Metasurface Biosensors Enabling Single-Molecule Sensing of Cell-Free DNA.

In this study, we have revealed that highly fluorescence (FL)-enhancing all-dielectric metasurface biosensors are capable of detecting single-target DNA, which is cell-free DNA (cfDNA) specific to the human practice effect. The ultimately high-precision detection was achieved in a scheme combining the metasurface biosensors with a short-time nucleic acid amplification technique, that is, a reduced-cycle polymerase chain reaction (PCR). In this combined scheme, we obtained a series of FL signals at a single-molecule concentration, reflecting the Poisson distribution, and moreover elucidated that the FL signals exhibit the single-molecule cfDNA detection with more than 84% statistical confidence in an automated FL detection system and with 99.9% statistical confidence in confocal FL microscopy. As a result, we have found a simple and practical test to discriminate the target of 1 copy/test from zero using metasurface biosensors, which has not been realized by other elaborate techniques such as digital PCR.

Outcomes of surgical resection for pulmonary metastasis from pancreatic cancer.

PURPOSE: As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer. METHOD: We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed. RESULTS: The observation period was 20 (range, 1-101) months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15 months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival. CONCLUSION: A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15 months. Our findings suggest that the disease-free interval may influence the prognosis.

Appraisal of ICH E14/S7B Q&As adopted in February 2022 using thorough QT/QTc study data for α4-integrin antagonist carotegrast methyl in Japanese healthy subjects.

We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF with the largest mean values (90% confidence interval) of 12.1 ms (9.3, 14.8) and 15.4 ms (12.6, 18.1), respectively. Meanwhile, carotegrast methyl hardly altered ΔQTcF and ΔΔQTcF with the largest mean values of 0.8 ms (-2.3, 3.9) and 2.1 ms (-0.7, 4.8) for the low dose, and -0.2 ms (-3.4, 3.0) and 1.6 ms (-0.9, 4.2) for the high dose, respectively. In concentration-response analysis, moxifloxacin attained the estimated mean values for ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean Cmax, whereas carotegrast methyl provided those of -4.6 ms (-7.3, -1.9) and 0.7 ms (-1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q&As.

Muscle stiffening is associated with muscle mechanoreflex-mediated cardioacceleration.

PURPOSE: Although the muscle mechanoreflex is an important mediator to cardiovascular regulation during exercise, its modulation factors remain relatively unknown. Therefore, the purpose of this study was to investigate the effect of muscle stiffness on the muscle mechanoreflex. METHODS: Participants were divided based on their median muscle stiffness (2.00 Nm/mm) into a low group (n = 15) and a high group (n = 15), and the muscle mechanoreflex was compared between the groups. After a 15-min rest in the supine position, heart rate (HR), blood pressure (BP), stroke volume (SV), and cardiac output (CO) were measured at rest for 3 min and during static passive dorsiflexion (SPD) at 20° for 1 min. Following a 15-min re-rest, muscle stiffness and passive resistive torque were evaluated in the distal end of the muscle belly of the medial gastrocnemius. RESULTS: Peak relative changes in HR (low group: 6 ± 4% and high group: 12 ± 4%) and CO (low group: 8 ± 10% and high group: 13 ± 9%) were greater in the high group than in the low group (both, P < 0.05). A significant positive correlation was found between resistive torque during SPD and muscle stiffness and peak relative changes in HR (r = 0.51 and 0.61, both P < 0.05). However, there was no correlation between muscle elongation during SPD and peak relative changes in HR (r = - 0.23, P = 0.20). CONCLUSION: These findings suggest that muscle stiffness may be modulatory factor of muscle mechanoreflex.

Eigenmode symmetry assignment of triangular-lattice photonic crystal slabs and their Dirac cones materialized by effective degeneracy in the mid-infrared region.

We measured angle-resolved reflection spectra of triangular-lattice photonic crystal slabs fabricated in a silicon-on-insulator wafer in the mid-infrared region. We achieved a high angle-resolution measurement by means of our homemade optical setup integrated in the sample chamber of an FT-IR spectrometer. By examining the reflection peak frequency as a function of the lateral component of the wave vector of the incident light and applying the selection rules expected from the spatial symmetry of electromagnetic eigenmodes in C6v-symmetric structures, we successfully obtained the dispersion relation and the mode symmetry of the photonic crystal slabs, which agreed well with numerical calculations by the finite element method. We also found the redistribution of diffraction loss between A1- and E1-symmetric modes, which was caused by the Dirac-cone formation due to their effective degeneracy.

Minute oscillation stretching: A novel modality for reducing musculo-tendinous stiffness and maintaining muscle strength.

A novel stretching modality was developed to provide repetitive small length changes to the plantar flexors undergoing passive stretch defined as "minute oscillation stretching" (MOS). This study investigated the effects of MOS on neuromuscular activity during force production, the rate of torque development (RTD), and the elastic properties of the plantar flexors and Achilles tendon. Ten healthy males participated in this study. The neuromuscular activity of the triceps surae and tibialis anterior muscles during maximal voluntary plantar flexion torque [MVT], RTD of plantar flexion, Achilles tendon stiffness, and muscle stiffness were measured before and after two types of interventions for a total of 5 minutes: static stretching (SS) and MOS at 15 Hz and without intervention (control). Achilles tendon stiffness was calculated from the tendon elongation measuring by ultrasonography. Muscle stiffness was determined for the medial gastrocnemius [MG] using shear wave elastography. The MVT, mean electromyographic amplitudes [mEMG] of MG and lateral gastrocnemius [LG], and RTD were significantly decreased following SS (MVT: -7.2 ± 7.9%; mEMG of MG: -8.7 ± 10.2%; mEMG of LG: -12.4 ± 10.5%; RTD: -6.6 ± 6.8%), but not after MOS. Achilles tendon stiffness significantly decreased after SS (-13.4 ± 12.3%) and MOS (-9.7 ± 11.5%), with no significant differences between them. Muscle stiffness significantly decreased in SS and MOS, with relative changes being significantly greater for MOS (-7.9 ± 8.3%) than SS (-2.3 ± 2.9%) interventions. All variables remained unchanged in the controls. In conclusion, MOS changed muscle-tendon compliance without loss of muscle function.

Effects of 6-Week Static Stretching of Knee Extensors on Flexibility, Muscle Strength, Jump Performance, and Muscle Endurance.

ABSTRACT: Ikeda, N and Ryushi, T. Effects of 6-week static stretching of knee extensors on flexibility, muscle strength, jump performance, and muscle endurance. J Strength Cond Res 35(3): 715-723, 2021-The purpose of this study was to evaluate the changes in flexibility and muscular performance after stretching training for 6 weeks. Twelve healthy young men were assigned to a stretching group and 13 to a control group. The subjects of the stretching group performed static stretching of knee extensors for 6 weeks. Knee flexion range of motion (KFROM), leg extension strength, rate of force development (RFD) in leg extension, jump performance (squat and countermovement jump height, and index of rebound jump), and strength decrement index of 50 repetitions of isokinetic knee extension (muscle endurance) were measured before and after the interventions. In the stretching group, KFROM significantly increased from 145.2 ± 17.3 to 158.7 ± 6.3° (p < 0.05), whereas RFD significantly improved from 10,173 ± 2,401 to 11,883 ± 2,494 N·s-1 (p < 0.05). By contrast, leg extension strength and jump performance of each jump type did not improve significantly. Furthermore, muscle endurance decreased significantly. All variables remained unchanged in the control group. In conclusion, 6 weeks of stretching training of knee extensors improved KFROM and RFD in leg extension, but not leg extension strength and jump performance; moreover, muscle endurance decreased. These findings indicate that this stretching training protocol can be used by athletes in sports who require high flexibility and those who require high-power exertion.

Long-Term Outcomes of Pulmonary Metastasectomy for Uterine Malignancies: A Multi-institutional Study in the Current Era.

BACKGROUND: Information on pulmonary metastasectomy (PM) for uterine malignancies in the current era is limited. In the present study, we analyzed the clinical course and results of PM for uterine malignancies in the era of modern imaging diagnostics to clarify the role of PM in the current era in a multi-institutional setting. METHODS: Fifty-seven patients who underwent PM for uterine malignancies between 2006 and 2015 were retrospectively reviewed. The short- and long-term outcomes, along with factors associated with the prognosis, were analyzed. Details of the clinical course after PM were described. RESULTS: The mean age of patients was 59.4 years. The primary tumor was located in the uterus corpus in 34 cases (60%) and in the uterus cervix in 23 cases (40%). The median disease-free interval (DFI) was 32 months. Forty patients (70%) received fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography before PM, and complete resection was achieved in 52 patients (91%). Postoperative complications occurred in 4 patients (7%). Of the 52 patients who underwent complete resection of pulmonary metastases, 28 experienced recurrence, and among these, 17 (60%) underwent local therapy, including six repeat PMs. Among the 52 patients who underwent complete resection, the 5-year relapse-free survival rate was 40.7% and the 5-year overall survival (OS) rate was 68.8%. The univariate analysis revealed that a DFI of ≤ 24 months was associated with significantly poorer OS. CONCLUSIONS: PM for uterine malignancies is safe and provides favorable long-term outcomes in selected patients. Patients with a DFI of > 24 months have better OS and are good candidates for PM.

Angle-resolved reflection spectra of Dirac cones in triangular-lattice photonic crystal slabs.

The dispersion relation and the angle-resolved reflection spectra of triangular-lattice photonic crystal slabs of the C6v symmetry were examined by the finite element method. The Dirac-cone dispersion relation on the Γ point of the reciprocal space was confirmed. The reflection spectra showed unique selection rules that agreed with the analytical calculation by the k · p perturbation theory. The distortion of the liner dispersion relation of the Dirac cones due to diffraction loss was also reproduced well by the numerical calculation, while we found distortion-free Dirac cones materialized with E2-symmetric modes.

Mid-IR Dirac-cone dispersion relation materialized in SOI photonic crystal slabs.

We materialized the isotropic Dirac-cone dispersion relation in the mid-infrared range by fabricating photonic crystal slabs of the C4v symmetry in SOI (silicon-on-insulator) wafers by electron beam lithography. The dispersion relation was examined by the angle-resolved reflection spectra with our home-made high-resolution apparatus, which showed a good agreement with the dispersion relation and the reflection spectra calculated by the finite element method. The reflection spectra also agreed with the selection rules derived from the spatial symmetry of the Dirac-cone modes, which proved to be a powerful tool for the mode assignment.

AJM300, a novel oral antagonist of α4-integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects.

AIMS: AJM300 is an oral antagonist of α4-integrin that reduces inflammation by blocking leucocyte trafficking. This study aimed to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of AJM300 in healthy male subjects. METHODS: A total of 23 subjects were randomised to receive 240 mg (n = 6), 480 mg (n = 5), 960 mg (n = 6) of AJM300 or the corresponding placebo (n = 2 per group). The study drugs were taken orally 3 times daily after each meal on the first day followed by a 4-day washout period. Thereafter, multiple-dose administration was conducted for 6 consecutive days. The pharmacokinetic parameters of AJM300 and its active metabolite (HCA2969) were assessed, and total white blood cells and the differential cell count were used to determine the pharmacodynamic effects. Adverse events (AEs) were also monitored. RESULTS: The plasma AJM300 and HCA2969 concentration-time curves displayed a triphasic pattern on Day 1 (single-day administration) and Day 10 (last day of multiple dosing), whereas the concentration of HCA2969 was much higher than that of AJM300. A significant but transient increase in lymphocyte count was observed after AJM300 dosing at all dosages tested compared with the placebo. The increase was sustained over a 24-h period only at the 960-mg dosage. In particular, a significant increase in the lymphocyte count compared to placebo (mean, 50.58%; 95% confidence intervals, 20.40-80.76) was observed at the first 960-mg dose on Day 10. Six (26.1%) subjects reported ≥1 AEs, all of which were mild and resolved spontaneously. CONCLUSION: The maximal and 24-h sustained pharmacodynamic effects were demonstrated at the 960-mg dosage after oral administration of AJM300 3 times daily for 6 days, which was also found to be safe and well tolerated.

Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation.

Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169+ macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169+ macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2-related factor 2-dominant, cytoprotective/antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation.

Stretching Combined with Repetitive Small Length Changes of the Plantar Flexors Enhances Their Passive Extensibility while Not Compromising Strength.

Static stretching increases flexibility but can decrease muscle strength; therefore, a method that would avoid the latter has been longed for. In this study, a novel stretching modality was developed that provides repetitive small length changes to the plantar flexor muscles undergoing passive static stretching (minute oscillation stretching). We investigated the effects of minute oscillation stretching on muscle strength and flexibility and its continuance. Isometric plantar flexion strength and maximal ankle joint dorsiflexion angle (dorsiflexion range of motion) were measured in 10 healthy young men (22 ± 2 years) before (pre) and immediately after (post) 3 types of stretching: static stretching, minute oscillation stretching at 15 Hz, and no intervention (control). The dorsiflexion range of motion was also measured at 15, 30, and 60 min post-stretching. Elongation of the medial gastrocnemius and Achilles tendon was determined by ultrasonography. Plantar flexion strength significantly decreased by 4.3 ± 3.5% in static stretching but not in minute oscillation stretching. The dorsiflexion range of motion significantly increased both in static stretching (7.2 ± 8.1%) and minute oscillation stretching (11.2 ± 14.6%), which was accompanied by a significantly larger muscle elongation but not tendon elongation. Elevated dorsiflexion range of motion was maintained until 30 min after minute oscillation stretching, while levels returned to baseline (pre-intervention) 15 min after static stretching. All variables remained unchanged in the control condition. In conclusion, minute oscillation stretching improves extensibility of the muscle belly without decreasing strength. Furthermore, the augmented flexibility to a similar extent to static stretching is retained for 30 min in minute oscillation stretching and within 15 min in static stretching.

[A Case of Laparoscopic Resection of Sigmoid Colon Cancer Complicated by an Iliopsoas Abscess Preceded by Abscess Drainage].

For colon cancer complicated by iliopsoas abscess, it is unclear whether surgery should be performed prior to abscess drainage. We were able to perform laparoscopic sigmoid resection safely after first draining the abscess. We believed it would be beneficial to avoid surgery in the presence of abscess and inflammation, and the minimally invasive operation was performed after improvements of the patient's general status and inflammation.

[A Case of an Elderly Patient with Unresectable Gastric Cancer Treated by Paclitaxel and Ramucirumab].

An 80-year-old man was admitted to our hospital with appetite loss in December 2014. Gastroduodenal scope, abdominal computed tomography(CT), and laparoscopy revealed type 4 advanced gastric cancer(poorly differentiated adenocarcinoma) with multiple lymph node(LN)involvement and multiple peritoneal metastasis. S-1(80mg/body)was administrated between January 2015 and September 2015 in the outpatient clinic. A partial response was obtained, but a gastric tumor, ascites, and LN re-growth were observed. Since October 2015, paclitaxel(PTX)(70mg/m2; day 1, 8, and 15)and ramucir- umab(RAM)(8mg/kg; day 1 and 15)have been administered. After 2 courses, bi-weekly PTX plus RAM were continued for grade 3 neutropenia and grade 2 anorexia. The tumor and LNs partially responded, and the ascites disappeared. With this dosage and administration schedule, the partial response(PR)was maintained for approximately 8 months without any severe adverse reactions. This successful case might indicate that it is important for elderly patients with gastric cancer that progressed with prior chemotherapy regimens to consider appropriate reduction of the PTX dosage, schedule, and continuation of RAM.

[Three Cases of Bleeding from Advanced Gastric Cancer during Chemotherapy Treated with Transcatheter Arterial Embolization(TAE)].

Case 1: An 71-year-old man underwent chemotherapy with S-1 plus trastuzumab to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4b[Panc], N3, H0, CY1, P0, M1). For anemia and active bleeding from the tumor, transcatheter arterial embolization(TAE)was performed with metallic coils on the splenic artery. Infarction of the spleen and left pleural effusion were observed. Second-line paclitaxel(PTX)chemotherapy was administered 4 weeks after TAE. Case 2: An 76-year-old man underwent chemotherapy with S-1 plus cisplatin to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H0, P1, M1). For anemia and active bleeding from the tumor, TAE with gelatin sponge(Serescure®)was performed on the left and right gastric artery. Radiotherapy(31 Gy)with S-1 was performed because TAE was not effective for bleeding. After chemoradiotherapy, nab-PTX was administered. Case 3: An 74- year-old man underwent second-line chemotherapy with nab-PTX to treat type 4 advanced gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H1, P0, M1). For progression of anemia due to tumor bleeding, TAE with gelatin sponge(Serescure®)was performed on the left gastric artery. TAE was effective, and he was discharged from the hospital. In 2 of 3 cases, hemostasis was achieved by TAE. Therefore, TAE is effective to decrease bleeding from gastric cancer during chemotherapy.

[Clinical Experience of Ramucirumab for Treating Advanced Gastric Cancer].

BACKGROUND: The REGARD and RAINBOW trials showed that ramucirumab(RAM)alone and RAM plus paclitaxel(PTX) were effective therapies for advanced gastric cancer patients previously treated with chemotherapy. In this retrospective study, we evaluated the safety and efficacy of RAM alone and PTX plus RAM in such patients. METHODS: Patients who were received RAM at 8mg/kg or RAM plus PTX at 80mg/m2(on days 1, 8, and 15 of a 28-day cycle)between June 2015 and March 2016 were enrolled in this study. We compared the clinical outcome of RAM alone(RAM group, n=10)with that of RAM plus PTX(PTX+RAM group, n=13). RESULTS: The RAM group contained many more patients with poor performance status or prior chemotherapy of 2 or more regimens than the PTX+RAM group. All patients in both groups received chemotherapy on an outpatient basis. One case of grade 3 or 4 hematological adverse events was found in the RAM group and 6 cases were found in the PTX+RAM group. The overall response rate was 10% in the RAM group and 30% in the PTX+RAM group. Progression-free survival was 54 days in the RAM group and 187 days in the PTX+RAM group(p=0.0374). Overall survival was 158 days in the RAM group and was not reached in the PTX+RAM group(p=0.1091). CONCLUSIONS: RAM alone and RAM plus PTX can be administered safely on an outpatient basis and are beneficial for advanced gastric cancer patients previously treated with chemotherapy.

[Efficacy and Safety of Pertuzumab for HER2-Positive Metastatic Breast Cancer].

The CLEOPATRA trial showed a significant improvement in the progression-free survival (PFS) and overall survival of patients with HER2-positive first-line metastatic breast cancer (MBC) who were treated with pertuzumab (PER), trastuzumab (TRA), and docetaxel (DTX), compared to those treated with placebo, TRA, and DTX. PER was approved in 2013 for treating HER2-positive MBC in Japan. Herein, we present the retrospective review of data from 10 HER2-positive MBC patients who received PER in our hospital between September 2013 and August 2014.T he median age was 52 years (range, 45-66 years), and 7 patients were positive for ER.Six patients had not received any previous chemotherapy for their metastatic disease, while the others had received comparatively heavy pretreatment doses of chemotherapy.Our patients received the PER, TRA, and DTX regimen, although 2 patients were treated without DTX. Four patients experienced a partial response, 6 patients experienced stable disease (SD), and 3 patients experienced SD for ≥6 months. The response rate was 40%, and the clinical benefit rate was 70%.The median PFS was 7.3 months (range, 2.5-11.5 months). Grade 3 neutropenia and allergic reactions were observed in 1 and 2 patients, respectively; no Grade 4 adverse events were observed, and thus, the regimen was well tolerated. Further clinical research seems to be warranted for developing new treatment strategies involving PER for HER2-positive MBC.

[A Case of Bone Metastasis from Early Gastric Cancer after a Five-Year Disease-Free Interval Following Gastrectomy].

A woman in her 50s underwent distal gastrectomy and D1+b dissection in December 2005 for early gastric cancer that was diagnosed as a signet-ring-cell carcinoma, fStage Ⅱ (T1a, N2, H0, P0, CY0, M0) with 12 lymph node metastases in the second field. Multiple bone metastases were diagnosed on the basis of CT and bone scintigraphy findings and serum ALP elevation (2,743 IU/L) I n December 2010. Fourteen courses of S-1 plus CDDP and 4 mg of zoledronate were administered from January to September in 2011. Pancytopenia, D-dimmer elevation, myelocytes, and metamyelocytes were observed in October 2012, indicating she had bone marrow metastasis. She was treated with a transfusion, anti-DIC therapy, and paclitaxel. She died from gastric cancer in December 2012. We report a rare case of recurrence with bone metastasis from early gastric cancer. S-1 plus CDDP chemotherapy and zoledronate therapy is an effective treatments for multiple bone metastases from gastric cancer.

[Two Cases of Bleeding Advanced Gastric Cancer Treated with Palliative Radiation Therapy].

Case 1: A man in his 70's was being treated with chemotherapy for unresectable advanced gastric cancer. Blood transfusion, endoscopic intervention including argon plasma coagulation, and transcatheter arterial embolization (TAE) were all used to treat repeated tumor bleeding causing anemia, but controlling the bleeding was difficult. In order to control the hemorrhage, radiation therapy of 31 Gy/10 Fr to the cancer was administered. After receiving radiation therapy, the anemia stopped. Case 2: A man in his 70's considered an operation for advanced gastric cancer, but his cardiac performance was poor and it was impossible to perform an operation. We conducted radiation therapy of 39 Gy/13 Fr for the purpose of preventing bleeding from gastric cancer. After receiving radiation therapy, the anemia stopped. We believe that radiation therapy is effective to stop bleeding from gastric cancer.