Capturing the generation and structural transformations of molecular ions.

Molecular ions are ubiquitous and play pivotal roles1-3 in many reactions, particularly in the context of atmospheric and interstellar chemistry4-6. However, their structures and conformational transitions7,8, particularly in the gas phase, are less explored than those of neutral molecules owing to experimental difficulties. A case in point is the halonium ions9-11, whose highly reactive nature and ring strain make them short-lived intermediates that are readily attacked even by weak nucleophiles and thus challenging to isolate or capture before they undergo further reaction. Here we show that mega-electronvolt ultrafast electron diffraction (MeV-UED)12-14, used in conjunction with resonance-enhanced multiphoton ionization, can monitor the formation of 1,3-dibromopropane (DBP) cations and their subsequent structural dynamics forming a halonium ion. We find that the DBP+ cation remains for a substantial duration of 3.6 ps in aptly named 'dark states' that are structurally indistinguishable from the DBP electronic ground state. The structural data, supported by surface-hopping simulations15 and ab initio calculations16, reveal that the cation subsequently decays to iso-DBP+, an unusual intermediate with a four-membered ring containing a loosely bound17,18 bromine atom, and eventually loses the bromine atom and forms a bromonium ion with a three-membered-ring structure19. We anticipate that the approach used here can also be applied to examine the structural dynamics of other molecular ions and thereby deepen our understanding of ion chemistry.

Cerium Photocatalyst in Action: Structural Dynamics in the Presence of Substrate Visualized via Time-Resolved X-ray Liquidography.

[Ce(III)Cl6]3-, with its earth-abundant metal element, is a promising photocatalyst facilitating carbon-halogen bond activation. Still, the structure of the reaction intermediate has yet to be explored. Here, we applied time-resolved X-ray liquidography (TRXL), which allows for direct observation of the structural details of reaction intermediates, to investigate the photocatalytic reaction of [Ce(III)Cl6]3-. Structural analysis of the TRXL data revealed that the excited state of [Ce(III)Cl6]3- has Ce-Cl bonds that are shorter than those of the ground state and that the Ce-Cl bond further contracts upon oxidation. In addition, this study represents the first application of TRXL to both photocatalyst-only and photocatalyst-and-substrate samples, providing insights into the substrate's influence on the photocatalyst's reaction dynamics. This study demonstrates the capability of TRXL in elucidating the reaction dynamics of photocatalysts under various conditions and highlights the importance of experimental determination of the structures of reaction intermediates to advance our understanding of photocatalytic mechanisms.

Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis.

Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.

Retreatment of Irinotecan in Later Lines of Therapy for Metastatic Colorectal Cancer: A Retrospective Study.

BACKGROUND: Due to few efficacious options in later lines of therapy in metastatic colorectal cancer (mCRC), there has been considerable interest in the possibility of retreatment with previously administered agents. This study investigated the efficacy and safety of irinotecan retreatment (IRI2) in patients with refractory mCRC. METHODS: We performed a retrospective analysis of patients with mCRC who were retreated with irinotecan-based regimens. The retreatment regimens with anti-epidermal growth factor receptor therapies were excluded. RESULTS: A total of 64 patients were included. Patients had a median age of 56 years and were offered mainly in the setting of third- or fourth-line therapy with IRI2. The disease control rate was 78.2% including an objective response of 23.5%. Median progression-free survival and overall survival were 5.5 and 19.3 months, respectively. The most frequent grade 3 or higher toxicities were nausea/vomiting (27.9%) and neutropenia (25%). CONCLUSION: IRI2 might be a reasonable option for heavily pretreated patients with mCRC who achieved disease control with prior irinotecan therapy.

Cross training effects of non-paralytic dorsiflexion muscle strengthening exercise on paralytic dorsiflexor muscle activity, gait ability, and balancing ability in patients with chronic stroke: A randomized, controlled, pilot trial.

OBJECTIVE: To investigate the effects of non-paralytic dorsiflexion muscle strengthening exercise on functional abilities in chronic hemiplegic patients after stroke. METHODS: A total of 21 patients with chronic stroke underwent dorsiflexion muscle strengthening exercise (MST) 5 times a week for 6 weeks (the experimental group, MST to non-paralytic dorsiflexion muscles, n=11; the control group, MST to paralytic dorsiflexion muscles; n=10). Paralytic dorsiflexor muscle activities (DFA) and 10 m walking tests (10MWT) and timed up and go tests (TUG) were measured before and after intervention. RESULTS: A significant increase in DFA was observed after intervention in the experimental and control groups (p<0.05) (experimental 886.6% for reference voluntary contraction (RVC), control 931.6% for RVC). TUG and 10MWT results showed significant reductions post-intervention in the experimental and control groups (experimental group -5.6 sec, control -4.8 sec; experimental group -3.1 sec, control, -3.9 sec; respectively). No significant intergroup difference was observed between changes in DFA or between changes in TUG and 10MWT results after intervention (p>.05). CONCLUSION: Strengthening exercise performed on non-paralytic dorsiflexion muscles had positive cross-training effects on paralytic dorsiflexor muscle activities, balance abilities, and walking abilities in patients with chronic stroke.

Pelvic Belt Wearing during Exercise Improves Balance of Patients with Stroke: A Randomized, Controlled, Preliminary Trial.

OBJECTIVES: To investigate whether wearing a pelvic belt during a trunk stability exercise program positively affects balance in patients with stroke. MATERIALS AND METHODS: Twenty-four patients with stroke were randomly allocated to the experimental or control group and performed a 60-min general physical therapy and an additional 30-min trunk stability exercise (five times/week for 6 weeks). Those in the experimental and control groups performed the trunk stability exercises with and without wearing the pelvic belt, respectively. RESULTS: The experimental group showed a significantly greater magnitude of improvements in balance than the control group (Postural Assessment Scale for Stroke: +18.3%, F (1, 22)=14.350, p=.001, η2=.395; Berg Balance Scale: +11%, F (1, 22)=19.062, p=.000, η2=.464; Timed Up and Go Test: -10.5%, F (1, 22)=8.562, p=.008, η2=.280; center of pressure path length with eyes open: -15.1%, F (1, 22)=6.770, p=.016, η2=.235; center of pressure path length with eyes closed: -19.5%, F (1, 22)=9.256, p=.006, η2=.296; center of pressure path velocity with eyes open: -22.6%, F (1, 22)=37.747, p=.000, η2=.632; center of pressure path velocity with eyes closed: -13.9%, F (1, 22)=6.511, p=.018, η2=.228, respectively). CONCLUSIONS: Wearing a pelvic belt while performing trunk stability exercise programs could be a more effective approach for improving balance in patients with stroke.

Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

BACKGROUND: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR. METHODS: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-ß, and PI3K). RESULTS: Mutation of genes within the WNT, P53, RTK-RAS, TGF-ß, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-ß pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-ß pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-ß pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-ß pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation. CONCLUSIONS: Mutation in genes within TGF-ß pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.

Analysis of unexplained carcinoembryonic antigen elevation after curative treatment of locally advanced rectal cancer.

BACKGROUND: To analyze the causes and patterns of unexplained carcinoembryonic antigen (CEA) elevation after curative treatment in locally advanced rectal cancer patients. METHODS: Among the 1309 locally advanced rectal cancer patients treated with curative resection and radiotherapy between January 2001 and June 2011, 325 patients who postoperatively developed abnormal CEA elevation were reviewed. The unexplained CEA elevation was defined as a CEA level higher than 5 ng/mL with no evidence of cancer recurrence at the time of elevation. RESULTS: Of the 325 patients, 143 (44%) had unexplained CEA elevations. The causes were categorized as delayed recurrence (n = 29, 20%), non-colorectal malignancy (n = 10, 7%), and non-malignancy-related conditions (n = 104, 73%). Shorter intervals between treatment and the first CEA elevation, and a higher peak CEA level, were observed in the delayed recurrence group compared with the non-colorectal malignancy or non-malignancy-related group (intervals of 6.8 vs. 44.9 vs. 23.2 months, respectively, p = 0.002; and peak CEA levels of 9.9 vs. 7.1 vs. 6.2 ng/mL, respectively, p = 0.034). In patients who showed delayed recurrence, the interval between the first CEA elevation and diagnosis of recurrence was a median of 13.0 months (range 3.8-60.6 months). Smoking was the most common cause for non-malignancy-related conditions. The patterns of unexplained CEA elevations were defined as sporadic (n = 78, 55%), stationary (n = 37, 26%), and increasing (n = 28, 20%). The patterns were significantly different depending on the cause (p < 0.001). CONCLUSIONS: Analysis of the patterns of unexplained CEA elevations is a reasonable approach to predict the cause of the cancer.

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor ß [TGF-ß]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-ß pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23. © 2017 American Cancer Society.

Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system.

BACKGROUND: Colorectal cancer (CRC) is a heterogeneous disease in terms of molecular carcinogenic pathways. Based on recent findings regarding the multiple serrated neoplasia pathway, we revised an eight-marker panel for a new CIMP classification system. METHODS: 1370 patients who received surgical resection for CRCs were classified into three CIMP subtypes (CIMP-N: 0-4 methylated markers, CIMP-P1: 5-6 methylated markers and CIMP-P2: 7-8 methylated markers). Our findings were validated in a separate set of high-risk stage II or stage III CRCs receiving adjuvant fluoropyrimidine plus oxaliplatin (n=950). RESULTS: A total of 1287/62/21 CRCs cases were classified as CIMP-N/CIMP-P1/CIMP-P2, respectively. CIMP-N showed male predominance, distal location, lower T, N category and devoid of BRAF mutation, microsatellite instability (MSI) and MLH1 methylation. CIMP-P1 showed female predominance, proximal location, advanced TNM stage, mild decrease of CK20 and CDX2 expression, mild increase of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-P2 showed older age, female predominance, proximal location, advanced T category, markedly reduced CK20 and CDX2 expression, rare KRAS mutation, high frequency of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-N showed better 5-year cancer-specific survival (CSS; HR=0.47; 95% CI: 0.28-0.78) in discovery set and better 5-year relapse-free survival (RFS; HR=0.50; 95% CI: 0.29-0.88) in validation set compared with CIMP-P1. CIMP-P2 showed marginally better 5-year CSS (HR=0.28, 95% CI: 0.07-1.22) in discovery set and marginally better 5-year RFS (HR=0.21, 95% CI: 0.05-0.92) in validation set compared with CIMP-P1. CONCLUSIONS: CIMP subtypes classified using our revised system showed different clinical outcomes, demonstrating the heterogeneity of multiple serrated precursors of CIMP-positive CRCs.

Action observation training of community ambulation for improving walking ability of patients with post-stroke hemiparesis: a randomized controlled pilot trial.

PURPOSE: To investigate the effects of action observation training involving community-based ambulation for improving walking ability after stroke. DESIGN: Randomized, controlled pilot study. SETTING: Inpatient rehabilitation hospital. SUBJECTS: A total of 25 inpatients with post-stroke hemiparesis were randomly assigned to either the experimental group ( n = 12) or control group ( n = 13). INTERVENTION: Subjects of the experimental group watched video clips demonstrating four-staged ambulation training with a more complex environment factor for 30 minutes, three times a week for four weeks. Meanwhile, subjects of the control group watched video clips, which showed different landscape pictures. MAIN MEASURES: Walking function was evaluated before and after the four-week intervention using a 10-m walk test, community walk test, activities-specific balance confidence scale, and spatiotemporal gait measures. RESULTS: Changes in the values for the 10-m walk test (0.17 ±0.19 m/s vs. 0.05 ±0.08 m/s), community walk test (-151.42 ±123.82 seconds vs. 67.08 ±176.77 seconds), and activities-specific balance confidence (6.25 ±5.61 scores vs. 0.72 ±2.24 scores) and the spatiotemporal parameters (i.e. stride length (19.00 ±11.34 cm vs. 3.16 ±11.20 cm), single support (5.87 ±5.13% vs. 0.25 ±5.95%), and velocity (15.66 ±12.34 cm/s vs. 2.96 ±10.54 cm/s)) indicated a significant improvement in the experimental group compared with the control group. In the experimental group, walking function and ambulation confidence was significantly different between the pre- and post-intervention, whereas the control group showed a significant difference only in the 10-m walk test. CONCLUSIONS: Action observation training of community ambulation may be favorably used for improving walking function of patients with post-stroke hemiparesis.

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer.

BACKGROUND: The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. METHODS: Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0). RESULTS: A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001). CONCLUSIONS: The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

Identification of long-range epigenetic silencing on chromosome 15q25 and its clinical implication in gastric cancer.

Recent genome-wide epigenomic and transcription profiling studies have demonstrated that epigenetic silencing can encompass multiple neighboring genes, termed as long-range epigenetic silencing (LRES). Herein, we identified a novel LRES region by comparing gene expression of human colon cancer HCT116 cells with their DNA methyltransferase 1 and DNA methyltransferase 3B double-knockout derivative double-knockout cells. Ten consecutive genes spanning 3 Mb of chromosome 15q25 were coordinately silenced, with eight genes showing promoter CpG island hypermethylation and enrichment of repressive histone marks, which were evaluated by bisulfite sequencing analysis and chromatin immunoprecipitation assay. Comparison of primary gastric tumor specimens with normal tissue confirmed that the long-range silencing of this region was tumor specific. Methylation of genes within the LRES region was evaluated in 190 gastric tumor tissues using the MethyLight assay, and their association with clinicopathological features, such as older age, high-grade differentiation, and diffuse or mixed-type histology, was determined. LRES-positive gastric cancer patients (six or more methylated genes) showed lower recurrence and better survival. Our findings emphasize the differential dynamics of DNA methylation and histone modification, indicating the importance of studying the relationship of each epigenetic modification in the context of chromatin domains. Patients with LRES showed lower recurrence and better prognosis, indicating that stratifying patients according to underlying molecular features, such as LRES regions, may better predict recurrence and survival.

Prognostic influence of body mass index and body weight gain during adjuvant FOLFOX chemotherapy in Korean colorectal cancer patients.

BACKGROUND: Asian population has different body mass index (BMI) profile compared to Caucasian population. However, the effect of obesity and body weight gain in Asian colorectal cancer patients treated with adjuvant chemotherapy has not been studied thus far. METHODS: We have analyzed the association between disease-free survival (DFS) and obesity/body weight change during treatment in Korean stage III or high-risk stage II colorectal cancer patients treated with adjuvant 5-fluorouracil/ leucovorin/oxaliplatin. BMI was classified according to WHO Asia-Pacific classification. Weight change was calculated by comparing body weights measured at the last chemotherapy cycle and before surgery. RESULTS: Among a total of 522 patients, 35.7 % of patients were obese (BMI ≥ 25 kg/m(2)) and 29.1 % were overweight (BMI, 23-24.9 kg/m(2)) before surgery. 18.0 % of patients gained ≥ 5 kg and 26.1 % gained 2-4.9 kg during the adjuvant chemotherapy period. Baseline BMI or body weight change was not associated with DFS in the overall study population. However, body weight gain (≥5 kg) was associated with inferior DFS (adjusted hazard ratio 2.04, 95 % confidence interval 1.02-4.08, p = 0.043) in overweight and obese patients (BMI ≥ 23.0 kg/m(2)). CONCLUSION: In Korean colorectal cancer patients treated with adjuvant FOLFOX chemotherapy, body weight gain during the treatment period has a negative prognostic influence in overweight and obese patients.

Effect of gait training with constrained-induced movement therapy (CIMT) on the balance of stroke patients.

[Purpose] The purpose of the present study was to examine the effect of intensive gait training using a constrained induced movement therapy (CIMT) technique applied to the non-paretic upper extremity on the balance ability of stroke patients. [Subjects and Methods] Twenty stroke patients were randomly assigned to an experimental group or a control group. The experimental group received gait training with CIMT for 30 minutes per session, three sessions per week for four weeks, and the control group received gait training alone. [Results] The experimental group showed improvements in dynamic balance and the degree of improvement in this group was greater than that observed in the control group. Furthermore, the experimental group showed improvements in movement distances to the paretic side. On the other hand, the control group showed no significant improvements in balance indices after the intervention. [Conclusion] Gait training of stroke patients using CIMT techniques should be regarded as a treatment that can improve the balance of stroke patients.

Isokinetic training effect of ankle positions on knee extensor strength.

[Purpose] The purpose of this study was to determine which ankle position most influences knee extensor strength in training programs for strengthening the knee extensors using three different active ankle positions. [Subjects] Twenty-one healthy adults (6 males and 15 females) participated in this study. [Methods] Subjects were trained isokinetically in knee extension and flexion at 70 or 80% of 1RM under three actively and naturally fixed, contracted ankle conditions: dorsiflexion, plantarflexion, and resting position. After each group successfully executed the training four times a week for three weeks, mean peak torque (PT) and total work (TW) variables were measured and compared at 60°/sec and 180°/sec among the three groups. [Results] Significant differences were revealed in knee extensor TW at 60°/sec, PT and TW at 180°/sec, with the greatest PT and TW observed with the ankle in active dorsiflexion position. [Conclusion] These results suggest that active ankle dorsiflexion in a knee strength training program may be more effective at increasing knee extensor strength than a resting or plantarflexion position.

Comparison of the plantar pressure distributions at different degrees of tilting: a preliminary report.

[Purpose] The purpose of this study was to investigate the amount of plantar pressures on the lower limb during tilt table standing and to indicate the ideal degree of tilting for partial weight bearing. [Subjects and Methods] Fifteen healthy subjects between the ages of 20 and 30 were recruited as volunteers for this study. All the measurements were taken while standing on a tilt table according to different inclination angles. [Results] The plantar pressures for 60° tilt table standing were lower by 7-9% of total body weight than the pressures during tilt table standing at 90°, and the pressures for 30° tilt table standing were lower by 18-20% of total body weight than the pressures for tilt table standing at 90°. [Conclusion] Standing training on a 60° tilt table might be equivalent to 80% of full weight bearing training, and tilt table standing training at 30° might be equivalent to 60% of full weight bearing training.

Determination of the Optimal Concentration of Natural Antimicrobial Agents in Marinade Sauce for Meal Kits.

This study aimed to determine the antimicrobial effectiveness of natural antimicrobial agents (NAAs) (yuzu juice, wasabi extract, and rosemary extract) against three target microorganisms (TMs) (Escherichia coli, Staphylococcus aureus, and Salmonella Typhimurium) and to determine the optimal concentration of these agents using response surface methodology (RSM) to ensure the safety of meal kits manufactured using marinade sauce. The three NAAs added to marinade sauce effectively inactivated TMs (P<0.05), in particular, yuzu juice had the greatest antimicrobial effect against TMs, followed by wasabi and rosemary extracts. To determine the optimal concentration of NAAs using RSM, 17 concentrations were tested with three TMs as dependent variables and three NAAs as independent variables. The results showed that E. coli was not present under any of the conditions tested, whereas S. aureus and S. Typhimurium exhibited different characteristics depending on the conditions. Through response surface analysis of the TMs except for E. coli, which was not detected, it was determined that S. aureus had a coefficient of determination (R2) of 0.928 and a lack of fit of 0.074, and the linear regression of [yuzu juice] (X1) and quadratic regression of [yuzu juice]2 (X12) were both significant (P<0.05). S. Typhimurium had an R2 of 0.8955 and a lack of fit of 0.051, and only the quadratic regression of [yuzu juice]2 (X12) was significant (P<0.05). Based on RSM and ridge analysis, the optimal mixed conditions were determined to be 3.92% (v/w) yuzu juice, 23.41% (v/w) wasabi extract, and 3.93% (v/w) rosemary extract. After investigating the antimicrobial effect under the optimal conditions, E. coli and S. Typhimurium were absent, and S. aureus was reduced to 2.50 ± 0.09 log colony-forming units/g after 24 h. The results indicated that mixed treatment with the three NAAs had a more significant antimicrobial effect due to their synergistic properties compared to when used in isolation.

A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer.

PURPOSE: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). MATERIALS AND METHODS: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. RESULTS: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). CONCLUSION: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Dynamic three-dimensional structures of a metal-organic framework captured with femtosecond serial crystallography.

Crystalline systems consisting of small-molecule building blocks have emerged as promising materials with diverse applications. It is of great importance to characterize not only their static structures but also the conversion of their structures in response to external stimuli. Femtosecond time-resolved crystallography has the potential to probe the real-time dynamics of structural transitions, but, thus far, this has not been realized for chemical reactions in non-biological crystals. In this study, we applied time-resolved serial femtosecond crystallography (TR-SFX), a powerful technique for visualizing protein structural dynamics, to a metal-organic framework, consisting of Fe porphyrins and hexazirconium nodes, and elucidated its structural dynamics. The time-resolved electron density maps derived from the TR-SFX data unveil trifurcating structural pathways: coherent oscillatory movements of Zr and Fe atoms, a transient structure with the Fe porphyrins and Zr6 nodes undergoing doming and disordering movements, respectively, and a vibrationally hot structure with isotropic structural disorder. These findings demonstrate the feasibility of using TR-SFX to study chemical systems.