Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells, one of CAF origins, with ESCC cells. Periostin (POSTN) was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes, such as survival, growth, and migration, as well as increased phosphorylation of Akt and extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin ß4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.

A compound eye-like morphology formed through hexagonal array of hemispherical microparticles where an alkyl-fullerene derivative self-assembled at atmosphere-sealed air/water interface.

Self-assembly processes are widely used in nature to form hierarchically organized structures, prompting us to investigate such processes at the macroscopic scale. We report an unprecedented approach toward the self-assembly of alkyl-fullerene (C60) derivatives into a hexagonal array of hemispherical microparticles akin to the morphology of a compound eye. The method includes casting solvated alkyl-C60compound on an air/water interface followed by controlled evaporation of the solvent under atmosphere-sealed conditions. This leads to the formation of a thin film floating on water with a diameter of up to 1.3 centimeters and exhibiting a hexagonally-packed hemispherical structure with a diameter of approximately 38µm. Various measurements of the formed film reveal that amorphousness is necessary for suppressing uncontrollable crystallization, which affects the microparticle size and film formation mechanism. We tested the feasibility of this approach for the self-assembly of a relatively common C60derivative, [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM), resulting in the formation of a film with a similar pattern of hexagonally-packed larger microparticles approximately 152µm in size of diameter.

Pegfilgrastim for the management of neutropenia during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer patients.

BACKGROUND: Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy is a new standard for locally advanced esophageal squamous cell carcinoma. The optimal timing of pegfilgrastim with the DCF regimen to prevent febrile neutropenia (FN) remains controversial. The effectiveness of concomitant pegfilgrastim administration with continuous 5-fluorouracil (5-FU) infusion in the DCF regimen was therefore assessed. METHODS: All patients who received neoadjuvant DCF for esophageal cancer were retrospectively assessed. Patients who had been scheduled to receive pegfilgrastim on days 3-5 (early group) or days 7-9 (regular group) of the DCF regimen were included. Uni- and multivariate analyses were used to assess risk factors for FN. RESULTS: Eighty-eight patients were included in the analysis. The 26 patients in the early group received pegfilgrastim as scheduled. In the 62 patients of the regular group, 51 received pegfilgrastim at a median of 7 days after starting DCF chemotherapy. However, 11 patients in the regular group could not receive pegfilgrastim. Twenty-two patients of the regular group and 2 patients of the early group developed FN after the first session of DCF. Early administration of pegfilgrastim and grade 4 neutropenia were significantly associated with onset of FN, with multivariate analysis identifying early administration of pegfilgrastim as an independent preventive factor and grade 4 neutropenia as a risk factor, after adjusting for sex and age. CONCLUSION: Early pegfilgrastim administration is a safe approach that reduces the incidence of FN in DCF therapy. Using pegfilgrastim with continuous 5-FU infusion in the DCF regimen represents a reasonable option to prevent FN.

Alkyl-π Functional Molecular Gels: Control of Elastic Modulus and Improvement of Electret Performance.

The development of optoelectronically-active soft materials is drawing attention to the application of soft electronics. A room-temperature solvent-free liquid obtained by modifying a π-conjugated moiety with flexible yet bulky alkyl chains is a promising functional soft material. Tuning the elastic modulus (G') is essential for employing optoelectronically-active alkyl-π liquids in deformable devices. However, the range of G' achieved through the molecular design of alkyl-π liquids is limited. We report herein a method for controlling G' of alkyl-π liquids by gelation. Adding 1 wt % low-molecular-weight gelator formed the alkyl-π functional molecular gel (FMG) and increased G' of alkyl-π liquids by up to seven orders of magnitude while retaining the optical properties. Because alkyl-π FMGs have functional π-moieties in the gel medium, this new class of gels has a much higher content of π-moieties of up to 59 wt % compared to conventional π-gels of only a few wt %. More importantly, the gel state has a 23 % higher charge-retention capacity than the liquid, providing better performance in deformable mechanoelectric generator-electret devices. The strategy used in this study is a novel approach for developing next-generation optoelectronically-active FMG materials.

Thermo-/Mechano-Chromic Chiral Coordination Dimer: Formation of Switchable and Metastable Discrete Structure through Chiral Self-Sorting.

Although strong chiral self-sorting often emerges in extended covalent or supramolecular polymers, the phenomenon is generally weak in discrete assemblies (e.g., dimers and oligomers) of small molecules due to the lack of a cooperative growth mechanism. Consequently, chiral self-sorting has been overlooked in the design of switchable and metastable discrete supramolecular structures. Here, we report a butyl-benzo[h]quinoline-based iridium(III) complex (Bu-Ir) with helical chirality at its metal center, which forms preferentially a homochiral dimer and exhibits thermo-/mechano-chromism based on a monomer-dimer transformation. While a five-coordinate monomer is formed in a racemic or an enantiopure Bu-Ir solution at 25 °C, a six-coordinate homochiral dimer complex is formed almost exclusively at low temperatures, with a higher degree of dimerization in enantiopure Bu-Ir solution. Estimation of apparent dimerization binding constants (K) and thermodynamic parameters (ΔH and ΔS) based on variable temperature ultraviolet-visible (UV-vis) and 1H NMR spectra reveals a strong preference for homochiral dimerization (largest known value for the coordination complex, Khomo/Khetero > 50). Notably, crystals of the homochiral dimer are metastable, undergoing a distinct color change upon grinding (from yellow to red) due to mechanical cleavage of coordination bonds (i.e., a dimer to monomer transformation). A comparison with control compounds having different substituents (proton, methyl, isopropyl, and phenyl groups) reveals that Bu-Ir dimerization involves both strong homochiral self-sorting preference and connected thermo-/mechano-chromic behavior, which is based on matched propeller-shaped chirality and subtle steric repulsion between alkyl substituents that render the homochiral dimer switchable and metastable. These findings provide substantial insights into the emergence of dynamic functionality based on the rational design of discrete chiral assemblies.

Quest for a Rational Molecular Design of Alkyl-Distyrylbenzene Liquid by Substitution Pattern Modulation.

Alkyl-π functional molecular liquids (FMLs) are of interest for fabricating soft electronic devices due to their fluidic nature and innate optoelectronic functions from the π-conjugated moiety. However, predictable development of alkyl-π FMLs with the desired liquid and optoelectronic properties is challenging. A series of alkyl-distyrylbenzene (DSB) liquids was studied in terms of the substituent position effect by attaching 2-octyldodecyl chains at (2,4-), (2,5-), (2,6-), and (3,5-). The effect of the alkyl chain length was investigated by attaching 2-hexyldecyl, 2-decyltetradecyl (C10 C14 ), and 2-dodecylhexadecyl at the (2,5-) substituent position. The 2,5-C10 C14 substituent pattern constructed a superior alkyl-DSB liquid with a lower viscosity, intrinsic optical properties, and high thermal- and photo-stabilities. The discovered 2,5-C10 C14 was applied to dicyanostyrylbenzene and comparable liquid physical and optical superiorities were confirmed. This molecular design is useful for creating alkyl-π FMLs with the aforementioned advantages, which are applicable for deformable and flowable optoelectronic devices.

[Significance of Preoperative Adjuvant Therapy and Subsequent Selective Inguinal Lymph Node Dissection for Rectal or Anal Canal Adenocarcinoma with Inguinal Lymph Node Metastases].

Adenocarcinoma of the rectum and anal canal with inguinal lymph node metastasis(ILNM)is rare and the prognosis is generally poor. The aim of this study was to clarify the clinical significance of selective inguinal lymph node dissection and total mesorectal excision after preoperative therapy for adenocarcinoma of the rectum and anorectal canal with clinically suspected ILNM. Of the 15 patients, 11 received preoperative chemoradiotherapy, 3 received chemotherapy, and 1 received chemotherapy after chemoradiotherapy. 14 patients received preoperative therapy followed by FDG-PET scans were performed in 14 patients after preoperative treatment. 5 patients had negative FDG accumulation in inguinal lymph nodes on FDG-PET scans, and postoperative pathological diagnosis was also negative for metastasis in the inguinal lymph nodes. Of the 9 patients with positive FDG accumulation, 4 had pathologically positive inguinal lymph nodes, 7 had postoperative inguinal seroma, the 5-year survival rate was 77.5%, and the 5-year recurrence-free survival rate was 64.2%. No patient had a recurrence in the inguinal region. Patients with adenocarcinoma of the rectum and anal canal with clinical ILNM had good long-term survival after radical resection with preoperative therapy.

Self-Assembled and Nonassembled Alkylated-Fullerene Materials.

Fullerene (C60), a π-conjugated cage molecule consisting of 60 sp2-hybridized carbon atoms that are arranged into perfect icosahedral symmetry, is one of the most extensively studied nanocarbon materials by virtue of its characteristic spherical structure, fascinating optoelectronic properties, and widespread applications in material science. To implement practical applications, C60 is generally used as a building motif to assemble into various ordered superstructures. Unlike the controllable face-to-face π-π interactions of planar π-conjugated molecules, the π-π interactions between the three-dimensional spherical C60 units are random and directionless, which generally lead to complicated aggregated structures and unpredictable properties. The primary target of our research is to produce a robust design strategy for functional C60 materials, by which the single C60 molecules can be engineered into desirable self-organized architectures with optimized functions. To this end, we focused on alkylated fullerene (alk-C60) derivatives, a simple molecular system whose two components, alkyl chains and C60, exhibit both hydrophobicity yet different affinities to organic solvents. As a result, the alk-C60 derivatives present an unusual "hydrophobic amphiphile" system. Through systematic tuning of the substitution pattern of a series of alkyl side chains (number, length, branching, and substitution position) and external experimental conditions, the factors influencing alk-C60 self-assembly behaviors were determined. In addition, the feasibility of forming hybrid coassemblies with alk-C60 and other nanocarbon materials was demonstrated. By taking full advantage of the hydrophobic nature and active optoelectronic properties of these self- or hybrid-assemblies, various superhydrophobic materials and/or optoelectronic devices were developed. However, supported only by weak noncovalent interactions, these ordered superstructures are intrinsically fragile under various external stimuli. To improve the structural stability and achieve consistent optoelectronic performance of these novel materials, we strengthened the ordered structures via metallization and plasticization. Both approaches gave rise to robust and endurable materials with functions inherited from the pristine assemblies but at the cost of their former softness and facile processability. Thereafter, we focused on amorphous materials in view of their consistent and predictable optoelectronic properties that are independent of their geometry and physical environment. Unexpectedly, the amorphous materials obtained were liquids at room temperature, whose excellent deformability might enable applications in flexible/wearable optoelectronic devices. However, the lack of sufficient molecular order impaired their optoelectronic performance. To address this, we devised a straightforward strategy toward the directed ordered self-assembly of the alk-C60 liquids by adding molecular cofactors (n-alkanes or C60) into the liquids. Using this strategy, the balance between intermolecular order and material softness can be readily adjusted to meet different application requirements. Through iterative refinements to our novel alk-C60 system, we have demonstrated its power in generating numerous self-assembled, hybrid-assembled, and nonassembled materials toward versatile applications. We believe such a comprehensive description of these alk-C60-based functional materials provides deep insights into these still-evolving materials, which will underpin more advanced applications in near future.

[Mastectomy Followed by Skin-Transplantation Restored QOL and Enabled Chemotherapy in Two Cases of Locally Advanced Breast Cancer with Uncontrollable Bleeding].

Here, we report 2 cases of locally advanced breast cancer with uncontrollable bleeding treated with mastectomy followed by skin transplantation. The operation restored the QOL and enabled chemotherapy in postoperative periods. Case 1: A woman in her 70s was brought by an ambulance because of heart failure symptoms. She had a huge breast tumor on her left chest wall that bled repeatedly, necessitating frequent blood transfusions. An operation was performed, and chemotherapy was provided until she died of brain metastasis 1 year and 8 months after surgery. Case 2: A woman in her 70s was urgently hospitalized with a lumbar vertebrae bone fracture. She had a huge breast tumor on her right chest wall that bled repeatedly. Blood examination revealed severe anemia. An operation was performed, and chemotherapy was introduced sequentially. She is alive with a good status 2 years and 1 month after surgery.

Comparison of Subjective and Objective Assessments of Neurosensory Function after Lingual Nerve Repair.

OBJECTIVE: Mandibular third molar extractions are important in oral maxillofacial surgery. Damage to the lingual nerves, although rare, is a possible complication. There are reports of postoperative recovery after lingual nerve repair, but few reports have compared subjective and objective assessments of neurosensory function. Therefore, this study aims to compare subjective and objective assessments of neurosensory function after lingual nerve repair. SUBJECTS AND METHODS: This retrospective cohort study comprised 52 patients with lingual nerve anesthesia after third molar extraction at the Department of Oral and Maxillofacial Surgery, Wakayama Medical University Hospital, Wakayama, Japan, between December 2008 and December 2015. We recorded pre- and postoperative (6 months and 12 months) neurosensory examinations. RESULTS: Patient's subjective assessments of neurosensory function suggested improvement between the preoperative period and 12 months postoperation, although this difference was not significant. Objective assessment based on examination and testing, on the other hand, showed a significant difference in improvement (p < 0.05). CONCLUSIONS: There was no evidence that improvement of subjective preoperative and postoperative assessments was significantly associated with improvement of objective neurosensory assessments after lingual nerve repair. Overall physical condition and background were thought to affect subjective evaluation. Subjective assessment is important in conjunction with objective evaluation because it may reveal dysesthesia that would otherwise be missed. In the future, we will examine those cases in whom subjective assessments showed no improvement although objective assessments showed improvement.

Viscoelastic Conjugated Polymer Fluids.

The introduction of optoelectronic functions into viscoelastic polymers can yield highly sophisticated soft materials for biomedical devices and autonomous robotics. However, viscoelasticity and excellent optoelectronic properties are difficult to achieve because the presence of a large number of π-conjugated moieties drastically stiffens a polymer. Here, we report a variation of additive-free viscoelastic conjugated polymers (VE-CPs) at room temperature by using an intact π-conjugated backbone and bulky, yet flexible, alkyl side chains as "internal plasticizers." Some of these polymers exhibit gel- and elastomer-like rheological behaviors without cross-linking or entanglement. Furthermore, binary blends of these VE-CPs exhibit a never-seen-before dynamic miscibility with self-restorable and mechanically induced fluorescence color changes.

Paintable Room-Temperature Phosphorescent Liquid Formulations of Alkylated Bromonaphthalimide.

Organic phosphors have been widely explored with an understanding that crystalline molecular ordering is a requisite for enhanced intersystem crossing. In this context, we explored the room-temperature phosphorescence features of a solvent-free organic liquid phosphor in air. While alkyl chain substitution varied the physical states of the bromonaphthalimides, the phosphorescence remained unaltered for the solvent-free liquid in air. As the first report, a solvent-free liquid of a long swallow-tailed bromonaphthalimide exhibits room-temperature phosphorescence in air. Doping of the phosphor with carbonyl guests resulted in enhanced phosphorescence, and hence a large-area paintable phosphorescent liquid composite with improved lifetime and quantum yield was developed.

Experimental and theoretical investigation of fluorescence solvatochromism of dialkoxyphenyl-pyrene molecules.

We investigated the fluorescence properties of dialkoxyphenyl-pyrene molecules experimentally as well as theoretically. Our experiments confirmed fluorescence solvatochromism in 2,5-dimethoxyphenyl-pyrene and, in contrast there was no significant solvent-effect on the emission properties of the isomers, 3,5- and 2,6-dimethoxyphenyl-pyrene. This clear difference in the solvent-dependence would reflect the difference in character of the excited-state between the isomers, which differ only in the substitution positions of the two methoxy groups. The positional effects of the di-substituted molecules are successfully explained theoretically by the topologies of the highest occupied molecular orbital of the phenyl group that are governed by the relative positions of the two substituents, though it is somewhat contradictory to the meta-effect for the mono-substituted molecules. Theoretical calculations were also used to analyze the character of the excited states; 2,5-dimethoxyphenyl-pyrene alone exhibited an intramolecular charge transfer character for the excited state, which was responsible for the solvatochromism effect. The dynamics of the excited states were analyzed using time-resolved fluorescence measurements, in which a characteristic increase of the fluorescence intensity was observed for 2,5-dialkoxyphenyl-pyrene; this observation was supported by the theoretical calculations as well.

The aggregation of an alkyl-C60 derivative as a function of concentration, temperature and solvent type.

Contrast-variation small-angle neutron scattering (CV-SANS), small-angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR) measurements of diffusion and isothermal titration calorimetry (ITC) are used to gain insight into the aggregation of an alkyl-C60 derivative, molecule 1, in n-hexane, n-decane and toluene as a function of concentration and temperature. Results point to an associative mechanism of aggregation similar to other commonly associating molecules, including non-ionic surfactants or asphaltenes in non-aqueous solvents. Little aggregation is detected in toluene, but small micelle-like structures form in n-alkane solvents, which have a C60-rich core and alkyl-rich shell. The greatest aggregation extent is found in n-hexane, and at 0.1 M the micelles of 1 comprise around 6 molecules at 25 °C. These micelles become smaller when the concentration is lowered, or if the solvent is changed to n-decane. The solution structure is also affected by temperature, with a slightly larger aggregation extent at 10 °C than at 25 °C. At higher concentrations, for example in solutions of 1 above 0.3 M in n-decane, a bicontinuous network becomes apparent. Overall, these findings aid our understanding of the factors driving the assembly of alkyl-π-conjugated hydrophobic amphiphiles such as 1 in solution and thereby represent a step towards the ultimate goal of exploiting this phenomenon to form materials with well-defined order.

Rapid clinical improvement of amyloid A amyloidosis following treatment with tocilizumab despite persisting amyloid deposition: a case report.

BACKGROUND: Amyloid A amyloidosis is one of the most common forms of amyloidosis. It is secondary to rheumatoid arthritis, which is difficult to manage and has a poor prognosis. We present a patient with rheumatoid arthritis and amyloid A amyloidosis who was treated with tocilizumab, a humanized monoclonal antibody against interleukin 6 receptor, resulting in improvement in both proteinuria and gastrointestinal symptoms; however, amyloid deposition remained. CASE PRESENTATION: A 67-year-old woman who had previously been treated for rheumatoid arthritis presented with abdominal pain and diarrhea. Right renal cell carcinoma was found, and amyloid A amyloidosis was diagnosed concomitantly based on colon biopsy. The renal cell carcinoma was resected, and the non-cancerous part of the renal tissue also showed amyloid A deposition. Following surgery, protein levels in the urine increased to the nephrotic range, and administration of tocilizumab was initiated, which resulted in resolution of the proteinuria. The patient's gastrointestinal symptoms were also alleviated. However, repeat colon biopsy showed amyloid deposition. CONCLUSIONS: This case of amyloid A amyloidosis suggests that amyloid deposition indicates only structural change of the affected tissue, and that it is not amyloid deposition per se that causes the clinical symptoms of amyloidosis.

Effect of feeding tamarind kernel powder extract residue on digestibility, nitrogen availability and ruminal fermentation in wethers.

OBJECTIVE: This study was to examine in vivo digestibility, nitrogen balance and ruminal fermentation of tamarind (Tamarind indica) kernel powder extract residue (TKPER) compared to soybean products and by-products in wethers. METHODS: Four wethers with initial body weight (BW) of 51.6±5.5 kg were assigned in a 4×4 Latin square design to investigate nutritional characteristics of TKPER, dry heat soybean (SB), dry soybean curd residue (SBCR) and soybean meal (SBM) feeding with ryegrass straw (R) at a ratio of 1:1 at 2% of BW in dry matter (DM) on a daily basis. RESULTS: The digestibility of DM, crude protein, and ether extract (EE) of TKPER-R diet were 57.0%, 87.0%, and 86.0%, respectively. Higher non-fiber carbohydrates digestibility was observed in TKPER-R diet (83.2%) than in SB-R diet (73.9%, p<0.05). Wethers fed the TKPER-R diet had lower retention of nitrogen (N) and ruminal ammonia nitrogen (NH3-N) contents at 4 h after feeding than those fed the SBM-R diet (p<0.05), which had values similar to the SB-R or SBCR-R diet. The TKPER feeding had higher propionate (C3) and lower butyrate content, as well as lower acetate to propionate ratio (C2:C3) in rumen fluid than SBM feeding at 4 h after feeding (p<0.05). CONCLUSION: TKPER did not bring any side effect to the wethers although it was lack of fiber, and could be used as a high protein and energy ingredient in concentrate with appropriate roughage to meet the fiber requirement for ruminants.

Alkyl-π engineering in state control toward versatile optoelectronic soft materials.

Organic π-conjugated molecules with extremely rich and tailorable electronic and optical properties are frequently utilized for the fabrication of optoelectronic devices. To achieve high solubility for facile solution processing and desirable softness for flexible device fabrication, the rigid π units were in most cases attached by alkyl chains through chemical modification. Considerable numbers of alkylated-π molecular systems with versatile applications have been reported. However, a profound understanding of the molecular state control through proper alkyl chain substitution is still highly demanded because effective applications of these molecules are closely related to their physical states. To explore the underlying rule, we review a large number of alkylated-π molecules with emphasis on the interplay of van der Waals interactions (vdW) of the alkyl chains and π-π interactions of the π moieties. Based on our comprehensive investigations of the two interactions' impacts on the physical states of the molecules, a clear guidance for state control by alkyl-π engineering is proposed. Specifically, either with proper alkyl chain substitution or favorable additives, the vdW and π-π interactions can be adjusted, resulting in modulation of the physical states and optoelectronic properties of the molecules. We believe the strategy summarized here will significantly benefit the alkyl-π chemistry toward wide-spread applications in optoelectronic devices.

Optimization of mRNA design for protein expression in the crustacean Daphnia magna.

The water flea Daphnia is a new model organism for ecological, evolutionary, and toxicological genomics. Detailed functional analysis of genes newly discovered through genomic approaches often requires overexpression of the identified protein. In the present study, we report the microinjection of in vitro-synthesized RNAs into the eggs as a method for overexpressing ubiquitous proteins in Daphnia magna. We injected a 1.3-kb mRNA that coded for the red fluorescent protein (DsRed2) flanked by UTRs from the ubiquitously expressed elongation factor 1α-1 (EF1α-1) into D. magna embryos. DsRed2 fluorescence in the embryos was measured 24 h after microinjection. Unexpectedly, the reporter RNA containing the 522-bp full-length EF1α-1 3' UTR failed to induce fluorescence. To assess reporter expression, the length of the 3' UTR that potentially contained negative regulatory elements of protein expression, including AU-rich regions and Musashi binding elements, was serially reduced from the 3' end. Assessing all injected RNA alternatives, mRNA containing the first 60 bp of the 3' UTR gave rise to the highest fluorescence, 14 times the Daphnia auto-fluorescence. In contrast, mRNA lacking the entire 3' UTR hardly induced any change in fluorescence intensity. This is the first evaluation of UTRs of mRNAs delivered into Daphnia embryos by microinjection for overexpressing proteins. The mRNA with truncated 3' UTRs of Daphnia EF1α-1 will be useful not only for gain-of-function analyses but also for labeling proteins and organelles with fluorescent proteins in Daphnia.