Efficient pathway-driven scyllo-inositol production from myo-inositol using thermophilic cells and mesophilic inositol dehydrogenases: a novel strategy for pathway control.

Mesophilic enzymes, which are active at moderate temperatures, may dominate enzymatic reactions even in the presence of thermophilic crude enzymes. This study was conducted to investigate this hypothesis with mesophilic inositol dehydrogenases (IolG and IolX) produced in Geobacillus kaustophilus HTA426. To ensure the efficient production of mesophilic enzymes, we first screened for promoters induced at moderate temperatures using transcriptome analysis and identified four genes highly expressed at 30°C in the thermophile. We further characterized these promoters using fluorescent reporter assays to determine that the mti3 promoter could direct efficient gene expression at 40°C. We cloned the promoter into an Escherichia coli-Geobacillus shuttle plasmid and confirmed that the resulting vector functioned in G. kaustophilus and other thermophiles. We then used this vector for the cooperative expression of the iolG and iolX genes from Bacillus subtilis 168. G. kaustophilus cells carrying the expression vector were incubated at 60°C for cellular propagation and then at 40°C for the production of IolG and IolX. When the cells were permeabilized, IolG and IolX acted as catalysts to convert exogenous myo-inositol into scyllo-inositol at 30°C. In a scaled-up reaction, 10 g of myo-inositol was converted to 1.8 g of scyllo-inositol, which was further purified to yield 970 mg of pure powder. Notably, myo-inositol was degraded by intrinsic enzymes of G. kaustophilus at 60°C but not at 30°C, supporting our initial hypothesis. We indicate that this approach is useful for preparing enzyme cocktails without the need for purification. IMPORTANCE: Enzyme cocktails are commonly employed for cell-free chemical synthesis; however, their preparation involves cumbersome processes. This study affirms that mesophilic enzymes in thermophilic crude extracts can function as specific catalysts at moderate temperatures, akin to enzyme cocktails. The catalyst was prepared by permeabilizing cells without the need for concentration, extraction, or purification processes; hence, its preparation was considerably simpler compared with conventional methods for enzyme cocktails. This approach was employed to produce pure scyllo-inositol from an economical substrate. Notably, this marks the first large-scale preparation of pure scyllo-inositol, holding potential pharmaceutical significance as scyllo-inositol serves as a promising agent for certain diseases but is currently expensive. Moreover, this approach holds promise for application in pathway engineering within living cells. The envisioned pathway is designed without chromosomal modification and is simply regulated by switching culture temperatures. Consequently, this study introduces a novel platform for both whole-cell and cell-free synthetic systems.

Impact of tumor shrinkage pattern with biweekly triplet gemcitabine+cisplatin+S-1 regimen for biliary tract cancers: Implications for neoadjuvant therapy from the data of KHBO1401 (KHBO1401-1A study).

BACKGROUND: The multicenter randomized phase III KHBO1401 study (gemcitabine+cisplatin+S-1 [GCS] versus GC in biliary tract cancers [BTC]) demonstrated that GCS not only prolonged patient survival but also achieved a high response rate and that it should be good for neoadjuvant therapy. Therefore, to explore the possibilities of neoadjuvant therapy, we investigated the tumor shrinkage pattern. METHODS: Among the total of 246 patients enrolled in the KHBO1401, the tumor shrinkage pattern and survival were investigated in patients with measurable BTC (n=183, 74%; GCS, n=91; GC, n=92). RESULTS: The tumor shrinkage pattern could be divided to 4 categories based on the response at 100 days after enrollment: category A (<-30% in size), B (-30% to 0%), C (0% to +20%), and D (>+20%). The GCS arm included more category A and B cases (61 [67%] vs. 33 [36%], P<0.0001). Each category predicted best response and overall survival (P<0.0001). Category A showed sustained tumor response compared with category B; in GCS, the time to maximum tumor response was 165 ± 76 days in category A and 139 ± 78 in category B. Categories C and D did not achieve tumor shrinkage. The maximum tumor shrinkage size in category A was -53% in the GCS arm and -65% in the GC arm (P=0.0892). Twenty percent of patients in the GCS showed tumor regrowth 154 ± 143 days later. CONCLUSION: GCS provided faster and greater tumor shrinkage with better survival in comparison to GC, although 20% of patients showed re-growth after 6 cycles.

Nonlocal Spin Correlation as a Signature of Ising Anyons Trapped in Vacancies of the Kitaev Spin Liquid.

In the Kitaev chiral spin liquid, Ising anyons are realized as Z_{2} fluxes binding Majorana zero modes, which, however, are thermal excitations with finite decay rates. On the other hand, a lattice vacancy traps a Z_{2} flux even in the ground state, resulting in the stable realization of a Majorana zero mode in a vacancy. We demonstrate that spin-spin correlation functions between two vacancy sites exhibit long-range correlation arising from the fractionalized character of Majorana zero modes, in spite of the strong decay of bulk spin correlations. Remarkably, this nonlocal spin correlation does not decrease as the distance between two vacancy sites increases, signaling Majorana teleportation. Furthermore, we clarify that the nonlocal correlation can be detected electrically via the measurement of nonlocal conductance between two vacancy sites, which is straightforwardly utilized for the readout of Majorana qubits. These findings pave the way to the measurement-based quantum computation with Ising anyons trapped in vacancies of the Kitaev spin liquid.

Instruments to assess post-intensive care syndrome assessment: a scoping review and modified Delphi method study.

BACKGROUND: The assessment of post-intensive care syndrome (PICS) is challenging due to the numerous types of instruments. We herein attempted to identify and propose recommendations for instruments to assess PICS in intensive care unit (ICU) survivors. METHODS: We conducted a scoping review to identify PICS follow-up studies at and after hospital discharge between 2014 and 2022. Assessment instruments used more than two times were included in the modified Delphi consensus process. A modified Delphi meeting was conducted three times by the PICS committee of the Japanese Society of Intensive Care Medicine, and each score was rated as not important (score: 1-3), important, but not critical (4-6), and critical (7-9). We included instruments with ≥ 70% of respondents rating critical and ≤ 15% of respondents rating not important. RESULTS: In total, 6972 records were identified in this scoping review, and 754 studies were included in the analysis. After data extraction, 107 PICS assessment instruments were identified. The modified Delphi meeting reached 20 PICS assessment instrument recommendations: (1) in the physical domain: the 6-min walk test, MRC score, and grip strength, (2) in cognition: MoCA, MMSE, and SMQ, (3) in mental health: HADS, IES-R, and PHQ-9, (4) in the activities of daily living: the Barthel Index, IADL, and FIM, (5) in quality of life: SF-36, SF-12, EQ-5D-5L, 3L, and VAS (6), in sleep and pain: PSQI and Brief Pain Inventory, respectively, and (7) in the PICS-family domain: SF-36, HADS, and IES-R. CONCLUSION: Based on a scoping review and the modified Delphi method, 20 PICS assessment instruments are recommended to assess physical, cognitive, mental health, activities of daily living, quality of life, sleep, and pain in ICU survivors and their families.

Imaging analysis of dural exposure in cholesteatomas with a skull base defect.

PURPOSE: Dural exposure during cholesteatoma surgery can pose a risk of cerebrospinal fluid leakage or residual disease. Therefore, delicate handling of the area surrounding the bone defect in the cranial fossa is required. However, in small-sized defects, preoperative prediction of dural exposure can be challenging. This study aimed to evaluate the diagnostic value of computed tomography (CT) for preoperative prediction of cholesteatoma-related dural exposure in bone discontinuities in the skull base. METHODS: We evaluated serial high-resolution CT images showing bone density discontinuities in the middle cranial fossa (MCF) requiring mastoidectomy for cholesteatoma. The CT and intraoperative findings were analyzed retrospectively. We evaluated the length between the superior margins of the bone density discontinuities using coronal CT planes. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cut-off values. RESULTS: We extracted data from 107 bone density discontinuities, among which 54 (50.5%) showed dural exposure intraoperatively. Discontinuities with dural exposure (n = 54) had significantly greater lengths than did those without (n = 53) (p < 0.001, Wilcoxon rank-sum test). The area under the curve was 0.9780 according to the ROC analysis, and the optimal cut-off value was determined to be 2.99 mm (sensitivity 92.59%; specificity 94.34%). CONCLUSION: A bone density discontinuity length of > 2.99 mm in the MCF on coronal CT plane is a reliable diagnostic marker for cholesteatoma-related dural exposure. Thus, preoperative high-resolution CT analysis can inform optimal surgical preparation and planning before manipulating the area surrounding the osteolytic lesion in the MCF.

Radiological and audiological predictors of stapes destruction in adherent pars tensa.

PURPOSE: Progressive adherent pars tensa occasionally induces ossicular erosion. Specifically, stapes discontinuity adversely affects postoperative hearing. However, this irretrievable sequela is challenging to prove preoperatively, partly because perimatrix inflammation on the pars tensa can obscure the visibility of the ossicles or the partial volume effect of computed tomography (CT) imaging can hamper detailed ossicular visualization. Therefore, there is no consensus regarding the ideal timing for switching from a wait-and-see approach to a surgical one. Herein, we aimed to explore the potential predictors of stapes superstructure destruction in adherent pars tensa. METHODS: This retrospective cohort study enrolled consecutive patients who underwent primary tympanoplasty for adherent pars tensa categorized as grade IV on Sadé's grading scale between April 2016 and September 2021. The impact of features on otoscopy and CT and air-bone gap (ABG) on stapes superstructure destruction was assessed using uni- and multivariable logistic regression analyses. RESULTS: Sixty-four ears were included. Multivariate analysis revealed the presence of debris on the adherent pars tensa (odds ratio [OR] [95% confidence interval {CI}]): 4.799 [1.063-21.668], p = 0.0415), presence of soft-tissue density occupying the oval window (OR [95% CI]: 13.876 [3.084-62.437], p = 0.0006), and a ≥ 20-dB preoperative ABG at 3 kHz (OR [95% CI]: 7.595 [1.596-36.132], p = 0.0108) as independent predictors for stapes superstructure destruction. CONCLUSION: High preoperative awareness of the possibility of destruction of the stapes superstructure would enable the surgeon to make a timely decision to provide surgical intervention before progression to severe stapes destruction, thereby maintaining long-term satisfactory hearing.

Radiological and audiological prediction for hearing outcome in cholesteatoma recidivism surgery.

PURPOSE: In cholesteatoma recidivism, achieving satisfactory hearing outcome after revision surgery remains challenging. The presence of concomitant recidivism pathology or related anatomical abnormalities can impact revision reconstruction of the sound transmission system. The current study aimed to identify prognostic factors affecting hearing outcomes after surgery for cholesteatoma recidivism. METHODS: This retrospective cohort study included consecutive patients whose ears required initial surgery for recidivism between January 2016 and December 2021. Patients followed up for < 6 months and those not indicated for ossiculoplasty were excluded. The impact of preoperative otoscopic findings, computed tomography (CT) features, and hearing levels on the prediction of satisfactory hearing (postoperative air-bone gap [ABG] ≤ 20 dB) was evaluated using univariate and multivariate logistic regression analyses. RESULTS: Overall, 102 patients were included, with a mean follow-up of 24.8 months. Multivariate logistic regression analysis revealed the following independent predictive factors for satisfactory hearing: presence of aeration in the tympanic cavity (odds ratio [OR] [95% confidence interval {CI}]: 13.287 [1.113-158.604], p = 0.0409), absence of soft-tissue density occupying the oval window (OR [95% CI]: 13.445 [3.178-56.887], p = 0.0040), and ≤ 22.5 dB preoperative ABG in four-frequency average (OR [95% CI]: 9.339 [2.026-43.050], p = 0.0042). CONCLUSIONS: For cholesteatoma recidivism, reliable preoperative prediction based on CT and ABG would facilitate decision-making regarding the probability of efficient revision ossiculoplasty or appropriate preoperative counseling, including early hearing rehabilitation using hearing aids or implementation of simultaneous implantable hearing equipment during surgery for recidivism.

Comparison of Maxillofacial Morphology Between Modified Furlow's and Modified two-Flap Palatoplasty in Orofacial Clefts During the Primary Dentition Period.

OBJECTIVE: To assess the effect of two palatoplasty procedures, modified Furlow's palatoplasty (F procedure) and modified two-flap palatoplasty (T procedure), on the maxillofacial morphology of unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) during the primary dentition period. DESIGN: Retrospective cohort study. SETTING: Department of Orthodontics, School of Dentistry, Showa University. PARTICIPANTS: We enrolled 106 pediatric patients (63 boys, 43 girls; aged 4.43 ± 0.34 years) with non-syndromic orofacial clefts who underwent cheiloplasty and palatoplasty. INTERVENTIONS: Patients were divided into four groups according to cleft type (BCLP or UCLP) and palatoplasty procedure type (F or T procedure). MAIN OUTCOME MEASURES: Maxillofacial morphology was assessed by examining parameters on lateral cephalograms. RESULTS: Multiple comparisons revealed significant differences among N-A, N-ANS, and ANS-PNS distances and SNA and ANB angles among the groups. There were significant differences in N-A, N-ANS, ANS-PNS, SNA, and SNB among the UCLP and BCLP groups. The calculated effect sizes were all within 0.3-0.5. The statistical power was as follows: N-A, 86.41%; N-ANS, 79.77%; ANS-PNS, 97.49%; SNA, 96.88%; and ANB, 99.25%. CONCLUSIONS: Although UCLP and BCLP both exhibited differences in craniofacial distances and angles, the procedure type (either F or T procedure) had no significant effect on the maxillofacial morphology (as determined by lateral cephalograms). However, to rule out additional bias, patient-specific factors should be considered that may be affected by maxillofacial development when deciding surgical approaches.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Population Pharmacokinetic Model of Amiodarone and N-Desethylamiodarone Focusing on Glucocorticoid and Inflammation.

Some population pharmacokinetic models for amiodarone (AMD) did not incorporate N-desethylamiodarone (DEA) concentration. Glucocorticoids activate CYP3A4 activity, metabolizing AMD. In contrast, CYP3A4 activity may decrease under inflammation conditions. However, direct evidence for the role of glucocorticoid or inflammation on the pharmacokinetics of AMD and DEA is lacking. The pilot study aimed to address this gap using a population pharmacokinetic analysis of AMD and DEA. A retrospective cohort observational study in adult patients who underwent AMD treatment with trough concentration measurement was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to March 2019. Both structural models of AMD and DEA applied 1-compartment models, which included significant covariates using a stepwise forward selection and backward elimination method. The eligible 81 patients (C-reactive protein level: 0.26 [interquartile range; 0.09-1.92] mg/dL) had a total of 408 trough concentrations for both AMD and DEA. The median trough concentrations were 0.49 [0.31-0.81] µg/mL for AMD and 0.43 [0.28-0.71] µg/mL for DEA during a median follow-up period of 446 [147-1059] d. Three patients received low-dose oral glucocorticoid. The final model identified that AMD clearance was 7.9 L/h, and the apparent DEA clearance was 10.3 L/h. Co-administered glucocorticoids lowered apparent DEA clearance by 35%. These results indicate that co-administered glucocorticoids may increase DEA concentrations in patients without severe inflammation.

Impact of Gleason pattern 5 on prognosis for newly diagnosed metastatic hormone-sensitive prostate cancer with Gleason score ≥8.

OBJECTIVE: We evaluated the impact of Gleason pattern 5 presence on prognosis among de novo metastatic hormone-sensitive prostate cancer patients with a Gleason score ≥8. METHODS: The data of 559 patients diagnosed as metastatic hormone-sensitive prostate cancer with a Gleason score ≥8, who were initially treated with androgen deprivation therapy from 2008 to 2016, were retrospectively collected. Patients were divided into two groups as high and low volume based on the CHAARTED trial criteria. RESULTS: The median overall survival of the 559 metastatic hormone-sensitive prostate cancer patients with Gleason score ≥8 was 70 months, with a median follow-up period of 36 months. Gleason pattern 5 was confirmed in 341 patients (61.0%), in which primary Gleason pattern 5 was confirmed in 164 patients (29.3%). The number of patients with high metastatic volume group was 363 (64.9%). In total and high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival, but both Gleason pattern 5 and primary Gleason pattern 5 did not show a statistically significant difference. In the low-volume metastatic group, the median overall survival in patients with or without primary Gleason pattern 5 was 40 and 78 months, respectively. In multivariate analysis, only primary Gleason pattern 5 was an independent predictive factor for overall survival in the low-volume metastatic group (hazard ratio 2.76, 95% confidence interval 1.88-8.67; P = 0.0026). CONCLUSION: The presence of Gleason pattern 5 was not associated with overall survival in metastatic hormone-sensitive prostate cancer with a Gleason score ≥8. In low-metastatic volume metastatic hormone-sensitive prostate cancer, primary Gleason pattern 5 was a poor prognostic factor, which might show a separate treatment option for this group.

The pre-chorda and post-chorda tympani approach in endoscopic stapes surgery based on the chorda tympani nerve classification.

PURPOSE: In most stapes surgeries, the posterior ear canal is enlarged and a piston is inserted posterior to the chorda tympani nerve (post-chorda tympani approach; Post C). Although reports vary, some indicate that more than 60% of the patients experience lingual symptoms following surgery. Endoscopic surgery may permit an anterior approach to the nerve (pre-chorda tympani approach; Pre C). Herein, we propose a suitable approach for endoscopic stapes surgery based on the classification of the chorda tympani nerve. METHODS: We retrospectively reviewed the medical records of 23 patients who underwent endoscopic stapes surgery at our institution between 2019 and 2021. The nerve classification previously reported, the modified nerve classification (attached long type is divided into Category 1: lenticular process is visible with 0° endoscope and Category 2: not visible), selected approach (Pre C or Post C), use of a 30° endoscope, and manipulation of the nerve (number of contacts and traction, with or without suction, with or without malposition or extension and amputation, and damage score) were evaluated. RESULTS: The damage score was significantly lower in the Pre C group (p < 0.05); however, using this approach for all cases is not desirable owing to the high risk of damage to the nerve during posterior malpositioning. CONCLUSION: The Post C should be used for the detached and attached long 1 types, while the Pre C with a 30° endoscope should be used for the attached long 2, attached short, ultrashort, and external auditory canal types.

Retrograde mastoidectomy with canal wall reconstruction versus intact canal wall tympanomastoidectomy for cholesteatoma with minimal mastoid extension.

PURPOSE: Appropriate reconstruction of the canal wall or maintenance of the middle ear pressure in cholesteatoma may help in preventing recurrence. Retrograde mastoidectomy with canal wall reconstruction (RMR) can overcome the challenge of a wider canal wall defect or temporal bone immaturity, which possibly increases the recurrence risk. This study compared the outcomes of RMR and intact canal wall tympanomastoidectomy (ICW) for cholesteatomas with minimal mastoid extension and quantitatively evaluate the relationship between anatomical features and recurrence. METHODS: This single-center retrospective cohort study included patients who had undergone primary ICW or RMR for pars flaccida cholesteatoma with minimal mastoid extension from 2009 to 2019. The main outcome measures were anatomical measurements of the shortest distance between the cranial fossa and the upper canal wall (SCU), attic volume, and bony defect area of the canal wall (BDC) on computed tomography; recidivism; and postoperative air-bone gap (ABG). RESULTS: There were no significant differences in the preoperative anatomical factors, recidivism incidence, and postoperative ABG between the RMR (n = 20) and ICW (n = 60) groups. However, the median BDC was significantly greater in the RMR group (58.3 vs. 37.0 mm2). There was no significant difference in the SCU and attic volume between patients with and without recurrence. CONCLUSION: Selection of RMR or ICW may not affect recidivism and hearing outcomes in cholesteatoma with minimal mastoid extension. Bony defect size and attic narrowness were not associated with recurrence. Considering wider visualization and one-staged operation, RMR can be more adaptable than ICW for cholesteatoma with minimal mastoid extension.

Methods in Genetic Analysis for Evaluation Mandibular Shape and Size Variations in Human Mandible.

ABSTRACT: The human mandible has been investigated from both clinical and evolutionary perspectives. Recent advances in genome science have identified the genetic regulation of human mandibular shape and size. Identification of genes that regulate mandibular shape and size would not only enhance our understanding of the mechanisms of mandibular growth and development but also help define a strategy to prevent mandibular dysplasia. This review provides a comprehensive summary of why and how the mandible was evaluated in the human mandible genome study. The variation in human mandibular shape and size has been progressively clarified, not only by focusing on the mandible alone but also by using extremely diverse approaches. The methods of data acquisition for evaluating human mandibular shape and size variation are well established. Furthermore, this review explains how to proceed with future research.

Three-Dimensional Assessment of Craniofacial Features in Patients With Down Syndrome During the Mixed Dentition Period: A Case-Control Study.

OBJECTIVES: Down syndrome (DS) is a common congenital chromosomal disorder related to trisomy 21. Lateral cephalometric radiography studies have shown that patients with DS have characteristic craniofacial morphology; however, no 3-dimensional analysis studies have been performed to investigate the craniofacial features, including volumetric aspects, of patients with DS. The present study was performed to evaluate the craniofacial features, including volumetric aspects, of patients with DS and to compare these findings with control participants using cone beam computed tomography (CBCT). MATERIALS AND METHODS: The study sample consisted of 12 patients with DS and 12 control participants. All participants were examined by means of CBCT; the resulting images were used for evaluation of maxillary and mandibular volume, cranial base, and craniofacial measurements. Differences between patients with DS and control participants were statistically analyzed using Student t test. RESULTS: Compared to control participants, patients with DS exhibited statistically significant reductions in maxillary and mandibular volumes. Both sagittal and axial cranial base linear measurements were shorter in patients with DS than in control participants. In contrast, the cranial base angle was enhanced in patients with DS, compared with control participants. Moreover, condylion (Co)-gnathion, anterior nasal spine-menton, and Co-subspinale (point A) measurements were shorter in patients with DS than in control participants; the sella-nasion-mandibular plane angle was significantly reduced in patients with DS, compared with control participants. CONCLUSION: Our results suggest that patients with DS have distinct skeletal volume and craniofacial morphology features, relative to individuals without DS.

[The Usefulness of Preoperative Modified Glasgow Prognostic Score Evaluation in Elderly Colorectal Cancer Cases].

BACKGROUND: In cancer treatment of the elderly, it is important to grasp the"degree of inflammation"and"nutritional status"in advance. OBJECTIVE: This study aims to investigate the usefulness of preoperative modified Glasgow Prognostic score(mGPS)evaluation in elderly patients with colorectal cancer. PATIENT: 89 cases of primary resection of colorectal cancer over 80 years old were enrolled. METHODS: In the preoperative mGPS score normal group(score 0)and abnormal group (scores 1 or 2)were divided. Clinicopathological factors(patient-related 13 factors, treatment-related 6 factors, and tumor-related 4 factors)were compared, and the long-term results were also investigated. RESULTS: Between 42 cases in the normal group and 47 cases in the abnormal group, there were significant differences(p<0.05)in 6 factors: BMI, total protein, cholinesterase, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and Onodera prognostic nutritional index. The long-term results(5-year survival rate)were also significantly different in the normal group(76.8%)and the abnormal group(51.6%)(p=0.007). CONCLUSION: Even in elderly patients with colorectal cancer, preoperative suppression of inflammatory conditions and improvement of nutritional status may contribute to the improvement of long-term prognosis, so mGPS evaluation is useful.

[Long-Term Response of Nivolumab for Peritoneal Dissemination and Recurrent Liver Metastasis after Surgery for Perforated Gastric Cancer-A Case Report].

A 39-year-old woman was hospitalized because of lower abdominal pain and fatigue. A laboratory study indicated severe anemia(hemoglobin 2.5 g/dL). Computed tomography(CT)revealed a perforated gastric tumor and free air. Distal gastrectomy was performed as an emergency surgery. Histopathologic examination showed adenocarcinoma(moderately differentiated > poorly differentiated), and she was diagnosed as having a pT4b, pN0, pM1, pStage ⅣB tumor. Postoperatively, adjuvant chemotherapy with S-1 was administered. CT imaging 2 years after the operation showed peritoneal dissemination and liver metastasis, and XELOX therapy was initiated. Response evaluation after 3 courses was progressive disease (PD), and ramucirumab plus paclitaxel was initiated. After 5 courses, CT imaging revealed ascites and progression of peritoneal dissemination and liver metastasis; nivolumab was initiated. CT imaging after 74 courses showed peritoneal dissemination, and liver metastasis became unclear. The patient at present has responded well to nivolumab for 52 months.

Neural crest-derived cells in nasal conchae of adult mice contribute to bone regeneration.

Neural crest-derived cells (NCDCs), a class of adult stem cells not restricted to embryonic tissues, are attractive tissue regenerative therapy candidates because of their ease of isolation, self-renewing properties, and multipotency. Although adult NCDCs can undergo osteogenic differentiation in vitro, whether they induce bone formation in vivo remains unclear. Previously, our group reported findings showing high amounts of NCDCs scattered throughout nasal concha tissues of adult mice. In the present study, NCDCs in nasal conchae labeled with enhanced green fluorescent protein (EGFP) were collected from adult P0-Cre/CAG-CAT-EGFP double transgenic mice, then cultured in serum-free medium to increase the number. Subsequently, NCDCs were harvested and suspended in type I atelocollagen gel, then an atelocollagen sponge was used as a scaffold for the cell suspension. Atelocollagen scaffolds with NCDCs were placed on bone defects created in a mouse calvarial bone defect model. Over the ensuing 12 weeks, micro-CT and histological analysis findings showed that mice with scaffolds containing NCDCs had slightly greater bone formation as compared to those with a scaffold alone. Furthermore, Raman spectroscopy revealed spectral properties of bone in mice that received scaffolds with NCDCs similar to those of native calvarial bone. Bone regeneration is important not only for gaining bone mass but also chemical properties. These results are the first to show the validity of biomolecule-free adult nasal concha-derived NCDCs for bone regeneration, including the chemical properties of regenerated bone tissue.

Factors related to specialized palliative care use and aggressive care at end of life in Japanese patients with advanced solid cancers: a cohort study.

PURPOSE: This study aimed to (1) describe characteristics of aggressive care at the end of life (EOL) and (2) identify factors associated with specialized palliative care use (SPC) and aggressive care at the EOL among Japanese patients with advanced cancer. METHODS: This single-center, follow-up cohort study involved patients with advanced cancer who received chemotherapy at Tohoku University Hospital. Patients were surveyed at enrollment, and we followed clinical events for 5 years from enrollment in the study. We performed multivariate logistic regression analysis to identify independent factors related to SPC use and chemotherapy in the last month before death. RESULTS: We analyzed a total of 135 patients enrolled between January 2015 and January 2016. No patients were admitted to the intensive care unit, and few received resuscitation or ventilation. We identified no factors significantly associated with SPC use. Meanwhile, younger age (20-59 years, odds ratio [OR] 4.10; 95% confidence interval [CI] 1.30-12.91; p = 0.02) and no receipt of SPC (OR 4.32; 95% CI 1.07-17.37; p = 0.04) were associated with chemotherapy in the last month before death. CONCLUSION: Younger age and a lack of SPC were associated with chemotherapy at the EOL in patients with advanced cancer in Japan. These findings suggest that Japanese patients with advanced cancer may benefit from access to SPC.

Spatiotemporal ATP Dynamics during AKI Predict Renal Prognosis.

BACKGROUND: Depletion of ATP in renal tubular cells plays the central role in the pathogenesis of kidney diseases. Nevertheless, inability to visualize spatiotemporal in vivo ATP distribution and dynamics has hindered further analysis. METHODS: A novel mouse line systemically expressing an ATP biosensor (an ATP synthase subunit and two fluorophores) revealed spatiotemporal ATP dynamics at single-cell resolution during warm and cold ischemic reperfusion (IR) with two-photon microscopy. This experimental system enabled quantification of fibrosis 2 weeks after IR and assessment of the relationship between the ATP recovery in acute phase and fibrosis in chronic phase. RESULTS: Upon ischemia induction, the ATP levels of proximal tubule (PT) cells decreased to the nadir within a few minutes, whereas those of distal tubule (DT) cells decreased gradually up to 1 hour. Upon reperfusion, the recovery rate of ATP in PTs was slower with longer ischemia. In stark contrast, ATP in DTs was quickly rebounded irrespective of ischemia duration. Morphologic changes of mitochondria in the acute phase support the observation of different ATP dynamics in the two segments. Furthermore, slow and incomplete ATP recovery of PTs in the acute phase inversely correlated with fibrosis in the chronic phase. Ischemia under conditions of hypothermia resulted in more rapid and complete ATP recovery with less fibrosis, providing a proof of concept for use of hypothermia to protect kidney tissues. CONCLUSIONS: Visualizing spatiotemporal ATP dynamics during IR injury revealed higher sensitivity of PT cells to ischemia compared with DT cells in terms of energy metabolism. The ATP dynamics of PTs in AKI might provide prognostic information.