Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma.

BACKGROUND: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined based on the capsaicin concentration that induced at least two (C2) or five coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 of ≤ 2.44 µM) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-interleukin (IL)-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared with those in their counterparts. CONCLUSION: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

Ablation of Dual-Specificity Phosphatase 6 Protects against Nonalcoholic Fatty Liver Disease via Cytochrome P450 4A and Mitogen-Activated Protein Kinase.

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.

Changes in spinal sagittal balance after a new osteoporotic vertebral compression fracture.

We conduct a longitudinal study to examine how new VCF alter spinal sagittal balance. New VCF increased SVA by an average of 2.8 cm. Sagittal balance deteriorates as a VCF develops in the lower lumbar spine. A new fracture below L1 increased the relative risk of a deterioration of sagittal balance 2.9-fold compared to one above Th12. PURPOSE: Studies on the relationship between osteoporotic vertebral fractures and spinal sagittal balance have all been limited to cross-sectional studies. The aim of this study is to conduct a longitudinal study to examine how new vertebral compression fracture (VCF) alter spinal sagittal balance. METHODS: Subjects were patients undergoing periodic examinations after treatment of a vertebral fracture or lumbar spinal canal stenosis. Forty patients who developed a new VCF were included in this study. Full-spine standing radiographs were compared before and after the fracture to examine changes in spinopelvic parameters and factors determining the changes in sagittal balance. RESULTS: The mean age of the patients was 79.0 years. The mean interval between pre- and post-fracture radiographs was 22.7 months, and the mean time between development of a fracture and post-fracture radiographs was 4.6 months. After a fracture, sagittal vertical axis (SVA) increased an average of 2.78 cm and spino-sacral angle (SSA) decreased an average of 5.3°. Both ⊿SVA and ⊿SSA were not related to pre-fracture parameters. The wedge angle of the fractured vertebra was not related to changes in sagittal balance. ⊿SVA increased markedly in patients with a fracture of the lower lumbar vertebrae. receiver operating characteristic analysis revealed that the relative risk of a deterioration of sagittal balance was 2.9 times higher for a new fracture below L1 than for a fracture above Th12. CONCLUSION: New VCF increased SVA by an average of 2.8 cm. Sagittal balance deteriorates as a new fracture develops in the lower lumbar spine. Early intervention in osteoporosis is vital for the elderly.

Structural and Functional Analysis of the Amorphous Calcium Carbonate-Binding Protein Paramyosin in the Shell of the Pearl Oyster, Pinctada fucata.

Amorphous calcium carbonate (ACC) is an important precursor phase for the formation of aragonite crystals in the shells of Pinctada fucata. To identify the ACC-binding protein in the inner aragonite layer of the shell, extracts from the shell were used in the ACC-binding experiments. Semiquantitative analyses using liquid chromatography-mass spectrometry revealed that paramyosin was strongly associated with ACC in the shell. We discovered that paramyosin, a major component of the adductor muscle, was included in the myostracum, which is the microstructure of the shell attached to the adductor muscle. Purified paramyosin accumulates calcium carbonate and induces the prism structure of aragonite crystals, which is related to the morphology of prism aragonite crystals in the myostracum. Nuclear magnetic resonance measurements revealed that the Glu-rich region was bound to ACC. Activity of the Glu-rich region was stronger than that of the Asp-rich region. These results suggest that paramyosin in the adductor muscle is involved in the formation of aragonite prisms in the myostracum.

Structural basis of the protochromic green/red photocycle of the chromatic acclimation sensor RcaE.

Cyanobacteriochromes (CBCRs) are bilin-binding photosensors of the phytochrome superfamily that show remarkable spectral diversity. The green/red CBCR subfamily is important for regulating chromatic acclimation of photosynthetic antenna in cyanobacteria and is applied for optogenetic control of gene expression in synthetic biology. It is suggested that the absorption change of this subfamily is caused by the bilin C15-Z/C15-E photoisomerization and a subsequent change in the bilin protonation state. However, structural information and direct evidence of the bilin protonation state are lacking. Here, we report a high-resolution (1.63Å) crystal structure of the bilin-binding domain of the chromatic acclimation sensor RcaE in the red-absorbing photoproduct state. The bilin is buried within a "bucket" consisting of hydrophobic residues, in which the bilin configuration/conformation is C5-Z,syn/C10-Z,syn/C15-E,syn with the A- through C-rings coplanar and the D-ring tilted. Three pyrrole nitrogens of the A- through C-rings are covered in the α-face with a hydrophobic lid of Leu249 influencing the bilin pKa, whereas they are directly hydrogen bonded in the ß-face with the carboxyl group of Glu217. Glu217 is further connected to a cluster of waters forming a hole in the bucket, which are in exchange with solvent waters in molecular dynamics simulation. We propose that the "leaky bucket" structure functions as a proton exit/influx pathway upon photoconversion. NMR analysis demonstrated that the four pyrrole nitrogen atoms are indeed fully protonated in the red-absorbing state, but one of them, most likely the B-ring nitrogen, is deprotonated in the green-absorbing state. These findings deepen our understanding of the diverse spectral tuning mechanisms present in CBCRs.

Factors influencing slippage after microsurgical single level lumbar spinal decompression surgery - Are the psoas and multifidus muscles involved?

PURPOSE: Patients with lumbar spinal stenosis (LSS) require microsurgical decompression (MSD) surgery; however, MSD is often associated with postoperative instability at the operated level. Paraspinal muscles support the spinal column; lately, paraspinal volume has been used as a good indicator of sarcopenia. This study aimed to determine preoperative radiological factors, including paraspinal muscle volume, associated with postoperative slippage progression after MSD in LSS patients. METHODS: Patients undergoing single-level (L3/4 or L4/5) MSD for symptomatic LSS and followed-up for ≥ 5 years in our institute were reviewed retrospectively to measure preoperative imaging parameters focused on the operated level. Paraspinal muscle volumes (psoas muscle index [PMI] and multifidus muscle index [MFMI]) defined using the total cross-sectional area of each muscle/L3 vertebral body area in the preoperative lumbar axial CT) were calculated. Postoperative slippage in the form of static translation (ST) ≥ 2 mm was assessed on the last follow-up X-ray. RESULTS: We included 95 patients with average age and follow-up periods of 69 ± 8.2 years and 7.51 ± 2.58 years, respectively. PMI and MFMI were significantly correlated with age and significantly larger in male patients. Female sex, preoperative ST, dynamic translation, sagittal rotation angle, facet angle, pelvic incidence, lumbar lordosis, and PMI were correlated with long-term postoperative worsening of ST. However, as per multivariate analysis, no independent factor was associated with postoperative slippage progression. CONCLUSION: Lower preoperative psoas muscle volume in LSS patients is an important predictive factor of postoperative slippage progression at the operated level after MSD. The predictors for postoperative slippage progression are multifactorial; however, a well-structured postoperative exercise regimen involving psoas muscle strengthening may be beneficial in LSS patients after MSD.

The safety of perioperative antiplatelet continuation without selection biases in microsurgical decompression surgery for single level lumbar spinal stenosis and lumbar disc herniotomy.

PURPOSE: Each institution or physician has to decide on an individual basis whether to continue or discontinue antiplatelet (AP) therapy before spinal surgery. The purpose of this study was to determine if perioperative AP continuation is safe during single-level microsurgical decompression (MSD) for treating lumbar spinal stenosis (LSS) and lumbar disc hernia (LDH) without selection bias. METHODS: Patients who underwent single-level MSD for LSS and LDH between April 2018 to December 2022 at our institute were included in this retrospective study. We collected data regarding baseline characteristics, medical history/comorbidities, epidural hematoma (EDH) volume, reoperation for EDH, differences between preoperative and one-day postoperative blood cell counts (ΔRBC), hemoglobin (ΔHGB), and hematocrits (ΔHCT), and perioperative thromboembolic complications. Patients were divided into two groups: the AP continuation group received AP treatment before surgery and the control group did not receive antiplatelet medication before surgery. Propensity scores for receiving AP agents were calculated, with one-to-one matching of estimated propensity scores to adjust for patient baseline characteristics and past histories. Reoperation for EDH, EDH volume, ΔRBC, ΔHGB, ΔHCT, and perioperative thromboembolic complications were compared between the groups. RESULTS: The 303 enrolled patients included 41 patients in the AP continuation group. After propensity score matching, the rate of reoperation for EDH, the EDH volume, ΔRBC, ΔHGB, ΔHCT, and perioperative thromboembolic complication rates were not significantly different between the groups. CONCLUSION: Perioperative AP continuation is safe for single-level lumbar MSD, even without biases.

Structure and Dynamics of Drk-SH2 Domain and Its Site-Specific Interaction with Sev Receptor Tyrosine Kinase.

The Drosophila downstream receptor kinase (Drk), a homologue of human GRB2, participates in the signal transduction from the extracellular to the intracellular environment. Drk receives signals through the interaction of its Src homology 2 (SH2) domain with the phosphorylated tyrosine residue in the receptor tyrosine kinases (RTKs). Here, we present the solution NMR structure of the SH2 domain of Drk (Drk-SH2), which was determined in the presence of a phosphotyrosine (pY)-containing peptide derived from a receptor tyrosine kinase, Sevenless (Sev). The solution structure of Drk-SH2 possess a common SH2 domain architecture, consisting of three ß strands imposed between two α helices. Additionally, we interpret the site-specific interactions of the Drk-SH2 domain with the pY-containing peptide through NMR titration experiments. The dynamics of Drk-SH2 were also analysed through NMR-relaxation experiments as well as the molecular dynamic simulation. The docking simulations of the pY-containing peptide onto the protein surface of Drk-SH2 provided the orientation of the peptide, which showed a good agreement with the analysis of the SH2 domain of GRB2.

Skin care by washing with water is not inferior to washing with a cleanser in children with atopic dermatitis in remission in summer: WASH study.

BACKGROUND: Washing with water is not inferior to washing with soaps and detergents in children with atopic dermatitis (AD) in remission during the fall-winter seasons. We investigated whether this finding varies during summer based on the type of cleanser (soaps and detergents). METHODS: This evaluator-blinded, pragmatic, randomized, and non-inferiority study enrolled patients with AD whose eczema was controlled following regular steroid ointment application 2 days/week. For 8 ± 4 weeks, participants washed their upper and lower limbs with a cleanser on one side and with water alone on the other. Each participant chose either a weakly alkaline soap or an acidic detergent. The primary outcome was the Eczema Area and Severity Index (EASI) score at week 8 ± 4. RESULTS: The data of 43 of the 47 registered participants were analyzed. The median patient age was 44 (23-99) months; 28 and 15 participants chose weakly alkaline and acidic cleansers, respectively. At week 8 ± 4, EASI scores of the water and cleanser sides were 0.00 (0.00-0.40) and 0.15 (0.00-0.40), respectively (p = 0.74). The difference between both sides was 0.00 (-0.07 to 0.14); the limits of the 95 % confidence interval did not reach the pre-specified non-inferiority margin. No difference was observed in the median Patient-Oriented Eczema Measure score, number of additional steroid ointment applications, and occurrences of skin infections. There were no differences between the cleanser types in any of the results. CONCLUSIONS: We demonstrated that washing with water was not inferior to that with a cleanser in patients with AD in the maintenance phase during summer, regardless of the type of cleanser.

Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study.

BACKGROUND: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. METHODS: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. RESULTS: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. CONCLUSIONS: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.

Frequent Transmission of Streptococcus pneumoniae Serotype 35B and 35D, Clonal Complex 558 Lineage, across Continents and the Formation of Multiple Clades in Japan.

Streptococcus pneumoniae is a common bacterial pathogen that causes infections in children worldwide, even after administration of the pneumococcal conjugate vaccine. S. pneumoniae serotype 35B, especially the clonal complex 558 (CC558) lineage, has emerged globally following implementation of the 13-valent pneumococcal conjugate vaccine. Serotype 35B strains are also associated with multidrug resistance to both ß-lactams and non-ß-lactam drugs. In addition, a novel serotype, 35D, which is closely related to 35B and differs in polysaccharide structure, was recently reported. However, the genetic relationship among globally disseminating serotype 35B and D (35B/D) strains remains unknown. To investigate the molecular epidemiology of global serotype 35B/D strains, we conducted a genomic analysis of serotype 35B/D strains from various continents, including those from the Japanese national surveillance collection. A total of 87 isolates were identified as serotype 35B/D in the Japanese surveillance collection (n = 1,358). All the isolates were assigned to either CC558 or CC2755. Serotype 35D isolates were interspersed with serotype 35B isolates. Phylogenetic analysis revealed the formation of multiple clusters by the Japanese serotype 35B/D-CC558 isolates among the foreign isolates, which suggested multiple events of introduction of the clone into Japan. The global 35B/D-CC558 strains were found to share specific penicillin-binding protein profiles, pbp1a-4, pbp2b-7, and pbp2x-7, associated with penicillin, cephalosporin, and carbapenem nonsusceptibility. Moreover, 88.5% of the Japanese 35B/D-CC558 and 35B/D-CC2755 isolates were found to harbor the Tn916-like integrative and conjugative elements Tn2009, Tn2010, and Tn6002, associated with multidrug resistance to macrolides and tetracyclines. The results of this study imply that serotype 35B/D-CC558 strains could be frequently transmitted intercontinentally.

Targeting the interleukin-5 pathway improves cough hypersensitivity in patients with severe uncontrolled asthma.

BACKGROUND: Capsaicin cough sensitivity (C-CS) reflects airway neuronal dysfunction and may be a significant biomarker of asthma. Although mepolizumab reduces cough in patients with severe uncontrolled asthma, it is unclear whether the cough reduction is associated with improved C-CS. OBJECTIVE: To clarify the effect of biologics on C-CS and cough-specific quality of life (QoL) in patients with severe uncontrolled asthma using our previous study cohort. METHODS: Overall, 52 consecutive patients who visited our hospital for severe uncontrolled asthma were included in the original study cohort, and 30 patients were eligible for this study. Changes in C-CS and cough-specific QoL were compared between patients treated with the anti-interleukin-5 (IL-5) pathway (n = 16) and those treated with other biologics (n = 14). The C-CS was measured as the concentration of capsaicin required to induce at least 5 coughs. RESULTS: Biologics significantly improved C-CS (P = .03). Anti-IL-5 pathway therapies significantly improved C-CS, whereas other biologics did not (P < .01 and P = .89, respectively). The C-CS improved significantly more in the anti-IL-5 pathway group than in the group treated with other biologics (P = .02). Changes in C-CS significantly correlated with improvements in cough-specific QoL in the anti-IL-5 pathway group (r = 0.58, P = .01) but not in the group treated with other biologics (r = 0.35, P = .22). CONCLUSION: Anti-IL-5 pathway therapies improve C-CS and cough-specific QoL, and targeting the IL-5 pathway may be a therapeutic strategy for cough hypersensitivity in patients with severe uncontrolled asthma.

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial.

BACKGROUND: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). OBJECTIVE: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. METHODS: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 µg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. RESULTS: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. CONCLUSION: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. TRIAL REGISTRATION: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Interactions of the N- and C-Terminal SH3 Domains of Drosophila Drk with the Proline-Rich Peptides from Sos and Dos.

Drk, a homologue of human GRB2 in Drosophila, receives signals from outside the cells through the interaction of its SH2 domain with the phospho-tyrosine residues in the intracellular regions of receptor tyrosine kinases (RTKs) such as Sevenless, and transduces the signals downstream through the association of its N- and C-terminal SH3 domains (Drk-NSH3 and Drk-CSH3, respectively) with proline-rich motifs (PRMs) in Son of Sevenless (Sos) or Daughter of Sevenless (Dos). Isolated Drk-NSH3 exhibits a conformational equilibrium between the folded and unfolded states, while Drk-CSH3 adopts only a folded confirmation. Drk interacts with PRMs of the PxxPxR motif in Sos and the PxxxRxxKP motif in Dos. Our previous study has shown that Drk-CSH3 can bind to Sos, but the interaction between Drk-NSH3 and Dos has not been investigated. To assess the affinities of both SH3 domains towards Sos and Dos, we conducted NMR titration experiments using peptides derived from Sos and Dos. Sos-S1 binds to Drk-NSH3 with the highest affinity, strongly suggesting that the Drk-Sos multivalent interaction is initiated by the binding of Sos-S1 and NSH3. Our results also revealed that the two Sos-derived PRMs clearly favour NSH3 for binding, whereas the two Dos-derived PRMs show almost similar affinity for NSH3 and CSH3. We have also performed docking simulations based on the chemical shift perturbations caused by the addition of Sos- and Dos-derived peptides. Finally, we discussed the various modes in the interactions of Drk with Sos/Dos.

Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma.

BACKGROUND: Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. METHODS: Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 µM was defined as heightened C-CS. RESULTS: Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 µM vs. 8.91 ± 5.5 µM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. CONCLUSIONS: Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.

[Three Cases of Conversion Surgery Resulted in Pathological Complete Response for Unresectable Pancreatic Cancer].

Conversion surgery(CS)post chemotherapy for unresectable pancreatic cancer is often reported recently. Although it is still controversial about adaptation of CS, it could possibly be one of the useful choices of treatment for unresectable pancreatic cancer. We report 3 cases of CS which eventually turned out to be pathological complete response.

[A Case of Jejunal Ectopic Pancreas Incidentally Found in Laparoscopic Rectal Cancer Surgery].

In laparoscopic surgery, intraabdominal examination is occasionally difficult due to restriction of operative field and palpation. This is a case report of a jejunal ectopic pancreas which was incidentally found during laparoscopic surgery. A 49-year- old male underwent endoscopic mucosal resection for a rectal polyp which pathologically resulted in 5,000 µm invasion in submucosa and lymphatic invasion. Laparoscopic low anterior resection was planned for the patient as an additional treatment. During the surgery, irregular shaped tumor-like lesion was incidentally found in jejunum which was located 30 cm distal side from the ligament of Treitz. Partial resection of jejunum was also performed for pathological diagnosis. Resected jejunal lesion was pathologically diagnosed as an ectopic pancreas of Heinrich classification type Ⅰ. Ectopic pancreas is defined as pancreatic tissue which is discontinuous to pancreas, asymptomatic in most cases, but some reported cases of pancreatitis, forming fistula or cancerous change. Reporting with some literature review.

Whole-Genome Analysis-Based Phylogeographic Investigation of Streptococcus pneumoniae Serotype 19A Sequence Type 320 Isolates in Japan.

After the introduction of the seven-valent pneumococcal conjugate vaccine, the global spread of multidrug-resistant serotype 19A-sequence type 320 (ST320) strains of Streptococcus pneumoniae became a public health concern. In Japan, the main genotype of serotype 19A was ST3111, and the identification rate of ST320 was low. Although the isolates were sporadically detected in both adults and children, their origin remains unknown. Thus, by combining pneumococcal isolates collected in three nationwide pneumococcal surveillance studies conducted in Japan between 2008 and 2020, we analyzed 56 serotype 19A-ST320 isolates along with 931 global isolates, using whole-genome sequencing to uncover the transmission route of the globally distributed clone in Japan. The clone was frequently detected in Okinawa Prefecture, where the United States returned to Japan in 1972. Phylogenetic analysis demonstrated that the isolates from Japan were genetically related to those from the United States; therefore, the common ancestor may have originated in the United States. In addition, Bayesian analysis suggested that the time to the most recent common ancestor of the isolates from Japan and the U.S. was approximately the 1990s to 2000, suggesting the possibility that the common ancestor could have already spread in the United States before the Taiwan 19F-14 isolate was first identified in a Taiwanese hospital in 1997. The phylogeographical analysis supported the transmission of the clone from the United States to Japan, but the analysis could be influenced by sampling bias. These results suggested the possibility that the serotype 19A-ST320 clone had already spread in the United States before being imported into Japan.

Insight into the C-terminal SH3 domain mediated binding of Drosophila Drk to Sos and Dos.

Drk, a Drosophila homologue of human GRB2, interacts with Sevenless (Sev) receptor via its SH2 domain, while the N- and C-terminal SH3 domains (Drk-NSH3 and Drk-CSH3, respectively) are responsible for the interaction with proline-rich motifs (PRMs) of Son of sevenless (Sos) or Daughter of Sevenless (Dos). Drk-NSH3 on its own has a conformational equilibrium between folded and unfolded states, and the folded state is stabilised by the association with a Sos-derived proline-rich peptide with PxxPxR motif. In contrast, Drk-CSH3 is supposed to bind PxxxRxxKP motifs in Dos. Aiming at clarifying the structural and functional differences between the two SH3 domains, we performed NMR studies of Drk-CSH3. The resulting solution structure and the 15N-relaxation data showed that Drk-CSH3 consists of a stable domain. Large chemical shift perturbation was commonly found around the RT loop and the hydrophobic patch, while there were also changes that occur characteristically for Sos- or Dos-derived peptides. Sos-derived two peptides with PxxPxR motif showed stronger affinity to Drk-CSH3, indicating that the Sos PRMs can bind both N- and C-SH3 domains. Dos-derived two peptides could also bind Drk-CSH3, but with much weaker affinity, suggesting a possibility that any cooperative binding of Dos-PRMs may strengthen the Drk-Dos interaction. The NMR studies as well as the docking simulations provide valuable insights into the biological and biophysical functions of two SH3 domains in Drk.

Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel.

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC50) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment.