An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping.

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes.

Fast QoT estimation method using cascaded artificial neural network for real-time path provisioning in IMDD based all-optical networks.

We propose a fast quality of transmission (QoT) estimation method based on cascaded artificial neural networks (ANNs) for intensity modulation-direct detection (IMDD) systems. The proposed method can calculate the bit error rate of three-span 36 km transmission within 0.7 seconds while taking account of the deterministic waveform distortion caused by the chromatic dispersion and self-phase modulation (SPM).

Analysis of Protein Folding Simulation with Moving Root Mean Square Deviation.

We apply moving root-mean-square deviation (mRMSD), which does not require a reference structure, as a method for analyzing protein dynamics. This method can be used to calculate the root-mean-square deviation (RMSD) of structure between two specified time points and to analyze protein dynamics behavior through time series analysis. We applied this method to the Trp-cage trajectory calculated by the Anton supercomputer and found that it shows regions of stable states as well as the conventional RMSD. In addition, we extracted a characteristic structure in which the side chains of Asp1 and Arg16 form hydrogen bonds near the most stable structure of the Trp-cage. We also determined that ≥20 ns is an appropriate time interval to investigate protein dynamics using mRMSD. Applying this method to NuG2 protein, we found that mRMSD can be used to detect regions of metastable states in addition to the stable state. This method can be applied to molecular dynamics simulations of proteins whose stable structures are unknown.

Simultaneous reception of AMCC signals and QPSK signals by a single coherent receiver with DSP.

This paper investigates an auxiliary management and control channel (AMCC) signal extraction method using digital signal processing (DSP) blocks with 3-step moving averaging that allows a single coherent receiver to receive main signal and AMCC signal simultaneously. Receiver sensitivity characteristics versus the modulation index (MI) and average number of the proposed DSP blocks are elucidated. Based on the results, we discuss a policy for designing the parameters. Experiments apply the design policy to achieve receiver sensitivity of -41.8 dBm with both 25 Gbit/s QPSK main signal and 128 kbit/s AMCC signal; the main signal sensitivity penalty is just 0.2 dB.

Skeletal Transformation Triggered by C-F Bond Activation after Photochemical Rearrangement of Fluorinated [7]Helicenes.

Tri- and tetra-fluorinated [7]helicenes are photolabile and undergo a double fluorine atom transfer. Herein, we show that the transferred product further undergoes a skeletal transformation on silica gel. The transformation begins with activation of the allylic C-F bond on the silanol surface. Then, the resulting carbocation readily undergoes a regioselective nucleophilic aromatic substitution with water, depending on the position of the fluorine substituents. Hexafluoro-2-propanol also activated the allylic C-F bond and acted as a nucleophile. These findings support the generation of a highly reactive cationic electrophilic intermediate in the successive transformations involving fluorine atoms.

Symmetric 10 Gbit/s 40-km reach DSP-based TDM-PON with a power budget over 50†dB.

This paper introduces the concept of a symmetric 10 Gbit/s high power-budget TDM-PON based on digital coherent technology and confirms its feasibility through a bidirectional transmission experiment with a transmission distance of 40 km and power budget of more than 50 dB. Burst-mode upstream 10 Gbit/s binary-phase-shift-keying (BPSK) signals synchronized by the clock recovered from downstream 10 Gbit/s NRZ signals are detected by using an optical pre-amplifier and coherent detection based on real-time burst-mode digital signal processing (DSP) in the optical line terminal (OLT). The real-time DSP implements coefficient handover in the adaptive equalizer to allow the reception of burst-mode upstream BPSK signals with short preamble length. An experimental bit error performance evaluation of the real-time burst-mode DSP yields the receiver sensitivity of -45.1 dBm for upstream burst-mode BPSK with a preamble length of 1.3 µs. For downstream signals, the receiver sensitivity of -38.9 dBm is achieved by using a chirp-controlled transmitter with optical post-amplifier so as to avoid the signal distortion created by the chromatic dispersion of single mode fiber (SMF) when the launched power is increased.

Catalytic alkylation reactions of weakly acidic carbonyl and related compounds using alkenes as electrophiles.

Catalytic alkylation reactions of weakly acidic carbonyl and related pronucleophiles such as amides, esters, and sulfonamides with substituted alkenes have been reported. In the presence of a strong Brønsted base catalyst system, potassium hexamethyldisilazide and 18-crown-6 ether, the desired reactions proceeded in high yields at ambient temperature with a wide substrate scope. These are atom-economical catalytic alkylation reactions of carbonyl and related compounds.

Optical Nyquist pulse generation by using a dual-electrode Mach-Zehnder modulator.

We demonstrate a simple and efficient optical Nyquist pulse generation by using a dual-electrode Mach-Zehnder modulator (MZM) driven by a combination of fundamental and second-harmonic RF signals. The method is based on a raised-cosine-shaped time filter and time lens created in the MZM under operation conditions given by a simple equation. Optical Nyquist pulses with a roll-off factor of 0.52 and intrinsic conversion efficiency of 37% are experimentally confirmed. Numerical analyses indicate that the roll-off factor can be moderately controlled down to ∼0.3 by increasing relative strength of fundamental RF signals.

An Exceptionally Narrow Band-Gap (∼4 eV) Silicate Predicted in the Cubic Perovskite Structure: BaSiO3.

The electronic structures of 35 A2+B4+O3 ternary cubic perovskite oxides, including their hypothetical chemical compositions, were calculated by a hybrid functional method with the expectation that peculiar electronic structures and unique carrier transport properties suitable for semiconductor applications would be hidden in high-symmetry cubic perovskite oxides. We found unique electronic structures of Si-based oxides (A = Mg, Ca, Sr, and Ba, and B = Si). In particular, the unreported cubic BaSiO3 has a very narrow band gap (4.1 eV) compared with conventional nontransition-metal silicates (e.g., ∼9 eV for SiO2 and the calculated value of 7.3 eV for orthorhombic BaSiO3) and a small electron effective mass (0.3m0, where m0 is the free electron rest mass). The narrow band gap is ascribed to the nonbonding state of Si 3s and the weakened Madelung potential. The existence of the predicted cubic perovskite structure of BaSiO3 was experimentally verified by applying a high pressure of 141 GPa. The present finding indicates that it could be possible to develop a new transparent oxide semiconductor of earth abundant silicates if the symmetry of its crystal structure is appropriately chosen. Cubic BaSiO3 is a candidate for high-performance oxide semiconductors if this phase can be stabilized at room temperature and ambient pressure.

Catalytic Direct-type 1,4-Addition Reactions of Alkylazaarenes.

1,4-addition reactions of alkylazaarenes catalyzed by strong Brønsted bases have been developed for the first time. The desired reactions with α,ß-unsaturated amides proceeded under mild reaction conditions to give the 1,4-adducts in high yields. Both ortho- and para-substituted azaarenes afforded the desired adducts in high yields. Regioselective reactions of di- or trimethylpyridine were found to be possible depending on the acidity of the α-hydrogen atoms. Furthermore, a candidate of allosteric protein kinase modulators was synthesized in two steps. An asymmetric variant of this reaction was also found to be feasible.

Guide Wire Selection (Straight vs. Angled) in Endoscopic Retrograde Cholangiopancreatography Using a Normal Contrast Catheter Performed by a Trainee: A Single-Center Prospective Randomized Controlled Cross-Over Study.

INTRODUCTION: Wire-guided cannulation (WGC) during endoscopic retrograde cholangiopancreatography (ERCP) is a selective biliary cannulation technique aimed at improving the successful selective biliary cannulation rate and reducing the rate of post-ERCP pancreatitis (PEP) incidence. This study aimed to evaluate the effectiveness of angled-tip guidewires (AGW) vs. straight-tip guidewires (SGW) for biliary cannulation via WGC by a trainee. METHODS: We conducted a prospective, single-center, open-labeled, randomized, and controlled trial. Fifty-seven patients were enrolled in this study and assigned randomly to two groups (Group A to S and Group S to A). In this study, we started selective biliary cannulation via WGC with an AGW or an SGW for 7 min. If cannulation was unsuccessful, the other guidewire was used, and cannulation was continued for another 7 min (cross-over method). RESULTS: The selective biliary cannulation success rate over 14 min was significantly higher with an AGW compared with an SGW over 14 min (57.8% vs. 34.3%, p = 0.04) and for the second 7-min segment (36.4% vs. 0%, p = 0.04). No significant difference was found for adverse events such as pancreatitis between the two guidewires. CONCLUSIONS: Our results suggest that an AGW is recommended for WGC performed by a trainee.

Pilot Study of Acupuncture's Antispasmodic Effect on Upper Gastrointestinal Tract during Endoscopic Submucosal Dissection for Early Gastric Cancer: Controlled Clinical Trial.

A prospective study was conducted in patients with early-stage gastric cancer to determine the efficacy and safety of acupuncture stimulation as an antispasmodic compared with conventional medication during the procedure of endoscopic submucosal dissection (ESD) of the upper gastrointestinal tract. This study was a prospective single blinded quasi-randomized controlled trial. Seventy-three patients who were scheduled to undergo ESD for gastric cancer at Aizu Medical Center between 19 February 2016 and 30 June 2016 were assessed for eligibility for the study. Sixty out of 73 patients were included in the study and assigned into two intervention groups: medication group (MG) and acupuncture group (AG). Ease of the procedure was evaluated using modified NIWA classification (MNC) by endoscopist considering the frequency and amplitude of the upper gastrointestinal peristalsis. For the statistical analysis, Mann-Whitney test was used to compare the differences of MNC values (baseline and end of procedure) between two groups. The difference of MNC found in the AG (-2.00 (-3.0 to -2.0)) was significantly greater than that in the MG (-1.00 (-2.0 to -1.0), p < 0.0001, Mann-Whitney test). We consider that acupuncture to the abdomen could be an alternative antispasmodic method during upper gastrointestinal endoscopic procedure.

Serum Endocrine Fibroblast Growth Factors as Potential Biomarkers for Chronic Kidney Disease and Various Metabolic Dysfunctions in Aged Patients.

Objective To prolong the health expectancy, it is important to prevent age-related diseases, such as osteoporosis and cerebrovascular disease, which are major causes of a bedridden state. Early predictable biomarkers for these diseases are urgently required in the clinical setting. Three members of the fibroblast growth factor (FGF) family - FGF19, FGF21, and FGF23 - are designated as endocrine FGFs and play crucial roles in various metabolic processes. We tried to clarify the clinical utility of endocrine FGFs as biomarkers for age-related diseases in elderly patients. Methods We examined the serum endocrine FGF levels and analyzed their association with various clinical parameters in 73 outpatients >60 years old as a single-center cross-sectional study. Results In a multivariable linear regression analysis, FGF19 was associated with ALT, a history of cardiovascular disease, and medication with active vitamin D3. FGF21 was associated with the estimated glomerular filtration rate (eGFR), triglyceride level, and hypertension. FGF23 was associated with the eGFR and the serum levels of 1,25-dihydroxy vitamin D3 and TRACP5b. In addition, a receiver operating characteristics analysis revealed that the measurement of FGF21 and FGF23 was useful for detecting chronic kidney disease (CKD) and its complications, including cardiovascular disease and metabolic bone disorder. Conclusion The measurement of FGF21 and FGF23 may be useful for evaluating CKD and its complications. Using serum endocrine FGFs as biomarkers for age-related conditions may help prevent elderly patients from entering a bedridden state.

MLS128 antibody-induced suppression of colon cancer cell growth is mediated by a desmocollin and a 110 kDa glycoprotein.

Protein glycosylation is a diverse form of post-translational modification. Two to three consecutive O-linked N-acetylgalactosamines (Tn-antigens) are recognized by antibodies such as MLS128. MLS128 mAb inhibited cell growth and bound to a 110 kDa glycoprotein (GP) in LS180 and HT29 colon cancer cells. However, purification and identification of the 110 kDa GP was unsuccessful due to its low abundance. The present study used a highly sophisticated and sensitive mass spectrometry method to identify proteins immunoprecipitated with MLS128 and separated by two-dimensional gel electrophoresis. Three desmosome components were identified. Of these, desmocollin and desmoglein shared many similar characteristics, including molecular mass, pI, and potential Tn-antigen sites. Western blotting analyses of LS180 cell lysates revealed a common 110 kDa band recognized by MLS128 and anti-desmocollin, but not by anti-desmoglein. Immunofluorescence microscopy of LS180 cells revealed that desmocollin is membrane-bound, while desmoglein is primarily localized in the cytosol. Confocal microscopy demonstrated colocalization of the desmocollin-specific antibody with the MLS128 antibody on the cell membrane, suggesting that desmocollin may contain Tn-antigens recognized by MLS128. Treatment of LS180 cells with siRNA to knock down desmocollin expression or a desmocollin-specific antibody decreased cell viability, suggesting a critical role for this protein in cell growth and survival. N-glycosidase F digestion of the 110 kDa GP and desmocollin suggested that although both proteins contain N-glycosylation sites, they are not identical. These findings suggest that desmocollin colocalizes with the 110 kDa GP and that growth inhibition induced by the MLS128 antibody may be mediated through a mechanism that involves desmocollin.

The Feasibility and Histological Diagnostic Accuracy of Novel Menghini Needle (EUS Sonopsy CY™) for Endoscopic Ultrasound-Guided Fine-Needle Aspiration Biopsy of Solid Pancreatic Masses: A Prospective Crossover Study Comparing Standard Biopsy Needles.

BACKGROUND AND OBJECTIVES: Recently, a 21G Menghini-type needle for EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been developed. The stylet of the EUS Sonopsy CY™ remains inside the needle during aspiration. Therefore, it is expected to obtain higher-quality histological core specimens without crushing the material or blood contamination. The aim of this study is to evaluate the feasibility and diagnostic accuracy of EUS-FNAB of solid pancreatic masses with this new biopsy needle. METHODS: A total of 30 patients with solid pancreatic masses who underwent EUS-FNAB with two different types of needles, EUS Sonopsy™ and ProCore™, were included in a prospective, randomized, controlled, crossover study. All the pancreatic masses were punctured with the two needles and were randomized regarding the order of the needle to be used. The primary outcome was to compare the diagnostic accuracy and the rates of tissue acquisition of the two needles. RESULTS: The tissue acquisition rate was not significantly different between the EUS Sonopsy CY™ needle and the ProCore™ needle (78.6% vs. 82.1%, P = 1.00). The histological diagnostic accuracy was also similar between the two needles (73% vs. 80%, P = .63). There was also no difference regarding the accuracy of cytology alone and the combination of both histological and cytological assessments between the EUS Sonopsy CY™ needle and the ProCore™ needle (90% vs. 87%, P = 1.00 and 90% vs. 90%, P = 1.00, respectively). CONCLUSIONS: EUS Sonopsy CY™ is a reliable device for EUS-FNAB of solid pancreatic masses.

New endoscopic ultrasonography criteria for malignant lymphadenopathy based on inter-rater agreement.

BACKGROUND AND AIMS: Various studies have been previously conducted on the diagnosis of lymphadenopathy as benign or malignant, but the results vary. These studies did not describe the inter-rater agreement on the EUS features of lymphadenopathy. In this study, we evaluate the inter-rater agreement on EUS features and propose EUS diagnostic norms for lymphadenopathy based on inter-rater agreement. METHOD: A total of 68 lymph nodes subjected to EUS-fine needle aspiration (FNA) were reviewed by five endoscopic experts. The EUS features evaluated lymph node size, shape, border, margin, echogenicity, homogeneity, and the hilum of the lymph node. Inter-rater agreement (multi-rater kappa statics) was performed. We established new criteria using results with a high degree of inter-rater agreement from EUS features and compared them with the former criteria. RESULT: There was a moderate agreement on shape, kappa (K) = 0.44 (95% confidence interval [CI]: 0.34-0.54), and fair agreement on echogenicity, homogeneity, border, and hilum of the lymph node, K (95% CI) = 0.33 (0.17-0.38), 0.34 (0.26-0.35), 0.22 (0.21-0.31), and 0.22 (0.11-0.26), respectively. This resulted in the establishment of new EUS diagnostic criteria using shape, long axis > 20 mm and short axis > 10 mm. New criteria were superior to old criteria (area under the curve 0.82 vs 0.52, P < 0.001). CONCLUSION: EUS diagnostic criteria for lymphadenopathy based on inter-rater agreement were more accurate than old criteria. This result will be useful for the diagnosis of lymphadenopathy.

Tensor renormalization group with randomized singular value decomposition.

An algorithm of the tensor renormalization group is proposed based on a randomized algorithm for singular value decomposition. Our algorithm is applicable to a broad range of two-dimensional classical models. In the case of a square lattice, its computational complexity and memory usage are proportional to the fifth and the third power of the bond dimension, respectively, whereas those of the conventional implementation are of the sixth and the fourth power. The oversampling parameter larger than the bond dimension is sufficient to reproduce the same result as full singular value decomposition even at the critical point of the two-dimensional Ising model.

Endoscopic Mucosal Resection Performed Underwater for Nonampullary Duodenal Epithelial Tumor: Evaluation of Feasibility and Safety.

OBJECTIVES: Recently, opportunities to encounter superficial nonampullary duodenal epithelial tumor (SNADET) have increased. EMR and ESD are performed to treat SNADET. However, the rate of perforation is higher than that of other gastrointestinal lesions, regardless of which method is used. Underwater EMR (UW-EMR) is immersion treatment of SNADET, which has low risk of perforation and can remove lesions safely and completely. In the present study, we retrospectively investigated patients in whom UW-EMR was performed to evaluate the feasibility and safety of UW-EMR for the treatment of SNADET. METHODS: The primary endpoint was to evaluate the feasibility of UW-EMR for the treatment of SNADET, and secondary objective was to determine the operation's safety. RESULTS: There were 14 participants, with a total of 16 lesions, who underwent UW-EMR between August 2015 and December 2017. Histological heteromorphism revealed that seven patients had low-grade adenoma, seven had high-grade adenoma, and two had adenocarcinoma. En bloc resection was performed in 14 lesions. In two patients, nodular lesions were observed in the scar and biopsy confirmed recurrences. There were no serious adverse events including bleeding or perforation. CONCLUSIONS: UW-EMR may be a safe and effective treatment method for SNADET, if its therapeutic indication is adequately considered.

Significance of normal appearance on endoscopic ultrasonography in the diagnosis of early chronic pancreatitis.

BACKGROUND AND OBJECTIVES: The Rosemont classification (RC) was developed as a consensus-based standard for the diagnosis of chronic pancreatitis (CP) by endoscopic ultrasonography (EUS), however, it is more complicated than the conventional scoring system. We have noticed that in the early stages of CP, it is not unusual to observe pancreas with abnormal appearance coexisting with the areas of normal parenchyma. The aim of this study was to investigate the validity of a "normal" pancreas appearance and to evaluate the usefulness of modified diagnostic criteria in comparison to the traditional EUS criteria and the RC. PATIENTS AND METHODS: One hundred and seventy-seven patients who had undergone both EUS and endoscopic retrograde pancreatography (ERP) within 2 months were enrolled in the study, and patients with pancreatic cancer were excluded from the study. ERP findings were used as the gold standard for the diagnosis of CP. The EUS images obtained were classified according to both the RC and our new modified criteria. The latter includes an additional criterion to the modified traditional criteria: fine-reticular pattern (F-RP) was defined as a normal pancreatic parenchyma. We compared the accuracy between the new modified EUS criteria and the RC. RESULTS: (1) Normal or equivocal findings on ERP were obtained for 132 patients; 113 patients had F-RP on EUS. In contrast, F-RP was found in only 6 out of 45 CP cases on ERP (P < 0.0001). (2) We investigated the diagnostic capability of our new criteria for endoscopic retrograde cholangiopancreatography normal/equivocal pancreas compared to the traditional criteria. In cases where fewer than two points were defined as normal, the incidence of normal pancreas was significantly higher based on the new criteria than on the traditional criteria (P = 0.002). (3) No significant differences were found between the new criteria and the RC across all ERP grades. CONCLUSION: Our new proposed "normal-added EUS criteria" for diagnosing CP was equivalent to the RC.