N NMR. From the chemical shifts, changes in the structural environments of 13 C and 14 N were evident. The 1 H spin-lattice relaxation time ( T 1ρ ) values at high temperatures undergo molecular motion according to the Bloembergen-Purcell-Pound theory, and the 13 C T 1ρ value also varied abruptly with increasing temperature. Although the phase-transition temperature was not detected from the differential scanning calorimetry result, the chemical shifts and T 1ρ results showed discontinuities around 300 K. Herein, the activation energies of molecular motion for 1 H and 13 C obtained from T 1ρ are discussed. In addition, we compare the structural dynamics of diammonium-type [NH 3 (CH 2 ) 2 NH 3 ]ZnCl 4 obtained in this study and monoammonium-type [CH 3 NH 3 ] 2 ZnCl 4 previously reported. The findings reported herein can provide important insights for potential applications of [NH 3 (CH 2 ) 2 NH 3 ]ZnCl 4 crystals., Competing Interests: The author declares no competing financial interest., (© 2020 American Chemical Society.)

Many countries provide preventive dental care for children to reduce inequalities. In Korea, the registered dentists' program was implemented to promote oral health and prevent oral diseases in primary school students. This study aimed to evaluate the registered dentist program through the sealant utilization rate using national cohort data and to compare the socioeconomic gap of the cohorts by participation. The sample cohort data were obtained from the National Health Insurance Sharing Service (NHISS) in South Korea. The utilization of dental sealants was analyzed using the chi-square test according to the independent variables of each year. To identify the independent effects of participation in the registered dentists' program, a panel logistic regression analysis of the utilization of dental sealants was performed. The participants were 1.35 times more likely to have dental sealants than non-participants. The significance of income quintiles disappeared in the case groups. The gap became more obvious in the employees of the control group even after adjusting for all variables. Implementing oral health programs can alleviate inequality with a relative increase in utilization in vulnerable populations.

We investigate the thermal behaviour and physical properties of the crystals of the organic inorganic hybrid perovskite [(NH 3 )(CH 2 ) 4 (NH 3 )]CuCl 4 . The compound's thermal stability curve as per thermogravimetric analysis exhibits a stable state up to ∼495 K, while the weight loss observed near 538 K corresponds to partial thermal decomposition. The 1 H nuclear magnetic resonance (NMR) chemical shifts for NH 3 change more significantly with temperature than those for CH 2 , because the organic cation motion is enhanced at both ends of the organic chain. The 13 C NMR chemical shifts for the 'CH 2 -1' units of the chain show an anomalous change, and those for 'CH 2 -2' (units closer to NH 3 ) are shifted sharply. Additionally, the 14 N NMR spectra reflect the changes of local symmetry near T C (=323 K). Moreover, the 13 C T 1ρ values for CH 2 -2 are smaller than those for CH 2 -1, and the 13 C T 1ρ data curve for CH 2 -1 exhibits an anomalous behaviour between 260 and 310 K. These smaller T 1ρ values at lower temperatures indicate that 1 H and 13 C in the organic chains are more flexible at these temperatures. The NH 3 group is attached to both ends of the organic chain, and NH 3 forms a N-H⋯Cl hydrogen bond with the Cl ion of inorganic CuCl 4 . When H and C are located close to the paramagnetic Cu 2+ ion, the T 1ρ value is smaller than when these are located far from the paramagnetic ion., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Even though Korea was known to have the highest number of coronavirus disease-2019 (COVID-19) infection in the early phase of the pandemic, Korea was able to successfully flatten the curve in a short period of time without extreme measures. We compared the status of cancer management before and after COVID-19 and analysed how cancer care continuity was maintained in Korea., Patients and Methods: We investigated the medical records on the number of cancer diagnosis, cancer surgery, radiation therapy and scheduled chemotherapy conducted in Korea University Anam Hospital from January 1 to April 30, 2019 and from the same period in 2020. We also collected the data of metastatic cancer patients who were hospitalised due to respiratory disease., Results: Of all diagnoses, 1694 cancer diagnoses were made in the study period of 2019, and 1445 diagnoses in 2020 (decreased by 14.7%); the cancer surgery performed 830 and 800 cases; the set-up for radiation therapy decreased from 185 to 140 cases; the number of systemic chemotherapies for metastatic cancer patients treated in department of medical oncology increased from 2555 to 2878 cases. Among hospitalised patients, emergency centre visit, intensive care unit admission, discharge after recovery and death reveal no drastic changes., Conclusions: Routine cancer care for patients with metastatic cancer has been maintained without significant difference before and after the COVID-19 pandemic. The Korean government's innovative countermeasures in the early phase of outbreak made it possible for cancer care practitioners to provide cancer patients with regular care under the standard infection control protocol., Competing Interests: Conflict of interest statement The authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Understanding the structural dynamics of lead-halide perovskites is essential for their advanced use as photovoltaics. Here, the structural dynamics of the CH 3 NH 3 cation and PbBr 6 octahedra in the perovskite CH 3 NH 3 PbBr 3 were studied via nuclear magnetic resonance (NMR) to determine the mechanism of the transition from the tetragonal to cubic phase. The chemical shifts were obtained by 1 H, 13 C, and 207 Pb magic angle spinning NMR and 14 N static NMR. The chemical shifts of the 1 H nuclei in CH 3 and NH 3 remained constant with increasing temperature, whereas those of the 13 C and 207 Pb nuclei varied near the phase transition temperature (T C  = 236 K), indicating that the structural environments of 13 C and 207 Pb change near T C . The spin-lattice relaxation time T 1ρ values for 1 H, 13 C, and 207 Pb nuclei increased with increasing temperature and did not exhibit an abrupt change near T C . In addition, the two lines in the 14 N NMR spectra superposed into one line near T C , indicating the occurrence of a phase transition to a cubic phase with higher symmetry than tetragonal. Consequently, the main factor causing the phase transition from the tetragonal to cubic phase near T C is a change in the surroundings of the 207 Pb nuclei in the PbBr 6 octahedra and of the C-N groups in the CH 3 NH 3 cations.

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes., Competing Interests: AL No competing interests declared, WR Incyte pharmaceutics, through a partnership with Vanderbilt University, our laboratory has a funded project unrelated to the topic of this review. JR Incyte pharmaceutics, through a partnership with Vanderbilt University, our laboratory has a funded project unrelated to the topic of this review; Sitryx, SAB and co-founder, a company with relevant project areas, (© 2020, Lim et al.)

The application of steroids has steadily increased thanks to their therapeutic effects. However, alternatives are required due their severe side effects; thus, studies on the activities of steroid derivatives are underway. Sugar derivatives of nandrolone, which is used to treat breast cancer, as well as cortisone and prednisone, which reduce inflammation, pain, and edema, are unknown. We linked O-glucose to nandrolone and testosterone using UDP-glucosyltransferase (UGT-1) and, then, tested their bioactivities in vitro. Analysis by NMR showed that the derivatives were 17β-nandrolone β-D-glucose and 17β-testosterone β-D-glucose, respectively. The viability was higher and cytotoxicity was evident in PC12 cells incubated with rotenone and, testosterone derivatives, compared to the controls. SH-SY5Y cells incubated with H 2 O 2 and nandrolone derivatives remained viable and cytotoxicity was attenuated. Both derivatives enhanced neuronal protective effects and increased the amounts of cellular ATP.

The thermal, physical, and molecular dynamics of layered hybrid type (C 2 H 5 NH 3 ) 2 M Cl 4 ( M = 59 Co, 63 Cu, 65 Zn, and 113 Cd) crystals were investigated by thermogravimetric analysis (TGA) and magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy. The temperatures of the onset of partial thermal decomposition were found to depend on the identity of M . In addition, the Bloembergen-Purcell-Pound curves for the 1 H spin-lattice relaxation time T 1ρ in the rotating frames of CH 3 CH 2 and NH 3 , and for the 13 C T 1ρ of CH 3 and CH 2 were shown to exhibit minima as a function of the inverse temperature. These results confirmed the rotational motion of 1 H and 13 C in the C 2 H 5 NH 3 cation. Finally, the T 1ρ values and activation energies E a obtained from the 1 H measurements for the H‒Cl··· M ( M = Zn and Cd) bond in the absence of paramagnetic ions were larger than those obtained for the H‒Cl··· M ( M = Co and Cu) bond in the presence of paramagnetic ions. Moreover, the E a value for 13 C, which is distant from the M ions, was found to decrease upon increasing the mass of the M ion, unlike in the case of the E a values for 1 H.

Background: Although a focus on late-life depression may help preventing suicide in older adults, many older people, especially those living in rural areas, have relatively low accessibility to treatment. This study examined the feasibility and effectiveness of a village-based intervention for depression targeting older adults living in rural areas., Methods: A community-based randomised pilot trial was performed in two small rural villages in South Korea. Two villages were randomly selected and assigned to the intervention or active control group; all older adults living in the two villages (n = 451) were included in the intervention program or received standard Community Mental Health Service (CMHS) care, and the effectiveness of the program was examined using representative samples from both groups (n = 160). The 12-week intervention included case management according to individual risk level and group-based activities. Healthy residents living in the intervention village who played major roles in monitoring at-risk older individuals were supervised by CMHS staff. The score on the Korean version of the Geriatric Depression Scale-Short Form (SGDS-K) was the primary outcome, while social network, functional status, and global cognitive function were secondary outcomes. Linear mixed models including the factors of intervention group, time, and their interaction were used to examine group differences in changes in primary and secondary outcomes from baseline to follow up., Results: Overall, there was no significant group × time interaction with respect to the SGDS-K score, but older individuals with more depressive symptoms at baseline (SGDS-K ≥ 6) tended to have a lower likelihood of progressing to severe depression at post-intervention. The social network was strengthened in the intervention group, and there was a significant group × time interaction (F[df1, df2], 5.29 [1, 153], p = 0.023)., Conclusion: This study examined a 12-week village-based intervention for late-life depression in which the CMHS helped village-dwellers deal with late-life depression in their communities. Although the intervention improved social interactions among older adults, it did not reduce depressive symptoms. Further studies including more rural villages and long-term follow up are needed to confirm the effectiveness of this prevention program., Trial Registration: NCT04013165 (date: 9 July 2019, retrospectively registered).

Expandable graphite (EG) and few-layer graphene (FLG) have proven to be instrumental materials for various applications. The production of EG and FLG has been limited to batch processes using numerous intercalating agents, especially organic acids. In this study, a Taylor-Couette reactor (TCR) setup is used to expand and exfoliate natural graphite and produce a mixture of EG and FLG in aqueous solutions using an amphiphilic dispersant and a semiflexible stabilizer. Laminar Couette flow structure and high shear rates are achieved via the rotation of the outer cylinder while the inner cylinder is still, which circumvents vortex formation because of the suppression of centrifugal forces. Our results reveal that the level of expansion and exfoliation using an aqueous solution and a TCR is comparable to that using commercial EG (CEG) synthesized by intercalating sulfuric acid. More importantly, the resultant EG and FLG flakes are more structurally homogeneous than CEG, the ratio of FLG to EG increases with increasing shearing time, and the produced FLG sheets exhibit large lateral dimensions (>10 μm). The aqueous solutions of EG and FLG are wet-spun to produce ultralight fibers with a bulk density of 0.35 g/cm 3 . These graphene fibers exhibit a mechanical strength of 0.5 GPa without any modification or thermal treatment, which offers great potential in light-weight composite applications.

Two series of thermotropic liquid crystal copolymers (TLCPs) with different monomer structures and compositions were synthesized. The copolymers in the first series consisted of 2,5-diethoxyterephthalic acid (ETA), hydroquinone (HQ), and p -hydroxybenzoic acid (HBA), whereas those in the second series contained ETA, 2,7-dihydroxynaphthalene (DHN), and HBA. In both series, the molar ratio of HBA to the other monomers varied from 0 to 5. The thermal properties, degree of crystallinity, and stability of the liquid crystalline mesophase of the copolymers obtained at each HBA ratio were evaluated and compared. Overall, at each HBA content, the DHN-containing copolymer had better thermal properties, but the HQ-containing copolymer exhibited a higher degree of crystallinity and a more stable liquid crystalline mesophase. Furthermore, similar thermal stabilities were observed in both series. The dependence of the molecular dynamics of the TLCPs on the monomer structure was explained using 13 C magic-angle spinning/cross-polarization nuclear magnetic resonance spectroscopy. An in-depth investigation of the relaxation time of each carbon revealed that the molecular motions of the TLCPs were greatly influenced by the structures of the monomers present in the main chain. The molecular dynamics of the HQ and DHN monomers in the two series were evaluated and compared.

The thermal and structural properties and molecular dynamics of layered perovskite-type (C 2 H 5 NH 3 ) 2 ZnCl 4 are investigated by differential scanning calorimetry, thermogravimetric analysis, and magic angle spinning nuclear magnetic resonance spectroscopy. The thermal properties and phase transitions are studied. Additionally, the Bloembergen-Purcell-Pound (BPP) curves for the 1 H spin-lattice relaxation time T 1ρ in the C 2 H 5 NH 3 cation and for the 13 C T 1ρ in C 2 H 5 are shown to have minima as a function of inverse temperature. This observation implies that these curves represent the rotational motions of 1 H and 13 C in the C 2 H 5 NH 3 cation. The activation energies for 1 H and 13 C in the C 2 H 5 NH 3 cation are obtained; the molecular motion of 1 H is enhanced at the C-end and N-end of the organic cation, and that at the carbons of the main chain is not as free as that for protons at the C-end and N-end., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N 6 -methyladenosine (m 6 A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m 6 A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m 6 A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m 6 A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m 6 A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m 6 A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

The thermal properties of organic-inorganic (CH 3 NH 3 ) 2 CoBr 4 crystals were investigated using differential scanning calorimetry and thermogravimetric analysis. The phase transition and partial decomposition temperatures were observed at 460 K and 572 K. Nuclear magnetic resonance (NMR) chemical shifts depend on the local field at the site of the resonating nucleus. In addition, temperature-dependent spin-lattice relaxation times (T 1ρ ) were measured using 1 H and 13 C magic angle spinning NMR to elucidate the paramagnetic interactions of the (CH 3 NH 3 ) + cations. The shortening of 1 H and 13 C T 1ρ of the (CH 3 NH 3 ) 2 CoBr 4 crystals are due to the paramagnetic Co 2+ effect. Moreover, the physical properties of (CH 3 NH 3 ) 2 CoBr 4 with paramagnetic ions and those of (CH 3 NH 3 ) 2 CdBr 4 without paramagnetic ions are reported and compared.

Two series of thermotropic liquid-crystalline polymers (TLCPs) were synthesized by reacting various dialkoxy terephthalate units with hydroquinone (HQ) and 2,6-naphthalene diol (Naph). The dialkoxy terephthalate moieties used in this study include 2,5-diethoxyterephthalate, 2,5-dibutoxyterephthalate, and 2,5-dihexyloxy-terephthalate. All the TLCPs synthesized in this study formed nematic phases. The molecular motions according to the length of the dialkoxy side groups in the TLCPs were evaluated by 13 C cross-polarization/magic angle spinning nuclear magnetic resonance spectroscopy. The thermal properties and molecular dynamics of the TLCPs are found to be affected by the length of the dialkoxy side group and the aromatic diol unit in the main chain. Further, the thermal behaviors, liquid crystalline mesophases, and degree of crystallinity of the two series of TLCPs, i.e., HQ- and Naph-TLCPs, are compared.

Recently, studies on the steroidal hormone activity in the brain have attracted attention, and the influences of the varied glucosides and their artificial derivatives have been discussed; additionally, it has been suggested that glucosides are the synthetic precursors of glucuronide as a label molecule. However, glucosides are formed with 11α-hydroxyprogesterone (1), which is important as a blood pressure regulator, but anti-androgen activity remains unknown. Using UDP-glucosyltransferase, glucoside synthesis was successful in linking β-d-glucopyranose and β-d-laminaribiose to 11α oxygen of 1 at a high conversion ratio, and full assignment structure was analyzed for the two glucosides by high-resolution quadrupole-time flight electrospray ionization-mass spectrometry, 1D ( 1 H and 13 C) NMR and 2D (COSY, ROESY, HSQC-DEPT and HMQC) NMR. Furthermore, the bioactivity of 1 and two 11α-hydroxyprogesterone glucosides [11α-(β-d-glucopyranosyl)oxyprogesterone, 2, and 11α-(β-d-laminaribiosyl)oxyprogesterone, 3] was tested in vitro. On rotenone-induced PC12 cells, the two 11α-hydroxyprogesterone glucosides (2 and 3) showed superior neuroprotective effects and increased cellular ATP levels compared with those of 1., (Copyright © 2019. Published by Elsevier Inc.)

The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascular endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand factor and vascular cell adhesion molecule 1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in prevention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.

Upregulation of the PI3K pathway has been implicated in the initiation and progression of several types of cancer, including renal cell carcinoma (RCC). Although several targeted therapies have been developed for RCC, durable and complete responses are exceptional. Thus, advanced RCC remains a lethal disease, underscoring the need of robust biomarker-based strategies to treat RCC. We report a synthetic lethal interaction between inhibition of phosphatidylinositol 3-kinase beta (PI3Kβ) and loss of SETD2 methyltransferase. Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3Kβ-specific) and AZD8186 (PI3Kβ- and δ-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells. Inhibition of the p110 δ and α isoforms alone had modest (δ) and no (α) effect on ccRCC cell viability, growth, and migration. In vivo , treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth. Interestingly, inhibition of the downstream effector AKT (MK2206) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells. Our data show that specific inhibition of PI3Kβ causes synthetic lethality with SETD2 loss and suggest targeting of the AKT downstream effector pathway offers a rationale for further translational and clinical investigation of PI3Kβ-specific inhibitors in ccRCC., Competing Interests: CONFLICTS OF INTEREST The authors declare no direct conflict of interest with the contents of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

To understand the dynamics of the cation in layered perovskite-type (CH 3 CH 2 NH 3 ) 2 CuCl 4 , the temperature-dependent chemical shifts and spin-lattice relaxation times T 1ρ in the rotating frame have been measured using 1 H magic angle spinning nuclear magnetic resonance (MAS NMR) and 13 C cross-polarization (CP)/MAS NMR techniques. Each proton and carbon in the (CH 3 CH 2 NH 3 ) + cation is distinguished in MAS NMR spectra. The Bloembergen-Purcell-Pound (BPP) curves for 1 H T 1ρ in CH 3 CH 2 and NH 3 , and for the 13 C T 1ρ in CH 3 and CH 2 are revealed to have minima at low temperatures. This implies that the curves represent the CH 3 and NH 3 + rotational motions. The amplitude of the cationic motion is enhanced at the C-end, that is, the N-end of the organic cation is fixed to the inorganic layer through N-H⋯Cl hydrogen bonds, and T 1ρ becomes short with larger-amplitude molecular motions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This study focused on how the local structures in pure [N(CH 3 ) 4 ] 2 ZnBr 4 crystal are affected by the partial replacement of Zn 2+ ions with Cu 2+ ions. The structures and phase transition temperatures T C of perovskite-type [N(CH 3 ) 4 ] 2 Zn 1-x Cu x Br 4 (x = 0, 0.5, 0.7, and 1) mixed crystals were almost unchanged by the partial doping of Cu 2+ ions. The environments for the local structures of [N(CH 3 ) 4 ] 2 Zn 1-x Cu x Br 4 mixed systems were studied according to differences in the chemical shifts of the 1 H magic angle spinning (MAS) NMR, 13 C cross-polarization (CP)/MAS NMR, and 14 N NMR spectra. The 1 H and 13 C NMR results showed that the local environments of 1 H and 13 C nuclei near T C are not affected by substituting Zn 2+ ions with Cu 2+ ions, whereas the 14 N NMR results showed that the local environment is affected near T C . Consequently, the main indicators of the phase transition in [N(CH 3 ) 4 ] 2 Zn 1-x Cu x Br 4 are related to the ferroelastic characteristics with different orientations.

Glucosylation of the 21-hydroxyl group of glucocorticoid changes its solubility into hydrophilicity from hydrophobicity and, as with glucocorticoid glucuronides as a moving object in vivo, it is conceivable that it exhibits the same behavior. Therefore, glucosylation to the 21-hydroxyl group while maintaining the 11 β -hydroxyl group is particularly important, and glucosylation of corticosterone was confirmed by high-resolution mass spectrometry and 1D (¹H and 13 C) and 2D (COSY, ROESY, HSQC-DEPT and HMBC) NMR. Moreover, the difference in bioactivity between corticosterone and corticosterone 21-glucoside was investigated in vitro. Corticosterone 21-glucoside showed greater neuroprotective effects against H₂O₂-induced cell death and reactive oxygen species (ROS) compared with corticosterone. These results for the first time demonstrate that bioconversion of corticosterone through the region-selective glucosylation of a novel compound can present structural potential for developing new neuroprotective agents.

The ionic dynamics of (CH 3 NH 3 ) 2 MCl 4 (M = Cu, Zn) by 1 H magic-angle spinning (MAS) nuclear magnetic resonance (NMR), 13 C cross-polarization (CP) MAS NMR, and 14 N NMR are investigated as a function of temperature with a focus on the role of the CH 3 NH 3 + cation. The molecular motions in (CH 3 NH 3 ) 2 MCl 4 are also discussed based on the 1 H spin-lattice relaxation time in the rotating coordinate frame T 1ρ . From the 1 H T 1ρ results, the activation energies for the tumbling motion of 1 H for CH 3 and NH 3 were similar, and the uniaxial rotations occurred within a large temperature range. The molecular motions for 13 C and 14 N of the main chain in the CH 3 NH 3 + cation were rigid, whereas those for 1 H of the side chain in the CH 3 NH 3 + cation were very free at high temperatures. T 1ρ provides insight into the changes in the cation reorientation rates induced by heating at high temperatures., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The 1 H chemical shifts and the spin-lattice relaxation time, T 1ρ , in the rotating frame of (NH 4 ) 2 ZnX 4 (X = Cl, Br) are observed in order to investigate local phenomena related to successive phase transitions. The temperature dependence of T 1ρ values for 1 H showed a minimum, and the T 1ρ values for 1 H appeared to be governed by tumbling molecular motions at high temperatures. In addition, 14 N NMR spectra are studied in each phase of (NH 4 ) 2 ZnX 4 single crystals in the laboratory frame. The phase transition temperatures strongly affect the 14 N number of symmetry related nitrogen centers within the unit cell. The 1 H MAS NMR and 14 N NMR results are discussed to elucidate the roles of NH 4 ions during the phase transitions of (NH 4 ) 2 ZnX 4 ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The structural changes and thermodynamic properties of (NH 4 ) 2 CuCl 4 ·2H 2 O were studied by differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis. In addition, the chemical shift, line width, and spin-lattice relaxation time of the crystals were also investigated by 1 H magic angle spinning nuclear magnetic resonance (MAS NMR), focusing on the role of NH 4 and H 2 O near the phase transition temperature. The change at T C2 (=406 K) and T C3 (=437 K) seems to be a chemical change caused by thermal decomposition rather than a physical change such as a structural phase transition. The changes in the temperature dependence of these data near T C2 are related to variations in the environments surrounding NH 4 and H 2 O. The 14 N NMR spectrum is also measured in order to investigate local phenomena related to the phase transition., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Assessment of healthy brain maturation can be useful toward better understanding natural patterns of brain growth and toward the characterization of a variety of neurodevelopmental disorders as deviations from normal growth trajectories. Structural magnetic resonance imaging (MRI) provides excellent soft-tissue contrast, which allows for the assessment of gray and white matter in the developing brain. We performed a large-scale retrospective analysis of 993 pediatric structural brain MRI examinations of healthy subjects (n = 988, aged 0-32 years) imaged clinically at 3 T, and extracted a wide variety of measurements such as white matter volumes, cortical thickness, and gyral curvature localized to subregions of the brain. All extracted structural biomarkers were tested for their correlation with subject age at time of imaging, providing measurements that may assist in the assessment of neurological maturation. Additional analyses were also performed to assess gender-based differences in the brain at a variety of developmental stages, and to assess hemispheric asymmetries. Results add to the literature by analyzing a realistic distribution of healthy participants imaged clinically, a useful cohort toward the investigation and creation of diagnostic tests for a variety of pathologies as aberrations from healthy growth trajectories. The next generation of diagnostic tests will be responsible for identifying pathological conditions from populations of healthy clinically imaged individuals. Hum Brain Mapp 38:5931-5942, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Fractional anisotropy (FA) threshold is commonly used to perform diffusion MRI tractography. However, FA threshold may be one aspect of tractography that needs additional scrutiny in accurately assessing pathways in immature, developing brains, as well as in adult brains. Using high-angular resolution diffusion MRI (HARDI) tractography without an FA threshold, we identified the arcuate fasciculus (AF) of 83 healthy subjects ranging in age from 40 gestational weeks (GW) (newborns) to 28-year-old adults. The AF was identified in both hemispheres in all subjects with high inter-rater reliability. The detected AF included regions with very low FA values. The entire AF was segmented into anterior, posterior, and long tracts. Growth and laterality patterns were investigated using tract count (number of detected streamlines), total volume of imaging voxels (touched by the detected streamlines), mean length, mean FA, and mean apparent diffusion coefficient (ADC). Comparison of subjects under 3 years old, to those that were older, revealed the three AF tracts that took different developmental courses. As expected, the anterior and long tracts showed lower ADC values in subjects over 3 years old, while the posterior tract showed higher ADC in that same age range. The posterior tract did not show age-related effect in terms of FA, tract count, length, and volume. These results suggest that the posterior AF tract shows a matured state, indexed by most of the used measurements in early postnatal developmental ages, and ADC is a measurement that can detect further maturation of the posterior tract. Interestingly, in all tracts, hemispheric asymmetries were found in raw (leftright) tract count, as well as in raw volume (left

Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis., (© 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Heat shock protein 90 is a chaperone molecule that aids in proper folding of target proteins. Recently, heat shock protein 90 was found to play a role in would healing through regulation of fibroblast functions. The aim of the present study was to investigate the role of heat shock protein 90 in collagen synthesis in human dermal fibroblasts. The effects of transforming growth factor-β, 17-N-allylamino-17-demethoxygeldanamycin, and transfection of heat shock protein 90 were evaluated by real-time PCR, western blot, and immunofluorescence assays. The Smad 2/3 and Akt pathways were evaluated to identify the signaling pathways involved in collagen synthesis. Heat shock protein 90 and collagen levels were compared in keloid and control tissues by immunohistochemical analysis. The expression of collagen was significantly increased after treatment with transforming growth factor-β, while 17-N-allylamino-17-demethoxygeldanamycin inhibited transforming growth factor-β-induced collagen synthesis. Overexpression of heat shock protein 90 itself with or without transforming growth factor-β increased collagen synthesis. These effects were dependent on Smad 2/3 pathway signaling. Finally, expression of heat shock protein 90 was increased in keloid tissue compared with control tissues. Taken together, these results demonstrate that modulation of heat shock protein 90 influences transforming growth factor-β-induced collagen synthesis via regulation of Smad 2/3 phosphorylation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Many neurologic and psychiatric disorders are thought to be due to, or result in, developmental errors in neuronal cerebellar connectivity. In this connectivity analysis, we studied the developmental time-course of cerebellar peduncle pathways in pediatric and young adult subjects., Methods: A cohort of 80 subjects, newborns to young adults, was studied on a 3T MR system with 30 diffusion-weighted measurements with high-angular resolution diffusion imaging (HARDI) tractography., Results: Qualitative and quantitative results were analyzed for age-based variation. In subjects of all ages, the superior cerebellar peduncle pathway (SCP) and two distinct subpathways of the middle cerebellar peduncle (MCP), as described in previous ex vivo studies, were identified in vivo with this technique: pathways between the rostral pons and inferior-lateral cerebellum (MCP cog ), associated predominantly with higher cognitive function, and pathways between the caudal pons and superior-medial cerebellum (MCP mot ), associated predominantly with motor function., Discussion: Our findings showed that the inferior cerebellar peduncle pathway (ICP), involved primarily in proprioception and balance appears to have a later onset followed by more rapid development than that exhibited in other tracts. We hope that this study may provide an initial point of reference for future studies of normal and pathologic development of cerebellar connectivity.

Major long-range white matter pathways (cingulum, fornix, uncinate fasciculus [UF], inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus [ILF], thalamocortical [TC], and corpus callosal [CC] pathways) were identified in eighty-three healthy humans ranging from newborn to adult ages. We tracked developmental changes using high-angular resolution diffusion MR tractography. Fractional anisotropy (FA), apparent diffusion coefficient, number, length, and volume were measured in pathways in each subject. Newborns had fewer, and more sparse, pathways than those of the older subjects. FA, number, length, and volume of pathways gradually increased with age and reached a plateau between 3 and 5 years of age. Data were further analyzed by normalizing with mean adult values as well as with each subject's whole brain values. Comparing subjects of 3 years old and under to those over 3 years old, the studied pathways showed differential growth patterns. The CC, bilateral cingulum, bilateral TC, and the left IFOF pathways showed significant growth both in volume and length, while the bilateral fornix, bilateral ILF and bilateral UF showed significant growth only in volume. The TC and CC took similar growth patterns with the whole brain. FA values of the cingulum and IFOF, and the length of ILF showed leftward asymmetry. The fornix, ILF and UF occupied decreased space compared to the whole brain during development with higher FA values, likely corresponding to extensive maturation of the pathways compared to the mean whole brain maturation. We believe that the outcome of this study will provide an important database for future reference., (Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.)

This study aimed to compare the effects of cabbage compression early breast care (CCEBC) and early breast care (EBC) on breast pain, breast hardness with general nursing breast care (GNBC) in primiparous women after cesarean birth. Sixty participants were divided to three groups including CCEBC, EBC and GNBC. Each group was treated with its intervention respectively more than 10 minutes before breast feeding from day two to day four after delivery. The primary outcomes were breast pain and breast hardness. Both CCEBC and EBC showed significantly lower pain level than GNBC at day 4 after delivery. There are significant differences of breast hardness among three groups. CCEBC group showed significantly lower breast hardness compared with EBC and GNBC. Neither core body temperature nor breast skin temperature was significantly different among the three groups. In conclusion, CCEBC may effective in relieving breast pain and breast hardness compared with EBC alone and GNBC in primiparous women after a cesarean birth.

Structure geometry changes in [N(CH3)4]2CuCl4 near the phase transition temperature were studied by (13)C CP/MAS NMR and (14)N NMR spectrum. We distinguished the two chemically inequivalent N(1)(CH3)4 and N(2)(CH3)4 groups by (13)C CP/MAS NMR and (14)N NMR spectrum. The abrupt changes in chemical shifts and the split of the NMR signals near the phase transition temperatures for (13)C and (14)N are explained by a structural phase transition, implying that the structural geometry depends on the temperature. The mechanism behind this phase transition is based on ferroelasticity, and is also mainly related to the (14)N ions in N(CH3)4 ions. Furthermore, both phases III and IV exhibit ferroelastic properties with identical orientational domains., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The structural nature underlying the nonlinear optical (NLO) properties of Li2B4O7 is characterized by nuclear magnetic resonance (NMR). The rotation patterns of (11)B NMR were measured. We observed sixteen different spectra which were divided into two groups, corresponding to two types of boron atoms, 4-coordinated B(1) and 3-coordinated B(2), which have different boron-oxygen rings and lie at chemically inequivalent sites. From these results, the quadrupole parameter and the principal axis of the electric field gradient (EFG) tensor were determined for the two borons., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To investigate the molecular dynamics of a Rb4LiH3(SO4)4 crystal below superionic phase transitions, we examined the temperature dependences of the NMR spectra and the spin-lattice relaxation time, T1, of the (1)H, (7)Li, and (87)Rb nuclei. The symmetry of (1)H signals resembles the Pake doublet containing a pair of dipolar-coupled protons. From the temperature dependence of T1, the activation energy of proton at high temperature is twice of those of (7)Li and (87)Rb. A striking feature was the formation of the weak hydrogen bond creating a significant influence of proton at high temperatures due to the mobility of the hydrogen-bond protons. And, we compared these data with (1)H and (7)Li results for (NH4)4LiH3(SO4)4 and K4LiH3(SO4)4 crystals, which have similar structures., (© 2013 Elsevier Inc. All rights reserved.)

Background: We previously reported that prior nasal administration of highly attenuated Bordetella pertussis BPZE1 provides effective and sustained protection against lethal challenge with influenza A viruses. The protective effect was mediated by suppressing the production of major pro-inflammatory mediators. To further explore the anti-inflammatory properties of BPZE1, we investigated the effect of BPZE1 nasal pretreatment on two mouse models of allergic disease, allergic airway inflammation, and contact hypersensitivity (CHS)., Methods: Allergic reactions were induced in mice nasally pretreated with live attenuated BPZE1 bacteria using the ovalbumin (OVA)-induced allergic airway inflammation and dinitrochlorobenzene (DNCB)-induced CHS models., Results: Prior BPZE1 nasal treatment suppressed OVA-induced lung inflammation and inflammatory cell recruitment and significantly reduced IgE levels and cytokine production. Similarly, BPZE1 nasal pretreatment markedly inhibited ear swelling, skin inflammation, and production of pro-inflammatory cytokines in the DNCB-induced CHS model. For both models, we showed that BPZE1 pretreatment does not affect the sensitization phase. Upon challenge, BPZE1 pretreatment selectively reduced the level of cytokines whose production is increased and did not affect the basal level of other cytokines. Together, our observations suggest that BPZE1 pretreatment specifically targets those cytokine-producing effector cells that are recruited and involved in the inflammatory reaction., Conclusion: Our study demonstrates the broad anti-inflammatory properties of the attenuated B. pertussis BPZE1 vaccine candidate and supports its development as a promising agent to prevent and/or treat allergic diseases., (© 2012 John Wiley & Sons A/S.)

Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is still unsatisfactory and innovative therapeutic approaches are urgently needed. Heat shock protein 90 (Hsp90) is overexpressed in a wide range of tumor types and is an emerging target for the treatment of cancer. However, the potential activity of Hsp90 inhibitors in GEP-NET has not yet been investigated. We studied the antineoplastic activity of the Hsp90 inhibitor IPI-504 on GEP‑NET cells, and characterized its mechanism of action. In human insulinoma (CM) and pancreatic carcinoid (BON) cells IPI-504 induced a dose-dependent growth inhibition by almost 70%. The antiproliferative effect of IPI-504 correlated with a reduction in protein levels of the IGF-1 receptor. Additionally, several proteins of the PI3K/AKT/mTOR pathway, downstream of IGF-1 receptor activation in GEP-NETs, were downregulated as a consequence of Hsp90 inhibition. Combination treatment of IPI-504 with mTOR- or AKT-inhibitors led to additive antiproliferative effects. In addition, effects of IGF-1 receptor tyrosine kinase inhibition were strongly enhanced by IPI-504. Cancer gene expression profiling and FACS analysis revealed that IPI-504 antiproliferative effects were due to both induction of cell cycle arrest and apoptosis. A modified chick chorioallantoic membrane (CAM) assay confirmed the antineoplastic activity of IPI-504 in GEP-NETs in vivo. In conclusion, this study showed that Hsp90 inhibition may be an attractive target for innovative GEP-NET treatment alone or in combination with either IGF-1R or mTOR inhibitors.

Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We find EML4-ALK to be more sensitive to Hsp90 inhibition than either HER2 or mutant epidermal growth factor receptor (EGFR) with an inhibitory concentration (IC)(50) for protein degradation in the low nanomolar range. This degradation leads to a potent inhibition of downstream signaling pathways and to the induction of growth arrest and apoptosis in cells carrying the EML4-ALK fusion. To generate a causative link between the expression of EML4-ALK and sensitivity to IPI-504, we introduced an EML4-ALK cDNA into HEK293 cells and show that the expression of the fusion protein sensitizes cells to IPI-504 both in vitro and in vivo. In a xenograft model of a human NSCLC cell line containing the ALK rearrangement, we observe tumor regression at clinically relevant doses of IPI-504. Finally, cells that have been selected for resistance to ALK kinase inhibitors retain their sensitivity to IPI-504. We have recently observed partial responses to administration of IPI-504 as a single agent in a phase 2 clinical trial in patients with NSCLC, specifically in patients that carry an ALK rearrangement. This study provides a molecular explanation for these clinical observations.

Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer.

LiRb(1-x)(NH₄)(x)SO₄ (x=0, 0.5, and 1) mixed crystals were grown using the slow evaporation method, and their lattice constants were determined by X-ray diffraction. The effects of replacing ammonium ions with rubidium on the phase transitions of and dynamics of LiRb(1-x)(NH₄)(x)SO₄ mixed crystals were studied. We investigated the structural properties and phase transition temperatures of the LiRb(1-x)(NH₄)(x)SO₄ mixed crystals by performing ¹H, ⁷Li, and ⁸⁷Rb NMR relaxation and DSC. When a fraction of rubidium ions in the pure LiRbSO₄ crystal is partially replaced by ammonium ions, we compare the structural properties for LiRbSO₄, LiRb₀.₅(NH₄)₀.₅SO₄, and LiNH₄SO₄ single crystals. The ¹H, ⁷Li, and ⁸⁷Rb NMR relaxation mechanisms of LiRb₀.₅(NH₄)₀.₅SO₄ are different from those of pure LiRbSO₄ and LiNH₄SO₄; the sequence of the structural phase transitions of LiRb₀.₅(NH₄)₀.₅SO₄ is different, which might be related to the dynamics and orientation of the sulfate tetrahedral groups in the crystal structure., (Copyright © 2011 Elsevier Inc. All rights reserved.)

IPI-504, a water-soluble ansamycin analogue currently being investigated in clinical trials, is a potent inhibitor of the protein chaperone heat shock protein 90 (Hsp90). Inhibition of Hsp90 by IPI-504 triggers the degradation of important oncogenic client proteins. In cells, the free base of IPI-504 hydroquinone exists in a dynamic redox equilibrium with its corresponding quinone (17-AAG); the hydroquinone form binding 50 times more tightly to Hsp90. It has been proposed recently that the NAD(P)H:quinone oxidoreductase NQO1 can produce the active hydroquinone and could be essential for the activity of IPI-504. Here, we have devised a method to directly measure the intracellular ratio of hydroquinone to quinone (HQ/Q) and have applied this measurement to correlate NQO1 enzyme abundance with HQ/Q ratio and cellular activity of IPI-504 in 30 cancer cell lines. Interestingly, the intracellular HQ/Q ratio was correlated with NQO1 levels only in a subset of cell lines and overall was poorly correlated with the growth inhibitory activity of IPI-504. Although artificial overexpression of NQO1 is able to increase the level of hydroquinone and cell sensitivity to IPI-504, it has little effect on the activity of 17-amino-17-demethoxy-geldanamycin, the major active metabolite of IPI-504. This finding could provide an explanation for the biological activity of IPI-504 in xenograft models of cell lines that are not sensitive to IPI-504 in vitro. Our results suggest that NQO1 activity is not a determinant of IPI-504 activity in vivo and, therefore, unlikely to become an important resistance mechanism to IPI-504 in the clinic.

Nuclear magnetic resonance (NMR) data and the spin-lattice relaxation times, T(1), of (69)Ga and (71)Ga nuclei in a beta-Ga(2)O(3):Cr(3+) single crystal were obtained using FT NMR spectrometry. Four sets of NMR spectra for (69)Ga (I=3/2) and (71)Ga (I=3/2) were obtained in the crystallographic planes. The (69)Ga and (71)Ga nuclei each had two chemically inequivalent Ga(I) and Ga(II) centers. Each of the (69)Ga and (71)Ga isotopes yielded two different central NMR resonance lines originating from Ga(I) and Ga(II) sites. The nuclear quadrupole coupling constants and asymmetry parameters of (69)Ga(I), (69)Ga(II), (71)Ga(I), and (71)Ga(II) centers in a beta-Ga(2)O(3):Cr(3+) crystal were obtained. Analysis of the EFG tensor principal axes (PAs) for Ga nuclei and the ZFS tensor PAs for the Cr(3+) ion confirmed that the Cr(3+) paramagnetic impurity ion substitutes for the Ga(3+) ion in the oxygen octahedron. In addition, the temperature dependencies of the (69)Ga and (71)Ga relaxation rates were consistent with Raman processes, as T(1)(-1) is proportional to T(2). Even though the Cr(3+) impurities are paramagnetic, the relaxations were dominated by electric quadrupole interactions of the nuclear spins in the temperature range investigated.