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A 75-year-old woman with colon cancer and distant metastases was treated with fluorouracil, levofolinate, and irinotecan (FOLFIRI) plus bevacizumab postoperatively. During the 32nd course, the patient developed massive proteinuria, and only bevacizumab was discontinued; the proteinuria improved rapidly over time. However, more than six months later, the patient developed massive proteinuria again, and her renal function declined. Renal biopsy revealed glomerular microangiopathy with prominent foam cell infiltration into the glomerulus, which was thought to be caused by chronic endothelial cell damage to the glomerular capillaries. Endothelial cell damage is thought to be caused not only by the inhibition of vascular endothelial growth factor action of bevacizumab in the glomerular capillary but also by the cytotoxicity of the concomitant anticancer drugs and coexisting clinical conditions such as dyslipidemia and hypertension. After discontinuing anticancer agents and intensifying diet and antihypertensive therapy, proteinuria and dyslipidemia slowly improved; however, it became difficult to continue adequate chemotherapy, and the tumor marker levels worsened. Combination therapies, including molecular targeted agents, have become common, and the side effects of anticancer agents are expected to continue to be complicated. To prevent the onset and severity of renal complications, management of blood pressure, lipid level, and glucose metabolism, as well as multidisciplinary medical management, including dietary therapy, is required., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Obara et al.)

Background: Acute cholangitis is a severe, life-threatening infection of the biliary system that requires early diagnosis and treatment. The Tokyo Guidelines recommend a combination of clinical, laboratory, and imaging findings for diagnosis and severity assessment, but there are still challenges in identifying severe cases that need immediate intervention. The microbiota and its derived products have been implicated in the pathogenesis of acute cholangitis. Corisin is a microbiome-derived peptide that induces cell apoptosis, acute tissue injury, and inflammation. This study aimed to evaluate the potential of plasma and bile corisin as a biomarker of acute cholangitis., Methods: Forty patients with acute cholangitis associated with choledocholithiasis or malignant disease were enrolled. Nine patients without acute cholangitis were used as controls. Corisin was measured by enzyme immunoassays in plasma and bile samples. Patients were classified into severe and non-severe groups. The associations of plasma and bile corisin with the clinical grade of acute cholangitis and other parameters were analyzed by univariate and multivariate regression analysis., Results: Plasma and bile corisin levels were significantly higher in patients with acute cholangitis than in controls. Patients with severe acute cholangitis had significantly higher plasma and bile corisin levels than those with non-severe form of the disease. Bile corisin level was significantly correlated with markers of inflammation, coagulation, fibrinolysis, and renal function. Univariate analysis revealed a significant association of bile corisin but a weak association of plasma corisin with the clinical grade of acute cholangitis. In contrast, multivariate analysis showed a significant relationship between plasma corisin level and the disease clinical grade. The receiver operating characteristic curve analysis showed low sensitivity but high specificity for plasma and bile corisin to detect the severity of acute cholangitis. The plasma and bile corisin sensitivity was increased when serum C-reactive protein level was included in the receiver operating characteristic curve analysis., Conclusions: Overall, these findings suggest that plasma and bile corisin levels may be useful biomarkers for diagnosing and monitoring acute cholangitis and that corisin may play a role in the pathophysiology of the disease by modulating inflammatory, coagulation and renal pathways., (© 2023. The Author(s).)

Block copolymers (P m M n ; P 20 M 101 and P 100 M 98 ) comprising poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC, P) containing biocompatible phosphorylcholin pendants and cationic poly((3-acryloylaminopropyl) trimethylammonium chloride) (PMAPTAC, M) were synthesized via a controlled radical polymerization method. The degrees of polymerization of the PMPC and PMAPTAC segments are denoted by subscripts (P m M n ). The mixture of cationic P m M n and anionic sodium chondroitin sulfate C (CS) with the pendant anionic carboxylate and sulfonate groups formed polyion complex (PIC) aggregates in phosphate-buffered saline. A charge-neutralized mixture of P 20 M 101 with CS formed P 20 M 101 /CS PIC vesicles with a hydrodynamic radius ( R h ) of 97.2 nm, zeta potential of ca. 0 mV, and aggregation number ( N agg ) of 23,044. PMPC shells covered the surface of the PIC vesicles. The mixture of P 100 M 98 and CS formed PIC spherical micelles with the PIC core and hydrophilic PMPC shells. The R h , zeta potential, and N agg of the PIC micelles were 26.4 nm, ca. 0 mV, and 404, respectively. At pH < 4, the carboxylate anions in CS were protonated. Thus, the charge balance in the PIC micelles shifted to decrease the core density owing to the electrostatic repulsions of the excess cations in the core. The PIC micelles dissociated at a NaCl concentration ≥0.6 M owing to the charge screening effect. The positively charged PIC micelles with excess P 100 M 98 can encapsulate anionic dyes owing to electrostatic interaction.

Background: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer., Methods: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates., Results: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher's exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1., Conclusions: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The prognosis of locally advanced colon cancer (LACC) with surgical resection followed only by adjuvant chemotherapy is poor. Preoperative chemotherapy for LACC patients with risk factors such as cT4bN+ or cT3-4aN2-3 has attracted attention. Here, the authors describe the rationale and design of JCOG2006, a randomized phase II study comparing preoperative chemotherapy with mFOLFOX6 versus FOLFOXIRI for LACC. Their efficacy and safety are evaluated and a determination of which is the more promising treatment will be conducted in a subsequent phase III trial. A total of 86 patients will be accrued from 44 institutions over 2 years. The primary end point is the proportion of patients with a Tumor Regression Score of 0-2, and secondary end points include overall survival, response rate and adverse events. Clinical Trial Registration : jRCTs031210365 (https://jrct.niph.go.jp/).

Large-scale genomic sequencing of colorectal cancers has been reported mainly for Western populations. Differences by stage and ethnicity in the genomic landscape and their prognostic impact remain poorly understood. We investigated 534 Japanese stage III colorectal cancer samples from the Phase III trial, JCOG0910. Targeted-capture sequencing of 171 potentially colorectal cancer-associated genes was performed, and somatic single-nucleotide variants and insertion-deletions were determined. Hypermutated tumors were defined as tumors with MSIsensor score >7 and ultra-mutated tumors with POLE mutations. Genes with alterations associated with relapse-free survival were analyzed using multivariable Cox regression models. In all patients (184 right-sided, 350 left-sided), mutation frequencies were TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%; 14.1% right-sided, 1.4% left-sided). Modest associations were observed: poorer relapse-free survival was seen with mutant KRAS (hazard ratio 1.66; p = 0.011) and mutant RNF43 (2.17; p = 0.055), whereas better relapse-free survival was seen with mutant COL6A3 (0.35; p = 0.040) and mutant NOTCH3 (0.18; p = 0.093). Relapse-free survival tended to be better for hypermutated tumors (0.53; p = 0.229). In conclusion, the overall spectrum of mutations in our Japanese stage III colorectal cancer cohort was similar to that in Western populations, but the frequencies of mutation for TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations appeared to impact relapse-free survival, suggesting that tumor genomic profiling can support precision medicine for colorectal cancer., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA., Methods: Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m 2 on days 1 and 29) and S-1 (60 mg/m 2 /day at level 0 and 80 mg/m 2 /day at level 1 on days 1-14 and 29-42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively., Results: Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m 2 /day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1-73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred., Conclusions: Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA., Clinical Trial Information: jRCTs031180002., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Enantioselectivity of helical aggregation is conventionally directed either by its homochiral ingredients or by introduction of chiral catalysis. The fundamental question, then, is whether helical aggregation that consists only of achiral components can obtain enantioselectivity in the absence of chiral catalysis. Here, by exploiting enantiospecific interaction due to chiral-induced spin selectivity (CISS) that has been known to work to enantio-separate a racemic mixture of chiral molecules, we demonstrate the enantioselectivity in the assembly of mesoscale helical supramolecules consisting of achiral cobalt phthalocyanines. The helical nature in our supramolecules is revealed to be mesoscopically incorporated by dislocation-induced discretized twists, unlike the case of chiral molecules whose chirality are determined microscopically by chemical bond. The relevance of CISS effect in the discretized helical supramolecules is further confirmed by the appearance of spin-polarized current through the system. These observations mean that the application of CISS-based enantioselectivity is no longer limited to systems with microscopic chirality but is expanded to the one with mesoscopic chirality., (© 2023. The Author(s).)

Chemotherapy plus antiangiogenic agents, including bevacizumab, ramucirumab and aflibercept, is a standard second-line treatment for patients with metastatic colorectal cancer, but which specific agents should be selected is ambiguous due to a lack of clear evidence from prospective studies. Previous reports have suggested ramucirumab and aflibercept could be more effective than bevacizumab in patients with high VEGF-D and high VEGF-A, respectively. JCOG2004 is a three-arm, randomized, phase II study to identify predictive biomarkers for these agents in patients who have failed first-line treatment. The study will enroll 345 patients from 52 institutions for 2 years, with progression-free survival in high VEGF-D (bevacizumab vs ramucirumab) and high VEGF-A (bevacizumab vs aflibercept) serving as the primary end point. Clinical Trial Registration: jRCTs031220058 (www.jrct.niph.go.jp).

Background: Essential tremor (ET) is a common involuntary movement disorder (IMD). Radiofrequency ablation (RFA) targeting the ventral intermediate nucleus (Vim) of the thalamus is a stereotactic neurosurgery performed in individuals with ET when pharmacotherapy is no longer effective. Though the reasons remain largely unclear, certain adverse events are known to appear post-RFA. These may be due to functional changes in the Vim, related to RFA-induced tremor reduction, or an adverse reaction to compensatory movement patterns used to perform movements in the presence of tremor symptoms., Objective: This study aimed to understand the characteristics of post-RFA symptoms in individuals with ET., Methods: In a longitudinal case-control study, we compared post-RFA symptoms between individuals with ET who underwent Vim-targeted RFA and those with IMD who underwent non-Vim-targeted RFA. Symptoms were compared preoperatively and 1-week and 1-month postoperatively. Quantitative assessments included center-of-pressure (COP) parameters, grip strength, Mini-Mental State Examination, two verbal fluency tests, and three types of physical performance assessments (upper extremity ability, balance ability, and gait ability)., Results: Individuals with ET after RFA showed horizontal displacements of the COP to the treated side (the dominant side of the RFA target's hemisphere) at 1-week postoperatively compared to the preoperative period. The horizontal COP displacement was associated with balance dysfunction related to postural stability post-RFA. Other COP parameters did not significantly differ between the ET and IMD groups., Conclusion: COP displacement to the treated side may be due to a time lag in adjusting postural holding strategies to the long-standing lateral difference in tremor symptoms associated with tremor improvement after RFA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sato, Taira, Kitada, Ando, Hamaguchi, Konno, Kitabatake and Ishioka.)

Retrograde menstruation is a widely accepted cause of endometriosis. However, not all women who experience retrograde menstruation develop endometriosis, and the mechanisms underlying these observations are not yet understood. Here, we demonstrated a pathogenic role of Fusobacterium in the formation of ovarian endometriosis. In a cohort of women, 64% of patients with endometriosis but <10% of controls were found to have Fusobacterium infiltration in the endometrium. Immunohistochemical and biochemical analyses revealed that activated transforming growth factor-β (TGF-β) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)-positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. Fusobacterium inoculation in a syngeneic mouse model of endometriosis resulted in a marked increase in TAGLN-positive myofibroblasts and increased number and weight of endometriotic lesions. Furthermore, antibiotic treatment largely prevented establishment of endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model. Our data support a mechanism for the pathogenesis of endometriosis via Fusobacterium infection and suggest that eradication of this bacterium could be an approach to treat endometriosis.

Background/aim: Irinotecan and trifluridine/tipiracil (FTD/TPI) are fourth-line treatment options after third-line nivolumab for advanced gastric cancer (AGC). However, the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab remains unclear. This study aimed to evaluate the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab., Patients and Methods: We identified 137 AGC patients treated with nivolumab as third-line treatment in our institute between October 2017 and July 2021. Of these, we recruited 19 AGC patients who initiated irinotecan and 23 AGC patients who initiated FTD/TPI in the fourth-line setting until September 2021., Results: The median overall survival was 5.83 months for irinotecan and 6.31 months for FTD/TPI. Median time-to-treatment failure was 2.07 months for irinotecan and 1.64 months for FTD/TPI. While the frequency of all-grade diarrhea was higher in irinotecan (36% vs. 17%), grade ≥3 neutropenia tended to be higher in FTD/TPI (21% vs. 35%)., Conclusion: Irinotecan and FTD/TPI may be clinically useful as fourth-line treatments after nivolumab., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hydrogen bonding, bond polarity, and charges in protein molecules play critical roles in the stabilization of protein structures, as well as affecting their functions such as enzymatic catalysis, electron transfer, and ligand binding. These effects can potentially be measured in Coulomb potentials using cryogenic electron microscopy (cryo-EM). We here present charges and bond properties of hydrogen in a sub-1.2 Å resolution structure of a protein complex, apoferritin, by single-particle cryo-EM. A weighted difference map reveals positive densities for most hydrogen atoms in the core region of the complex, while negative densities around acidic amino-acid side chains are likely related to negative charges. The former positive densities identify the amino- and oxo-termini of asparagine and glutamine side chains. The latter observations were verified by spatial-resolution selection and a dose-dependent frame series. The average position of the hydrogen densities depends on the parent bonded-atom type, and this is validated by the estimated level of the standard uncertainties in the bond lengths., (© 2023. The Author(s).)

Trifluridine/tipiracil (FTD/TPI) is an oral anticancer agent used as a third- or later-line treatment for patients with metastatic gastric cancer/gastroesophageal junction cancer (mGC/GEJC). The C-reactive protein-to-serum albumin ratio (CAR) is an inflammation-based prognostic marker in gastric cancer. This retrospective study evaluated CAR's clinical significance as a prognostic factor in 64 patients with mGC/GEJC administered FTD/TPI as a third- or later-line therapy. Patients were categorized into high- and low-CAR groups based on pre-treatment blood data. This study evaluated associations between CAR and overall survival (OS), progression-free survival (PFS), clinicopathological features, treatment efficacy, and adverse events. The high-CAR group had significantly worse Eastern Cooperative Oncology Group performance status, a higher prevalence of patients administered with a single course of FTD/TPI, and a higher rate of patients not administered chemotherapy after FTD/TPI therapy than the low-CAR group. Median OS and PFS were significantly poorer in the high-CAR group than in the low-CAR group (113 vs. 399 days; p < 0.001 and 39 vs. 112 days; p < 0.001, respectively). In multivariate analysis, high CAR was an independent prognostic factor for OS and PFS. The overall response rate was not significantly different between the high- and low-CAR groups. Regarding adverse events, the high-CAR group had a significantly lower incidence of neutropenia and a higher incidence of fatigue than the low-CAR group. Therefore, CAR may be a potentially useful prognostic factor for patients with mGC/GEJC treated with FTD/TPI as third- or later-line chemotherapy.

Insect body colors and patterns change markedly during development in some species as they adapt to their surroundings. The contribution of melanin and sclerotin pigments, both of which are synthesized from dopamine, to cuticle tanning has been well studied. Nevertheless, little is known about how insects alter their body color patterns. To investigate this mechanism, the cricket Gryllus bimaculatus, whose body color patterns change during postembryonic development, was used as a model in this study. We focused on the ebony and tan genes, which encode enzymes that catalyze the synthesis and degradation, respectively, of the precursor of yellow sclerotin N-β-alanyl dopamine (NBAD). Expression of the G. bimaculatus (Gb) ebony and tan transcripts tended to be elevated just after hatching and the molting period. We found that dynamic alterations in the combined expression levels of Gb'ebony and Gb'tan correlated with the body color transition from the nymphal stages to the adult. The body color of Gb'ebony knockout mutants generated by CRISPR/Cas9 systemically darkened. Meanwhile, Gb'tan knockout mutants displayed a yellow color in certain areas and stages. The phenotypes of the Gb'ebony and Gb'tan mutants probably result from an over-production of melanin and yellow sclerotin NBAD, respectively. Overall, stage-specific body color patterns in the postembryonic stages of the cricket are governed by the combinatorial expression of Gb'ebony and Gb'tan. Our findings provide insights into the mechanism by which insects evolve adaptive body coloration at each developmental stage., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Inoue et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Parkinson's disease (PD) is pathologically characterized by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra and other brain regions, although the role of Lewy bodies remains elusive. Constipation usually precedes the motor symptoms in PD, which is in accordance with the notion that α-synuclein fibrils start from the intestinal neural plexus and ascend to the brain in at least half of PD patients. The gut microbiota is likely to be involved in intestinal and brain pathologies. Analyses of the gut microbiota in PD, rapid-eye-movement sleep behavior disorder, and dementia with Lewy bodies suggest three pathological pathways. First, Akkermansia, which is increased in PD, degrades the intestinal mucus layer and increases intestinal permeability, which triggers inflammation and oxidative stress in the intestinal neural plexus. Second, decreased short-chain fatty acids (SCFAs)-producing bacteria in PD reduce the number of regulatory T cells. Third, SCFAs also aggravate microglial activation with an unelucidated pathway. In addition, in dementia with Lewy bodies (DLB), which is another form of α-synucleinopathies, increased genera, Ruminococcus torques and Collinsella, may mitigate neuroinflammation in the substantia nigra by increasing secondary bile acids. Interventions for the gut microbiota and their metabolites may potentially delay or mitigate the development and progression of PD and other Lewy body diseases., (© 2023. The Author(s).)

Background/aims: Symptoms of irritable bowel syndrome (IBS), a common gut-brain interaction disorder, deteriorate patients' quality of life and increase medical needs; therefore, IBS represents a significant global burden. The estimated global prevalence is approximately 10%; however, accumulated evidence shows international heterogeneity. In this study, we have described and compared the prevalence of IBS in 3 East Asian countries: Japan (Tokyo and Fukuoka), China (Beijing), and South Korea (Seoul)., Methods: We conducted an internet-based cross-sectional survey of the urban population aged > 20 years in the abovementioned countries. We recruited equal numbers of age- (20s-60s) and sex-matched participants (3910 residents). IBS was diagnosed according to the Rome III criteria, and the subtypes were analyzed., Results: The overall prevalence of IBS with 95% CI was 12.6% (11.6-13.7); the prevalence was significantly different across Japan, China, and South Korea (14.9% [13.4-16.5], 5.5% [4.3-7.1], and 15.6% [13.3-18.3], respectively) ( P < 0.001). Furthermore, 54.9% of patients were male. IBS-mixed was the most prevalent subtype; the prevalence of other subtypes varied., Conclusions: The overall prevalence of IBS in the 3 countries was slightly higher than the global prevalence, and it was significantly lower in China than in Japan and South Korea. IBS prevalence was the highest and lowest among individuals in their 40s and 60s, respectively. Male individuals had a higher prevalence of IBS with diarrhea. Further studies are needed to elucidate the factors associated with this regional heterogeneity.

Background: Radiological features in patients with sporadic Creutzfeldt-Jakob disease (sCJD) are hyperintensity of the cerebral cortex and the basal ganglia displayed by diffusion-weighted magnetic resonance imaging (DW-MRI). We performed a quantitative study on neuropathological and radiological findings., Methods: Patient 1 received a definite diagnosis of MM1-type sCJD, while patient 2 received a definite diagnosis of MM1 + 2-type sCJD. Two DW-MRI scans were performed on each patient. DW-MRI was either taken the day before or on the day of the patient's death, and several hyperintense or isointense areas were marked as a region of interest (ROI). Mean signal intensity of the ROI was measured. Pathological quantitative assessments of the vacuoles, astrocytosis, infiltration of monocytes/macrophages, and proliferation of microglia was performed. Vacuole load (% area vacuole), glial fibrillary acidic protein (GFAP), CD68, and Iba-1 load were calculated. We defined spongiform change index (SCI) to indicate vacuoles related to a tissue neuron-astrocyte ratio. We assessed the correlation of intensity of the last DW-MRI and the pathological findings as well as association of changes of the signal intensity on the sequential images and the pathological findings., Result: We observed a strong positive correlation between SCI and DW-MRI intensity. In the analysis using serial DW-MRI and pathological findings, we found that CD68 load was significantly larger in areas where signal intensity decreased, as compared to those areas where hyperintensity remained unchanged., Conclusion: DW-MRI intensity in sCJD is associated with the ratio of neuron to astrocyte in the vacuoles and the infiltration of macrophages and/or monocytes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest directly relevant to the content of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

Stress granules (SGs) are dynamic, non-membranous structures composed of non-translating mRNAs and various proteins and play critical roles in cell survival under stressed conditions. Extensive proteomics analyses have been performed to identify proteins in SGs; however, the molecular functions of these components in SG formation remain unclear. In this report, we show that ubiquitin-associated protein 2-like (UBAP2L) is a crucial component of SGs. UBAP2L localized to SGs in response to various stresses, and its depletion significantly suppressed SG organization. Proteomics and RNA sequencing analyses found that UBAP2L formed a protein-RNA complex with Ras-GTP-activating protein SH3 domain binding protein 1 (G3BP1) and small nucleolar RNAs (snoRNAs). In vitro binding analysis demonstrated that snoRNAs were required for UBAP2L association with G3BP1. In addition, decreased expression of snoRNAs reduced the interaction between UBAP2L and G3BP1 and suppressed SG formation. Our results reveal a critical role of SG component, the UBAP2L/snoRNA/G3BP1 protein-RNA complex, and provide new insights into the regulation of SG assembly., (© 2023. The Author(s).)

Inclusion structures incorporating more than one guest molecule are elusive because confinement alters their molecular properties. We report the solid-state characterization of an inclusion complex comprising two γ-cyclodextrins and two [Cu(2-pyridinemethanolate)(2-pyridinemethanol)]PF 6 units. Quantum calculation reveals that interfragment charge transfer occurs. The confined Cu fragment and the unincluded "linear chain [Cu(2-pyridinemethanolate)(2-pyridinemethanol)]PF 6 " exhibit different properties.

Structure analysis of small crystals is important in areas ranging from synthetic organic chemistry to pharmaceutical and material sciences, as many compounds do not yield large crystals. Here we present the detailed characterization of the structure of an organic molecule, rhodamine-6G, determined at a resolution of 0.82 Å by an X-ray free-electron laser (XFEL). Direct comparison of this structure with that obtained by electron crystallography from the same sample batch of microcrystals shows that both methods can accurately distinguish the position of some of the hydrogen atoms, depending on the type of chemical bond in which they are involved. Variations in the distances measured by XFEL and electron diffraction reflect the expected differences in X-ray and electron scatterings. The reliability for atomic coordinates was found to be better with XFEL, but the electron beam showed a higher sensitivity to charges., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Although the importance of kinematic evaluation of the sit-to-stand (STS) test of total knee arthroplasty (TKA) patients is clear, there have been no reports analyzing STS during the 30-s chair sit-up test (30 s-CST) with a focus on kinematic characteristics. This study aimed to demonstrate the clinical utility of kinematic analysis of STS during the 30 s-CST by classifying STS into subgroups based on kinematic parameters, and to determine whether differences in movement strategies are expressed as differences in clinical outcomes., Methods: The subjects were all patients who underwent unilateral TKA due to osteoarthritis of the knee and were followed up for one year postoperatively. Forty-eight kinematic parameters were calculated using markerless motion capture by cutting STS in the 30 s-CST. The principal components of the kinematic parameters were extracted and grouped by kinematic characteristics based on the principal component scores. Clinical significance was examined by testing whether differences in patient-reported outcome measures (PROMs) were observed., Results: Five principal components were extracted from the 48 kinematic parameters of STS and classified into three subgroups (SGs) according to their kinematic characteristics. It was suggested that SG2, using a kinematic strategy similar to the momentum transfer strategy shown in previous studies, performed better in PROMs and, in particular, may be associated with achieving a "forgotten joint", which is considered the ultimate goal after TKA., Conclusions: Clinical outcomes differed according to kinematic strategies used STS, suggesting that kinematic analysis of STS in 30 s-CST may be useful in clinical practice., Trial Registration: This study was approved by the Medical Ethical Committee of the Tokyo Women's Medical University (approval number: 5628 on May 21, 2021)., (© 2023. The Author(s).)

Background/aim: Trifluridine/tipiracil (FTD/TPI) is an anticancer-agent that is administered as third-line or later chemotherapy for metastatic gastric/gastroesophageal junction cancer (mGC/GEJC). Although inflammatory and nutritional statuses have attracted attention as prognostic factors for patients with mGC/GEJC in this therapy, their usefulness has not been fully clarified. Thus, this study investigated the clinical significance of prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), and NLR/serum albumin (Alb) ratio in patients administered FTD/TPI., Patients and Methods: This retrospective study included 64 patients who underwent FTD/TPI treatment for mGC/GEJC at Kanagawa Cancer Center, Kanagawa, Japan, between October 2019 and June 2022. Patients were divided into high and low PNI, NLR, and NLR/Alb groups according to their pretreatment blood data. This study evaluated the associations between the inflammatory and nutritional indexes and survivals., Results: Overall survival (OS) and progression-free survival (PFS) of patients with low PNI were significantly poorer than those with high PNI. However, low PNI was not an independent prognostic factor for OS and PFS. There was no significant association between NLR and OS or PFS. In contrast, the OS of patients with high NLR/Alb was significantly poorer than those with high PNI and low NLR/Alb. Furthermore, multivariate analysis showed that high NLR/Alb was an independent prognostic factor for OS., Conclusion: The NLR/Alb may be a useful prognostic factor in patients with mGC/GEJC being administered FTD/TPI as third-line or later chemotherapy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Mycoplasma mobile is a fish pathogen that glides on solid surfaces by means of its own gliding machinery composed of internal and surface structures. In the present study, we focused on the function and structure of Gli123, a surface protein that is essential for the localization of other surface proteins. The amino acid sequence of Gli123, which is 1,128 amino acids long, contains lipoprotein-specific repeats. We isolated the native Gli123 protein from M. mobile cells and a recombinant protein, rGli123, from Escherichia coli. The isolated rGli123 complemented a nonbinding and nongliding mutant of M. mobile that lacked Gli123. Circular dichroism and rotary-shadowing electron microscopy (EM) showed that rGli123 has a structure that is not significantly different from that of the native protein. Rotary-shadowing EM suggested that Gli123 adopts two distinct globular and rod-like structures, depending on the ionic strength of the solution. Negative-staining EM coupled with single-particle analysis revealed that Gli123 forms a globular structure featuring a small protrusion with dimensions of approximately 15.7, 14.7, and 14.1 nm for the "height," major axis and minor axis, respectively. Small-angle X-ray scattering analyses indicated a rod-like structure composed of several tandem globular domains with total dimensions of approximately 34 nm in length and 6 nm in width. Both molecular structures were suggested to be dimers, based on the predicted molecular size and structure. Gli123 may have evolved by multiplication of repeating lipoprotein units and acquired a role for Gli521 and Gli349 assembly. IMPORTANCE Mycoplasmas are pathogenic bacteria that are widespread in animals. They are characterized by small cell and genome sizes but are equipped with unique abilities for infection, such as surface variation and gliding. Here, we focused on a surface-localizing protein named Gli123 that is essential for Mycoplasma mobile gliding. This study suggested that Gli123 undergoes drastic conformational changes between its rod-like and globular structures. These changes may be caused by a repetitive structure common in the surface proteins that is responsible for the modulation of the cell surface structure and related to the assembly process for the surface gliding machinery. An evolutionary process for surface proteins essential for this mycoplasma gliding was also suggested in the present study.

Alcohol use disorder (AUD) may be associated with increased attentional bias (AB) toward alcohol-related information. Accordingly, our aim was to explore the relationships between alcohol-related AB, cravings, and risk of relapse among individuals with AUD after treatment. The study group included 24 in-patients with AUD who had completed alcohol withdrawal management. AB was evaluated using an image-based task, with participants asked to select the nonalcoholic image as fast and as accurately as possible and the response time (RT) measured. The intensity of the desire to drink was evaluated using a 100-mm Visual Analog Scale and the risk of relapse using the Alcohol Relapse Risk Scale. Linear regression was used to evaluate the relationship between these variables, with age, gender, duration of hospitalization, and depression score used as covariates. Intensity of cravings was significantly associated with AB RT (R2 =.625) and risk of relapse of drinking behavior (Alcohol Relapse Risk Scale score, R2 =.64). Gender and γ-GTP were significant explanatory variables of identified relationships. The main limitations of our study are a higher proportion of men than women in our study group and the absence of a control group for baseline comparison of AB RTs. This study results suggested that the desire to drink is related to AB among patients with AUD and that the intensity of the desire to drink is related to the risk of a relapse in drinking behavior after AUD treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

In this study, we constructed a semiartificial protein assembly of alternating ring type, which was modified from the natural assembly state via incorporation of a synthetic component at the protein interface. For the redesign of a natural protein assembly, a scrap-and-build approach employing chemical modification was used. Two different protein dimer units were designed based on peroxiredoxin from Thermococcus kodakaraensis , which originally forms a dodecameric hexagonal ring with six homodimers. The two dimeric mutants were reorganized into a ring by reconstructing the protein-protein interactions via synthetic naphthalene moieties introduced by chemical modification. Cryo-electron microscopy revealed the formation of a uniquely shaped dodecameric hexagonal protein ring with broken symmetry, distorted from the regular hexagon of the wild-type protein. The artificially installed naphthalene moieties were arranged at the interfaces of dimer units, forming two distinct protein-protein interactions, one of which is highly unnatural. This study deciphered the potential of the chemical modification technique that constructs semiartificial protein structures and assembly hardly accessible by conventional amino acid mutations.

Background: The acoustic noise in magnetic resonance imaging (MRI) potentially depends on the measurement position and presence of a patient inside the scanner bore., Purpose: To analyze the spatial characteristics of the acoustic noise by using the gradient-pulse-to-acoustic-noise transfer function (GPAN-TF) with and without a human-body phantom on the examination table., Material and Methods: Acoustic noise waveforms were acquired at 80 and 110 measurement positions with and without a phantom. The GPAN-TFs µPa/(mT/m) in the coils were calculated by deconvolution. The phantom effect on the spatial distribution of the acoustic noise was assessed using the peak sound pressure levels (SPLs), mean values, peak values, and peak frequencies of the GPAN-TFs., Results: The peak SPLs in all positions for the X-, Y-, and Z-gradient coils were increased by 11.1 dB, 1.4 dB, and 6.1 dB, respectively, compared with the peak SPL of the magnetic isocenter. The maximum peak SPLs among all positions of the X-, Y-, and Z-gradient coils with the phantom were increased by 4.9 dB, 7.4 dB, and 6.9 dB, respectively, relative to those without the phantom. However, the peak SPLs decreased at some positions with the phantom placed on the table (X-gradient coil = 4.6 dB, Y-gradient coil = 5.0 dB, Z-gradient coil = 8.4 dB). The most common peak frequencies were in the range of 2000-3000 Hz., Conclusion: "Hotspot" areas with and without the phantom were associated with acoustic noise sources in the clinical MRI scanner and were enhanced by the phantom's presence.

Iron-stress-induced-A proteins (IsiAs) are expressed in cyanobacteria under iron-deficient conditions. The cyanobacterium Anabaena sp. PCC 7120 has four isiA genes; however, their binding property and functional roles in PSI are still missing. We analyzed a cryo-electron microscopy structure of a PSI-IsiA supercomplex isolated from Anabaena grown under an iron-deficient condition. The PSI-IsiA structure contains six IsiA subunits associated with the PsaA side of a PSI core monomer. Three of the six IsiA subunits were identified as IsiA1 and IsiA2. The PSI-IsiA structure lacks a PsaL subunit; instead, a C-terminal domain of IsiA2 occupies the position of PsaL, which inhibits the oligomerization of PSI, leading to the formation of a PSI monomer. Furthermore, excitation-energy transfer from IsiAs to PSI appeared with a time constant of 55 ps. These findings provide insights into both the molecular assembly of the Anabaena IsiA family and the functional roles of IsiAs., (© 2023. The Author(s).)

Repetitive transcranial magnetic stimulation (rTMS) with intensive occupational therapy improves upper limb motor paralysis and activities of daily living after stroke; however, the degree of improvement according to paralysis severity remains unverified. Target activities of daily living using upper limb functions can be established by predicting the amount of change after treatment for each paralysis severity level to further aid practice planning. We estimated post-treatment score changes for each severity level of motor paralysis (no, poor, limited, notable, and full), stratified according to Action Research Arm Test (ARAT) scores before combined rTMS and intensive occupational therapy. Motor paralysis severity was the fixed factor for the analysis of covariance; the delta (post-pre) of the scores was the dependent variable. Ordinal logistic regression analysis was used to compare changes in ARAT subscores according to paralysis severity before treatment. We implemented a longitudinal, prospective, interventional, uncontrolled, and multicenter cohort design and analyzed a dataset of 907 patients with stroke hemiplegia. The largest treatment-related changes were observed in the Limited recovery group for upper limb motor paralysis and the Full recovery group for quality-of-life activities using the paralyzed upper limb. These results will help predict treatment effects and determine exercises and goal movements for occupational therapy after rTMS.

Background: Previous in vitro and in vivo studies on Alzheimer's disease (AD) models have reported that rosmarinic acid (RA) can inhibit the formation of amyloid-β fibrils as well as the oligomerization and deposition of amyloid-β protein. Melissa officinalis (M. officinalis) extract containing 500 mg of RA is tolerable and safe in healthy individuals and patients with mild AD dementia., Objective: This randomized placebo-controlled double-blind trial aimed to assess the effects of M. officinalis extract on cognition in older adults without dementia., Methods: This study included individuals who were diagnosed with subjective or mild cognitive impairment (n = 323). The trial involved M. officinalis extract supplementation (500 mg of RA per day) period of 96 weeks followed by a washout period of 24 weeks. The primary endpoint was the Alzheimer's Disease Assessment Scale-cognitive subscale score, and the secondary endpoints were other cognitive measure results as well as safety and tolerability., Results: There were no significant differences in cognitive measures between the placebo and M. officinalis groups from baseline to 96 weeks. However, based on the analysis of Clinical Dementia Rating Sum of Boxes scores in participants without hypertension, the score was found to be increased by 0.006 and decreased by 0.085 in the M. officinalis and placebo groups, respectively; this difference was statistically significant (p = 0.036). Furthermore, there were no differences in vital signs, physical and neurological measures, or hippocampal volume between the two groups., Conclusion: These results indicate that M. officinalis extract may help prevent cognitive decline in older adults without hypertension.

Background: Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results., Objective: We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri., Methods: We examined Aβ40 and Aβ42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer's disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ40 and Aβ42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri., Results: The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42, 324 pg/ml) and AD-CAA (Aβ40, 7669 pg/ml, p = 0.345; Aβ42, 355 pg/ml, p = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p = 0.056; Aβ42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40, 20.8% versus 3.9%, p = 0.0714; Aβ42, 27.4% versus 2.0%, p = 0.0714, respectively)., Conclusion: Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.

We report a self-induced spatially-coherent dot array consisting of fourteen units of vertical-cavity surface-emitting modes that exhibit spatially uniform spectra. A 47.5 µm total beam width and 0.5° narrow emission are achieved using an oblong cavity enclosed with a flat top mirror, cylindrically curved bottom mirror, and side facet. Notably, terminating the side of the cavity with a perpendicular facet enhances the horizontal propagation, which couples with the vertical resonance in each dot, similar to the case of master lasers in injection-locked lasers that delocalize the modes. Conventional semiconductor lasers, edge-emitting lasers, and vertical-cavity surface-emitting lasers have a Fabry-Pérot cavity; furthermore, emission and resonance are in identical directions, limiting the beam width to micrometers. Though the present structure has the same scheme of propagation, the right-angled facet synchronizes the modes and drastically expands the beam width., (© 2022. The Author(s).)

Gut microbiota and fecal bile acids were analyzed in 278 patients with α-synucleinopathies, which were comprised of 28 patients with dementia with Lewy bodies (DLB), 224 patients with Parkinson's disease (PD), and 26 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Similarly to PD, short-chain fatty acids-producing genera were decreased in DLB. Additionally, Ruminococcus torques and Collinsella were increased in DLB, which were not changed in PD. Random forest models to differentiate DLB and PD showed that high Ruminococcus torques and high Collinsella, which presumably increase intestinal permeability, as well as low Bifidobacterium, which are also observed in Alzheimer's disease, were predictive of DLB. As Ruminococcus torques and Collinsella are also major secondary bile acids-producing bacteria, we quantified fecal bile acids and found that the production of ursodeoxycholic acid (UDCA) was high in DLB. Increased UDCA in DLB may mitigate neuroinflammation at the substantia nigra, whereas neuroinflammation may not be critical at the neocortex. Theraeutic intervention to increase Bifidobacteirum and its metabolites may retard the development and progression of DLB., (© 2022. The Author(s).)

During recovery from upper limb motor paralysis after stroke, it is important to (1) set the exercise difficulty level according to the motor paralysis severity, (2) provide adequate exercises, and (3) motivate the patient to achieve the goal. However, these factors have not been well-formulated. This multicenter, randomized controlled trial study aims to examine the therapeutic effects of these three factors on patients undergoing a novel intervention using repetitive transcranial magnetic stimulation and intensive one-to-one training (NEURO ® ) and to formulate a corresponding research protocol. The control group will receive conventional NEURO ® occupational therapy. In the intervention group, four practice plans will be selected according to the Fugl-Meyer assessment (FMA-UE) scores of the upper extremity. The goal is to predict the post-treatment outcomes based on the pre-treatment FMA-UE scores. Based on the degree of difficulty and amount of practice required, we can formulate a practice plan to promote upper limb motor recovery. This occupational therapy plan will be less influenced by the therapist's skill, facilitating effective rehabilitation. The study findings may be utilized to promote upper limb motor paralysis recovery and provide a basis for proposing activities of daily living adapted to upper limb function.

Among continuous glucose monitoring (CGM) devices, which continuously measure glucose concentration in subcutaneous interstitial fluid for comprehensive monitoring of blood glucose profile, only FreeStyle Libre Pro® (Abbott Diabetes Care) is currently available in Japan as a professional system. FreeStyle Libre Pro® is easy to use because it does not require calibration by self-monitoring of blood glucose (SMBG), but information on its accuracy has been insufficient. To evaluate the measurement accuracy of FreeStyle Libre Pro®, we have now compared blood glucose levels determined by this device with those measured by SMBG in 40 individuals with type 2 diabetes mellitus. The mean absolute relative difference (MARD) for FreeStyle Libre Pro® measurements compared with SMBG measurements was calculated as an index of CGM accuracy. Overall blood glucose values measured by SMBG were 167.0 ± 60.1 mg/dL, and those determined by FreeStyle Libre Pro® were 155.0 ± 60.7 mg/dL, with this difference being statistically significant. The MARD for FreeStyle Libre Pro® relative to SMBG was 12.7 ± 9.3%. It was substantially higher in 2 of the 40 patients, at 49.2% and 47.5%, than in the other 38 individuals. MARD values did not differ significantly between before and 2 h after meals. However, the MARD was significantly higher for SMBG values of <100 mg/dL than for those of ≥250 mg/dL. Our results thus indicate that the measurement accuracy of FreeStyle Libre Pro® is relatively good, but that some cases in which values determined by the device deviate from SMBG values require caution in interpretation.

Nivolumab is an immune-checkpoint inhibitor (ICI) that can induce unique treatment-related toxicities, such as immune-related adverse events (irAEs). Myocarditis is a serious irAE with an incidence between 0.06% and 1.14%. Although the peak onset of irAE is generally within three months from the start of treatment, we experienced an autopsy case of late-onset fulminant myocarditis caused by nivolumab in Epstein Barr virus-associated gastric cancer. Pathological complete remission of the primary lesion was confirmed by the autopsy. We should consider possible complications of cardiac irAEs, especially fulminant myocarditis, even beyond three months after starting ICI therapy.

Gemcitabine plus cisplatin is the mainstay of first-line chemotherapy for unresectable biliary tract cancer, but the standard of care for second-line has not been established. In recent years, genetic abnormalities in biliary tract cancers have been identified, and therapeutic development targeting these genetic abnormalities has been promoted. In March 2021, based on the results of the FIGHT-202 trial, pemigatinib was approved for the treatment of FGFR2 fusion gene-positive biliary tract cancer. Pemigatinib is attracting attention as new treatment option for unresectable biliary tract cancer. Clinical trial data and other information on cancer therapies targeting the FGFR2 fusion gene will be presented.

Acute cholecystitis is an infectious disease of the gallbladder caused mainly by Escherichia coli , Klebsiella , and Enterococcus species. Streptococcus gallolyticus subsp. pasteurianus , previously known as Streptococcus bovis biotype II/2, rarely causes endocarditis, meningitis, and septicemia, mainly in children. Biliary tract infections by Streptococcus gallolyticus subsp. pasteurianus are extremely rare. There have been no reports of cases in Japan. Here, we describe the first case in Japan of acute calculous cholecystitis caused by Streptococcus gallolyticus subsp. pasteurianus infection. A 63-year-old man was admitted to our hospital with epigastric pain and vomiting. He had moderate tenderness and a full sensation in the epigastrium. Abdominal imaging revealed multiple stones in the gallbladder. After admission, he had a high fever that did not improve with antibiotics. Percutaneous transhepatic gallbladder drainage was performed. The patient underwent open cholecystectomy. During surgery, several small stones in the gallbladder and an abscess were observed at the gallbladder base. Streptococcus gallolyticus subsp. pasteurianus was detected by bacterial culture of the bile juice. The gallstones were bilirubin calcium stones. The endoscopic study showed three adenomas in the colon, but the histopathological examination demonstrated no malignant cells. Although infection by this bacterium may not be rare, this is the first reported case in Japan of acute calculous cholecystitis caused by Streptococcus gallolyticus subsp. pasteurianus infection.

Background and Aims: Parkinson's disease (PD) is the second most neurodegenerative disease after Alzheimer's disease. Accumulating knowledge points to the notion that abnormal aggregation of alpha-synuclein (αSyn) starts in the gut and ascends to the substantia nigra via the vagus nerve in about a half of PD patients. Epidemiological studies revealed that ulcerative colitis (UC) increases a risk for PD 1.3 to 1.8-folds. However, it remains unknown whether αSyn is abnormally aggregated in the enteric neurons in UC patients., Methods: We first inspected and optimized the immunostaining protocols with an anti-phosphorylated αSyn antibody, pSyn#64, using the brain and the gut of eight autopsied cases (five with PD and three without PD). Then, we examined abnormal αSyn aggregation in the enteric neurons in 23 and 18 colectomized patients with and without UC, respectively. Five or more sections were stained for αSyn in each of 87 and 25 paraffin- embedded blocks in patients with and without UC, respectively., Results: Ten different protocols of epitope exposure appropriately stained aggregated αSyn in the brain, but only complete lack of epitope exposure stained aggregated αSyn in the colon with low background. Abnormal αSyn aggregates, which was confirmed by co-localization of p62, in the enteric neurons were detected in a single patient with UC but not in any patients without UC., Conclusions: Omission of epitope exposure enabled us to immunostain aggregated αSyn in the colon by pSyn#64 with low nonspecific staining, but the number of 23 UC patients was not high enough to discern whether abnormal αSyn aggregation in the colonic neural plexus was increased in UC or not.

Deposition of amyloid β protein (Aβ) in the brain (cerebral β-amyloidosis) is a hallmark of Alzheimer's disease (AD). So far, there have been increasing number of experimental studies using AD mouse model that cerebral β-amyloidosis could be transmitted among individuals as prion-like mechanism. Furthermore, several pathological studies using autopsied patients with iatrogenic Creutzfeldt-Jakob disease (CJD) showed that cerebral β-amyloidosis in addition to the CJD pathology could be transmitted among humans via medical procedures, such as human growth hormone derived from cadaver injection and cadaveric dura mater graft. In addition, although cerebral amyloid angiopathy (CAA), which is Aβ deposition in the cerebral vessels, related cerebral hemorrhage rarely develops in young people, several patients with CAA-related cerebral hemorrhage under the age of 55 with histories of neurosurgeries with and without dura mater graft in early childhood have been reported. These patients might show that Aβ pathology is often recognized as Aβ-CAA rather than parenchymal Aβ deposition in the transmission of cerebral β-amyloidosis in humans, and we proposed an emerging concept, "acquired CAA". Considering that there have been several patients with acquired CAA with an incubation period from neurosurgery and the onset of CAA related cerebral hemorrhage of longer than 40 years, the number of cases is likely to increase in the future, and detailed epidemiological investigation is required. It is necessary to continue to elucidate the pathomechanisms of acquired CAA and urgently establish a method for preventing the transmission of cerebral β-amyloidosis among individuals., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The preferred regimen for unresectable pancreatic cancer following gemcitabine-based chemotherapy is not well-established. This study compared the efficacy of (ⅰ) liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/leucovorin (LV) (nal-IRI/5-FU/LV) versus modified FOLFIRINOX (mFFX) and (ⅱ) nal-IRI/5-FU/LV versus FOLFIRI, respectively, and the safety of the three regimens each other, as second-line chemotherapies for unresectable pancreatic cancer., Methods: This was a retrospective single-center analysis of all patients who were administered nal-IRI/5-FU/LV, mFFX, or FOLFIRI from December 2014 to July 2021 as second-line chemotherapy for pancreatic cancer. The primary endpoint was the overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. Regarding safety, we assessed the incidence of grade ≥3 adverse events of interest in all patients., Results: A total of 137 patients (nal-IRI/5-FU/LV, n = 55; mFFX, n = 39; FOLFIRI, n = 43) were included. The median OS in the nal-IRI/5-FU/LV group, the mFFX group, and the FOLFIRI group was 7.4, 11.8, and 8.4 months, respectively. Compared with the nal-IRI/5-FU/LV group, the mFFX and FOLFIRI groups displayed a hazard ratio of 0.66 [95% confidence interval 0.40-1.08] and 0.87 [95% confidence interval 0.55-1.39], respectively. In the FOLFIRI group, the incidence of grade ≥3 treatment-related adverse events tended to be low among all three groups., Conclusions: Given the trend toward longer OS in the mFFX group and the lower incidence of adverse events in the FOLFIRI group, both mFFX and FOLFIRI, as well as nal-IRI/5-FU/LV, can be treatment options for second-line chemotherapy for unresectable pancreatic cancer., Competing Interests: Declaration of competing interest All authors have no known competing financial interests, personal relationships, or competing interests that could have influenced the work reported in this study., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Flavor hops (Humulus lupulus L.) are recognized as key raw materials that impart unique flavors to beer, especially in the emerging craft-beer industry. In this study the sensory evaluation of hop cone aromas using hop water extract by boiling (HWEB) was applied to develop new flavor hop cultivars in a screening from tens of varieties and breeding lines., Results: The sensory scores of HWEB showed a significant correlation with polyfunctional thiol content in hop cones, including substances such as 4-methyl-4-sulfunylpentan-2-one (4MSP) and 3-sulfunyl-4-methylpentan-1-ol (3S4MP), which are known to be difficult to analyze mechanically. As a result of the sensory evaluation of HWEB, a breeding line, 'K906901060' was found to have a strong fruity note. Subsequent chemical analyses revealed that this cultivar had 80-136 μg kg -1 of 4MSP in its cones, which is similar to the concentration present in current leading flavor hop cultivars, such as Citra (37-114 μg kg -1 ) and Simcoe (2-112 μg kg -1 ). Beer late-hopped with K906901060 provoked a greater tropical flavor impression than beer hopped using Nelson Sauvin hops., Conclusion: The sensory evaluation of HWEB was indicated to be useful to search for hops containing polyfunctional thiols. The plant was registered, as 'Furano K906901060 Go' in Japan, in the EU, and in the USA, and the cultivar was given the commercial name 'Furano Magical'. This cultivar was derived from a cross performed in 1989 and had been kept as a mid-mother plant from 1997, until being selected in 2014, as described here. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.

Objective: It is well known that the burden on the families of cancer patient extends across many aspects, but there have been no reports of family members developing delirium due to the burden of caring for a cancer patient., Methods: We reported a caregiver who developed Wernicke encephalopathy (WE) while caring for a family member with advanced cancer., Results: The subject was a 71-year-old woman who had been caring for her husband, diagnosed with gastric cancer and liver metastases, for 5 months. She visited the "caregivers' clinic" after referral by an oncologist who was worried about a deterioration in her mental condition that had appeared several weeks previously. The woman had a history of diabetes mellitus. Some giddiness was observed and, based on her inability to answer questions, her level of consciousness was checked and some disorientation was observed. She was diagnosed with delirium. A blood sample was collected to investigate the cause of the delirium, but the test data showed no hypoglycemia. Her appetite had declined since her husband was diagnosed with cancer. Thiamine deficiency was suspected as thiamine stores in the body are depleted within about 18 days and her loss of appetite had continued for 5 months. On intravenous injection of 100 mg of thiamine, her consciousness level was returned to normal in 1 h. A diagnosis of WE was supported by the patient's abnormally low serum thiamine level., Significance of the Results: The family members of cancer patients may develop a loss of appetite due to the burden of caring, resulting in WE. When providing care for signs of distress in family members, it is necessary to pay attention not only to the psychological aspects but also to their level of consciousness and physical aspects, particularly the possibility of serious illness resulting from reduced nutritional status.

Background: No studies have assessed the independent association of methionine homozygosity at codon 129 with the susceptibility to prion diseases, controlling for the effects of the codon 219 polymorphisms and other potential confounders, using a large-scale population-based dataset., Methods: We conducted a case-control study using a Japanese nationwide surveillance database for prion diseases. The main exposure was methionine homozygosity at codon 129, and the outcome was development of prion diseases. Multivariable logistic regression models were employed for specific disease subtypes (sporadic Creutzfeldt-Jakob disease (CJD), genetic CJD and Gerstmann-Sträussler-Scheinker disease (GSS))., Results: Of 5461 patients registered in the database, 2440 cases and 796 controls remained for the analysis. The cases comprised 1676 patients with sporadic CJD (69%), 649 with genetic CJD (27%) and 115 with GSS (5%). For patients with methionine homozygosity, potential risk for occurring prion diseases: adjusted OR (95% CI) was 2.21 (1.46 to 3.34) in sporadic CJD, 0.47 (0.32 to 0.68) in genetic CJD and 0.3 (0.17 to 0.55) in GSS. Among patients with specific prion protein abnormalities, the potential risk was 0.27 (0.17 to 0.41) in genetic CJD with 180 Val/Ile, 1.66 (0.65 to 5.58) in genetic CJD with 200 Glu/Lys, 3.97 (1.2 to 24.62) in genetic CJD with 232 Met/Arg and 0.71 (0.34 to 1.67) in GSS with 102 Pro/Leu., Conclusions: Methionine homozygosity at codon 129 was predisposing to sporadic CJD, but protective against genetic CJD and GSS, after adjustment for codon 219 polymorphism effect. However, the impacts differed completely among patients with specific prion protein abnormalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an inflammatory disorder of the central nervous system. On magnetic resonance imaging, the neuroradiological signature is a linear radial enhancement pattern of cerebral white matter (MRI). Dawson's fingers, on the other hand, and ovoid lesions with open-ring enhancement have long been recognized as distinct features of multiple sclerosis (MS). We herein report a case of autoimmune GFAP astrocytopathy presenting with these MRI findings specific to MS. Autoimmune GFAP astrocytopathy could mimic the MRI features of MS and should be included in the differential diagnosis of MS., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cyanobacteria, glaucophytes, and rhodophytes utilize giant, light-harvesting phycobilisomes (PBSs) for capturing solar energy and conveying it to photosynthetic reaction centers. PBSs are compositionally and structurally diverse, and exceedingly complex, all of which pose a challenge for a comprehensive understanding of their function. To date, three detailed architectures of PBSs by cryo-electron microscopy (cryo-EM) have been described: a hemiellipsoidal type, a block-type from rhodophytes, and a cyanobacterial hemidiscoidal-type. Here, we report cryo-EM structures of a pentacylindrical allophycocyanin core and phycocyanin-containing rod of a thermophilic cyanobacterial hemidiscoidal PBS. The structures define the spatial arrangement of protein subunits and chromophores, crucial for deciphering the energy transfer mechanism. They reveal how the pentacylindrical core is formed, identify key interactions between linker proteins and the bilin chromophores, and indicate pathways for unidirectional energy transfer., (© 2022. The Author(s).)

Studies on the very early electroencephalography (EEG) features prior to the emergence of generalized periodic discharges (GPDs, generally known as periodic sharp-wave complexes) in Creutzfeldt-Jakob disease (CJD) are rare. Fourteen patients with sporadic CJD (sCJD) (eight with MM1/classic and six with MM2c) were included in this study. The predominant findings of the first EEG were categorized as 1) lateralized periodic discharges (LPDs), 2) central sagittal sporadic epileptiform discharges (CSSEDs) showing midline predominant generalized spike-and-wave complexes and/or sharp waves in the central sagittal regions, or 3) focal epileptiform discharges. Clinical records, magnetic resonance imaging (MRI), and changes in EEG were compared between three groups (LPD in MM1/classic, CSSED in MM1/classic, and focal epileptiform discharge in MM2c). Three (37.5%) and five (62.5%) patients with MM1/classic sCJD were classified into the LPD and CSSED groups, respectively. Patients in the LPD group were accompanied by cortical hyperintensities at the corresponding areas on MRI, while those in the CSSED group showed hyperintensities on MRI at unassociated cortical areas. Follow-up EEG of three (100%) patients in the LPD group and four (80%) in the CSSED group showed transitions to GPDs. All patients with MM1/classic sCJD showed myoclonus on initial EEG, and the symptomatic side was opposite to the hemisphere showing LPDs or higher-amplitude central sagittal epileptiform activity. The periodicity after these EEGs likely contributes to the diagnostic confidence of physicians when patients are in the very early stages of MM1/classic sCJD., (Copyright © 2022 Elsevier B.V. All rights reserved.)