Fourier Transform Coherent Anti-Stokes Raman Scattering Spectroscopy: A Comprehensive Review.

Fourier transform coherent anti-Stokes Raman scattering (FT-CARS) spectroscopy is a powerful spectroscopic method that combines the principles of Fourier transform spectroscopy with coherent anti-Stokes Raman scattering (CARS). This method stands out in spectroscopy for its ability to rapidly acquire coherent Raman spectra, achieving an impressive rate of over 10 000 spectra per second. The method involves scanning the optical delay between two femtosecond pulses; the initial pulse induces a vibrational coherence in the sample, while the subsequent pulse probes this coherence over increasing delays. The anti-Stokes scattering intensity generated is modulated by the vibrational dynamics of the sample, enabling the retrieval of Raman spectra through Fourier transformation. Over the past two decades, FT-CARS spectroscopy has undergone substantial evolution, paving the way for its application in a wide array of fields, including material analysis and flow cytometry. In this comprehensive Review, we explore the fundamental principles and diverse applications of FT-CARS spectroscopy and delve into the potential future advances and challenges associated with this emerging method.

Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders.

Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We demonstrate that a CatC inhibitor, MOD06051, dose-dependently suppresses the cellular activity of NSPs, including neutrophil elastase (NE), in vitro. Neutrophils derived from MOD06051-administered rats exhibit significantly lower NE activity and NET-forming ability than controls. Furthermore, MOD06051 dose-dependently ameliorates vasculitis and significantly decreases NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV.

Adjuvant 5-fluorouracil and portal vein infusion chemotherapy followed by gemcitabine for pancreatic cancer.

BACKGROUND: Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. METHODS: 5-fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse-free survival (RFS) and the secondary endpoints were OS and treatment completion. RESULTS: Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1-, 3-, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1-, 3-, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). CONCLUSION: Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.

Conversion surgery for gastric remnant cancer with liver metastasis after nivolumab combination chemotherapy achieving pathological complete response: a case report and literature review.

BACKGROUND: Nivolumab combination chemotherapy has recently emerged as a potential first-line treatment for patients with unresectable or metastatic gastric cancer (GC). Further research has indicated that R0 resection by conversion surgery could be an effective treatment strategy to improve overall survival. However, there have been limited reports on the successful application of conversion surgery following combination chemotherapy achieving pathological complete response (pCR) in cases of advanced gastric remnant cancer with liver metastasis. Here, we present a case of long-term survival in a patient who underwent this treatment. CASE PRESENTATION: A 54-year-old man was initially referred to our department for treatment of stage III (cT3N1M0) gastric cancer where he underwent laparoscopic distal gastrectomy and D2 lymph node dissection. After a year of uneventful follow-up, the patient was diagnosed with a tumor in the gastric remnant combined with liver metastasis, resulting in a diagnosis of stage IV (cT3N0M1) gastric remnant cancer. Subsequently, the patient was treated with four cycles of TS-1, Oxaliplatin, and Nivolumab as the first-line regimen. Remarkably, both the remnant tumor and liver metastasis exhibited significant shrinkage, and no new lesions were found. Given this response, conversion surgery was performed to achieve complete resection of the remnant gastric cancer and liver metastasis, followed by laparoscopic remnant gastrectomy and partial hepatectomy. Pathological examination revealed the absence of residual carcinoma cells and lymph node metastases. Postoperatively, the patient was treated with adjuvant chemotherapy with S-1 for 1 year, and survived without recurrence for 18 months after conversion surgery. CONCLUSIONS: Nivolumab combination chemotherapy shows promise as a clinically beneficial treatment approach for gastric remnant cancer with liver metastasis, particularly when pCR can be achieved following conversion surgery.

Fluorescence-Encoded Time-Domain Coherent Raman Spectroscopy in the Visible Range.

Fluorescence-encoded vibrational spectroscopy has attracted increasing attention by virtue of its high sensitivity and high chemical specificity. We recently demonstrated fluorescence-encoded time-domain coherent Raman spectroscopy (FLETCHERS), which enables low-frequency vibrational spectroscopy of low-concentration fluorophores using near-infrared (800-900 nm) light excitation. However, the feasibility of this study was constrained by the scarcity of excitable molecules in the near-infrared range. Consequently, the broader applicability of FLETCHERS has not been investigated. Here we extend the capabilities of FLETCHERS into the visible range by employing a noncollinear optical parametric amplifier as a light source, significantly enhancing its versatility. Specifically, we use the method, which we refer to as visible FLETCHERS (vFLETCHERS), to individually acquire Raman spectra from five visible fluorophores that have absorption peaks in the 600-700 nm region. These results not only confirm the versatility of vFLETCHERS for a wide range of molecules but also allude to its widespread applicability in biological research through highly sensitive supermultiplexed imaging.

Neonatal Brains Exhibit Higher Neural Reparative Activities than Adult Brains in a Mouse Model of Ischemic Stroke.

The neonatal brain is substantially more resistant to various forms of injury than the mature brain. For instance, the prognosis following ischemic stroke is generally poor in the elderly but favorable in neonates. Identifying the cellular and molecular mechanisms underlying reparative activities in the neonatal brain after ischemic injury may provide feasible targets for therapeutic interventions in adults. To this end, we compared the reparative activities in postnatal day 13 and adult (8-12-week-old) mouse brain following middle cerebral artery occlusion. Immunohistochemistry revealed considerably greater generation of ischemia-induced neural stem/progenitor cells (iNSPCs) expressing nestin or Sox2 in ischemic areas of the neonatal brain. The iNSPCs isolated from the neonatal brain also demonstrated greater proliferative activity than those isolated from adult mice. In addition, genes associated with neuronal differentiation were enriched in iNSPCs isolated from the neonatal brain according to microarray and gene ontogeny analyses. Immunohistochemistry further revealed considerably greater production of newborn doublecortin+ neurons at the sites of ischemic injury in the neonatal brain compared to the adult brain. These findings suggest that greater iNSPC generation and neurogenic differentiation capacities contribute to the superior regeneration of the neonatal brain following ischemia. Together, our findings may help identify therapeutic targets for enhancing the reparative potential of the adult brain following stroke.

Boosting the Brightness of Raman Tags Using Cyanostar Macrocycles.

Raman probes have received growing attention for their potential use in super-multiplex biological imaging and flow cytometry applications that cannot be achieved using fluorescent probes. However, obtaining strong Raman scattering signals from small Raman probes has posed a challenge that holds back their practical implementation. Here, we present new types of Raman-active nanoparticles (Rdots) that incorporate ionophore macrocycles, known as cyanostars, to act as ion-driven and structure-directing spacers to address this problem. These macrocycle-enhanced Rdots (MERdots) exhibit sharper and higher electronic absorption peaks than Rdots. When combined with resonant broadband time-domain Raman spectroscopy, these MERdots show a ∼3-fold increase in Raman intensity compared to conventional Rdots under the same particle concentration. Additionally, the detection limit on the concentration of MERdots is improved by a factor of 2.5 compared to that of Rdots and a factor of 430 compared to that of Raman dye molecules in solution. The compact size of MERdots (26 nm in diameter) and their increased Raman signal intensity, along with the broadband capabilities of time-domain resonant Raman spectroscopy, make them promising candidates for a wide range of biological applications.

[A Case of Advanced Gastric Cancer with Pancreatic Invasion Completely Resected after Chemotherapy].

An 80-year-old man with severe anemia was found to have a circumferential type 3 lesion with obstruction in the gastric pylorus during upper gastrointestinal endoscopy. A contrast-enhanced CT scan of the abdomen showed severe invasion of the pancreatic head, and the diagnosis was gastric cancer L, Circ, cType 3, tub2, cT4b, N(+), M0, cStage ⅣA. The patient underwent laparoscopic gastrojejunostomy for gastrointestinal transit obstruction followed by 4 courses of SOX therapy as systemic chemotherapy. After chemotherapy, the invasion to the head of the pancreas was obscured, and pyloric gastrectomy and lymph node dissection were performed. The patient was recurrence-free as of 18 months after surgery. In this case, we performed gastric jejunal bypass surgery followed by chemotherapy with oral anticancer agents to achieve the downstaging of unresectable advanced gastric cancer with pancreatic invasion and pyloric stenosis in patients with poor general condition. As a result, the patient was able to undergo distal gastrectomy, which is one of the recommended multidisciplinary treatments.

Clinical characteristics and predictive factors of postoperative intra-abdominal abscess after distal pancreatectomy.

PURPOSE: The postoperative mortality rate of distal pancreatectomy is lower than that of pancreaticoduodenectomy, although persistent complications may occur after distal pancreatectomy. Fluid collection (FC) is frequently observed after distal pancreatectomy; however, FC may occasionally progress to postoperative intra-abdominal abscess (PIAA), which requires conservative or progressive interventional treatment. This study aimed to compare the status between patients with or without PIAA, identify predictive factors for PIAA and clinically relevant postoperative pancreatic fistula, and investigate the clinical characteristics of patients with PIAA with interventional drainage. METHODS: We retrospectively reviewed data of patients who underwent distal pancreatectomy between January 2012 and December 2019 at two high-volume centers, where hepatobiliary-pancreatic surgeries were performed by expert specialist surgeons. Logistic regression analysis was performed to determine the predictive factors for PIAA. RESULTS: Overall, 242 patients were analyzed, among whom 49 (20.2%) had PIAA. The median postoperative period of PIAA formation was 9 (range: 3-49) days. Among the 49 patients with PIAA, 25 (51.0%) underwent percutaneous ultrasound, computed tomography, or endoscopic ultrasound-guided interventions for PIAA. In the univariate analysis, preoperative indices representing abdominal fat mass (i.e., body mass index, subcutaneous fat area, and visceral fat area) were identified as predictive factors for PIAA; in the multivariate analysis, C-reactive protein (CRP) level (continuous variable) on postoperative day (POD) 3 (odds ratio: 1.189, 95.0% confidence interval: 1.111 - 1.274; P < 0.001) was the only independent and significant predictive factor for PIAA. CONCLUSIONS: CRP level on POD 3 was an independent and significant predictive factor for PIAA after distal pancreatectomy.

Color-scalable flow cytometry with Raman tags.

Flow cytometry is an indispensable tool in biology and medicine for counting and analyzing cells in large heterogeneous populations. It identifies multiple characteristics of every single cell, typically via fluorescent probes that specifically bind to target molecules on the cell surface or within the cell. However, flow cytometry has a critical limitation: the color barrier. The number of chemical traits that can be simultaneously resolved is typically limited to several due to the spectral overlap between fluorescence signals from different fluorescent probes. Here, we present color-scalable flow cytometry based on coherent Raman flow cytometry with Raman tags to break the color barrier. This is made possible by combining a broadband Fourier-transform coherent anti-Stokes Raman scattering (FT-CARS) flow cytometer, resonance-enhanced cyanine-based Raman tags, and Raman-active dots (Rdots). Specifically, we synthesized 20 cyanine-based Raman tags whose Raman spectra are linearly independent in the fingerprint region (400 to 1,600 cm-1). For highly sensitive detection, we produced Rdots composed of 12 different Raman tags in polymer nanoparticles whose detection limit was as low as 12 nM for a short FT-CARS signal integration time of 420 µs. We performed multiplex flow cytometry of MCF-7 breast cancer cells stained by 12 different Rdots with a high classification accuracy of 98%. Moreover, we demonstrated a large-scale time-course analysis of endocytosis via the multiplex Raman flow cytometer. Our method can theoretically achieve flow cytometry of live cells with >140 colors based on a single excitation laser and a single detector without increasing instrument size, cost, or complexity.

[Staging Laparoscopy in the Treatment of Advanced Gastric Cancer].

OBJECTIVE: We examined the applicability and safety of staging laparoscopy(SL)in the treatment of advanced gastric cancer. METHODS: We retrospectively reviewed the gastric cancer cases that were examined using SL between January 2015 and December 2019 at our hospital. RESULTS: Within this period, 59 gastric cancer patients underwent SL, of whom 53 were diagnosed with SL at first examination. The rare complications of SL were postoperative nausea and vomiting(1 case). In 47.5%(28/59)of patients, we observed peritoneal dissemination including positive lavage cytology. In 2 cases, peritoneal dissemination was found during curative resection despite not being detected by SL. Thus, the false negative rate of peritoneal dissemination discovery was 6.7%(2/30). Among the individuals who were diagnosed as P1 or CY1 at first, subsequent SLs were performed in 6 cases, and 5 patients were re-assigned as P0CY0, of whom 4 underwent conversion surgery. CONCLUSIONS: SL is an essential and safe examination method for defining the treatment strategy in advanced gastric cancer. However, further improvements are needed to reduce the false negative discovery rate and to advance gastric cancer treatment by increasing reliability of diagnosis.

Structural rationalities of tapered hollow cylindrical beams and their use in Japanese traditional bamboo fishing rods.

Bamboo has historically been used in Japan as a structural material and for building tools such as fishing rods owing to its remarkable structural properties. In recent years, the materials used for manufacturing fishing rods have changed greatly owing to the development of composite materials; however, the basic slender tapered hollow cylindrical fishing rod design has remained unchanged throughout the long history of fishing. However, the mechanical rationale behind this structural design has not yet been sufficiently verified, and this study clarifies this. The analysis was performed by solving the nonlinear bending equation of a slender tapered cantilever beam with a concentrated load at the tip, which causes large deflection, using the Runge-Kutta method. The deflection curves and bending stresses were obtained, and the structural design to minimize the stresses was explored. Our results may prove useful for bamboo-inspired bionic design and bring to light our ancestors' deep knowledge of natural materials and their advanced technological capabilities.

[A Case of DIC Following Mixed Acidosis during Laparoscopic Hepatectomy].

The patient was an 81-year-old man. Laparoscopic sigmoidectomy was performed for a sigmoid colon cancer(S, type 2, pT3[SS], INF a, Ly0, V0, BD1, Pn0, pPM0, pDM0, RM0, pN0, pM0, pStage Ⅲa, R0, Cur A). One year after the surgery, a blood test showed CEA as high as 68.9 ng/mL, and an abdominal enhanced computed tomography revealed a hepatic tumor showing marginal contrast in the 4th liver segment. Positron emission tomography showed an accumulation of SUVmax 19.0 at the same site, and a metastatic liver tumor was diagnosed. A laparoscopic medial hepatectomy was performed. Bleeding from the hepatectomy site increased significantly after completion. Subcutaneous emphysema spreading from the face to the trunk and thigh was observed, and blood tests revealed a pH of 7.172, PaCO2 of 71.0 mmHg, lactate of 67 mg/dL, mixed acidosis, D-dimer of 118 µg/mL, and a disseminated intravascular coagulation(DIC)syndrome was diagnosed. Following the difficulty of hemostasis, the surgery was changed to laparotomy and terminated by gauze packing. We encountered a case of acidosis exacerbated by hypercapnia that progressed to DIC during laparoscopic medial hepatectomy.

Frailty is a useful predictive marker of postoperative complications after pancreaticoduodenectomy.

BACKGROUND: Frailty results in a high risk for disability, hospitalization, and mortality. This study aimed to investigate perioperative details of frail patients who underwent pancreatectomy and whether frailty can be a predictive factor of postoperative complications, especially of clinically relevant postoperative pancreatic fistula (CR-POPF). METHODS: This retrospective study included patients who underwent pancreatectomy in our hospital between August 2016 and March 2019. The patients were divided into frail and pre-/non-frail groups. The diagnostic criteria were based on the Japanese version of the Cardiovascular Health Study. RESULTS: Of 93 patients, 11 (11.8%) and 82 (88.2%) were frail and pre-/non-frail patients, with median ages of 82 and 72 years, respectively (p = 0.041). Postoperative complications (Clavien-Dindo ≧ IIIa) were found in 8 and 32 patients (p = 0.034), CR-POPF in 3 and 13 patients (p = 0.346), and postoperative hospital stays were 21 and 17 days (p = 0.041), respectively. On multivariate analysis, frailty was an independent predictive factor (odds ratio [OR] 5.604, 95.0% confidence interval [CI] 1.002-30.734; p = 0.047) of postoperative complications (Clavien-Dindo ≧ IIIa) after pancreaticoduodenectomy. On multivariate analysis, a soft pancreas (OR 5.696, 95.0% CI 1.142-28.149; p = 0.034) was an independent and significant predictive factor of CR-POPF after pancreaticoduodenectomy. CONCLUSIONS: Frailty may be a useful predictive factor of postoperative complications in patients undergoing pancreaticoduodenectomy.

The impact of epidural catheter insertion level on pain control after esophagectomy for esophageal cancer.

BACKGROUND: Although the effectiveness of epidural anesthesia on pain control after esophagectomy has been reported, the appropriate insertion level of the epidural catheter remains unclear for adequate postoperative pain control. We investigated the relationship between the epidural catheter insertion level and postoperative pain control after esophagectomy for esophageal cancer. METHODS: We analyzed retrospectively 63 patients who underwent McKeown esophagectomy for esophageal cancer between October 2014 and November 2018. The epidural catheter was inserted at the T4-T10 level before general anesthesia induction, and epidural anesthesia was started during the operation. In the analysis, the epidural catheter insertion level was divided into three groups (over T6/T7, T7/T8, and under T8/T9) and determined. Postoperative pain was evaluated a numeric rating scale (NRS) for at least 7 postoperative days, and the first NRS after extubation was used to evaluate the impact of the epidural catheter insertion level on pain control. RESULTS: Ten patients (15.9%) failed pain control. The χ2 test and a forward stepwise logistic regression analysis revealed that only the epidural catheter insertion level affected pain control (P < 0.05). The T7/T8 insertion level significantly decreased postoperative pain after esophagectomy. In the subgroup analysis, epidural catheter insertion under T8/T9 significantly increased postoperative pain after esophagectomy when thoracoscopy/laparoscopy was assisted. No significant differences were observed in the incidence of postoperative complications among the epidural catheter insertion levels. CONCLUSIONS: The T7/T8 epidural catheter insertion level contributed to postoperative pain relief and could lead to enhanced recovery after esophagectomy for esophageal cancer.

[A Case of Giant Hematogenous Left Quadricep Muscle Metastasis of Hepatocellular Carcinoma].

The patient was a 62-year-old man with no specific medical history. Lateral segmentectomy was performed for hepatocellular carcinoma with a tumor size of approximately 14×13 cm. The histopathological diagnosis was moderately differentiated hepatocellular carcinoma: Fc(-), Fc-Inf(-), Sf(-), S0, N0, Vp2, Vv1, Va0, B0, P0, SM(-), CH. Five years after the first surgery, computed tomography(CT)revealed a left lung tumor in segment 9/10 and left lymph nodes; thus, left pneumonectomy was performed, and these tumors were identified to have metastasized from the primary tumor. Six years after the first surgery, his serum alpha-fetoprotein level was remarkably elevated from 254.9 ng/mL to 3,143.0 ng/mL for three months, and at the same time, he developed left meralgia and swelling of the left femur. Magnetic resonance imaging showed a high-density mass(30×14 cm)in the left quadriceps, and positron emission tomography-CT revealed high uptake in the left quadriceps with a maximum standardized uptake value of 12.3. A needle biopsy of the left femur tumor confirmed metastasis from the primary tumor. Radiotherapy was administered because general anesthesia can prove to be hazardous due to the patient having undergone left pneumonectomy.

A case of extrahepatic bile duct cancer with distant metastases showing pathological complete response to treatment combining gemcitabine and cisplatin.

The patient was a 69-year-old female with a chief complaint of yellow staining of her urine. A detailed physical examination and laboratory tests were carried out, and as a result, her condition was diagnosed as unresectable advanced extrahepatic cholangiocarcinoma with liver metastases. Chemotherapy using gemcitabine + cisplatin was initiated, and computed tomography after six cycles revealed that the liver metastases had disappeared, and that a partial response was achieved in the primary tumor. After tan cycles, a pylorus-preserving pancreaticoduodenectomy was performed as conversion surgery, and as a result, a pathological complete response was achieved in the primary tumor. After the primary lesion was resected, we were able to start an adjuvant chemotherapy immediately. Approximately 19 months have passed since the surgery, and the patient is currently alive and recurrence-free. If an improvement of the outcomes of chemotherapy in unresectable advanced biliary tract carcinomas is achieved in the future, there could be an increase in the number of treatment-responsive cases like the one reported in this study. Accumulating a large number of cases successfully treated by conversion surgery, and conducting a detailed analysis of the postoperative course, may help design adequate treatment strategies.

Life-threatening giant esophageal neurofibroma with severe tracheal stenosis: a case report.

BACKGROUND: Benign esophageal tumors are relatively rare, and a neurofibroma in the esophagus is extremely rare. Dysphagia is the most common clinical manifestation in patients with esophageal neurofibroma, and no cases of giant esophageal neurofibroma with severe tracheal stenosis have been reported. CASE PRESENTATION: A 73-year-old woman presented with shortness of breath, and computed tomography scan exhibited a giant mediastinal tumor causing severe tracheal stenosis. An upper gastrointestinal endoscopy revealed a giant submucosal lesion without mucosal changes located 18-23 cm from the incisor teeth. 18F-fluorodeoxyglucose (FDG)-positron emission tomography image revealed an upper mediastinal homogeneous mass and left supraclavicular lymph node with increased FDG accumulation. We performed endoscopic ultrasound-guided fine-needle aspiration biopsy; however, a definitive diagnosis could not be determined. During further investigation, her shortness of breath suddenly worsened and she suffered from wheezing. Because of risk of smothering, we decided to perform quasi-urgent lifesaving surgery. Under the preparation of extracorporeal membrane oxygenation (ECMO) when tracheal intubation fails, bronchial blocker was inserted over the tracheal stenosis and the left-lung ventilation was performed via intubation alone. Under general anesthesia, the patient was placed in the left lateral position and we performed right thoracotomy. The tumor strongly adhered to the trachea; however, the trachea or recurrent laryngeal nerves were not damaged in the surgery. Following esophagectomy, we performed gastric conduit reconstruction through the posterior mediastinum, and hand-sewn anastomosis was performed in the left neck. Immunohistochemical staining was positive for S-100 but negative for c-KIT, CD34, α-SMA, and desmin; these morphological and immunohistochemical characteristics were consistent with the diagnosis of neurofibroma. CONCLUSIONS: It is often difficult to diagnose esophageal neurofibroma preoperatively. The preparation of ECMO could be considered in patients with severe airway obstruction for safe tracheal intubation. This is the first case of life-threatening giant esophageal neurofibroma with severe tracheal stenosis.

Hemoadsorption of high-mobility-group box 1 using a porous polymethylmethacrylate fiber in a swine acute liver failure model.

BACKGROUND: High-mobility-group box chromosomal protein 1 has been identified as an important mediator of various kinds of acute and chronic inflammation. In this study, we aimed to develop a column that effectively adsorbs high-mobility-group box chromosomal protein 1 by altering the pore size of the fiber. MATERIALS AND METHODS: First, we produced three types of porous polymethylmethacrylate fiber by altering the concentration of polymethylmethacrylate dissolved in dimethylsulfoxide. We then selected a fiber based on the results of an in vitro incubation test of high-mobility-group box chromosomal protein 1 adsorption. Using the selected fiber, we constructed a new column and tested its high-mobility-group box chromosomal protein 1 adsorption capacity during 4-h extracorporeal hemoperfusion in a swine acute liver failure model. RESULTS: Electron microscope observation showed that the three types of fibers had different pore sizes on the surface and in cross section, which were dependent on the concentration of polymethylmethacrylate. In the in vitro incubation test, fiber with moderate-sized pores demonstrated the highest adsorption capacity. In the in vivo hemoperfusion study, the ratio of the high-mobility-group box chromosomal protein 1 concentration at the outlet versus the inlet of the column was significantly lower with the new column than with the control column during 4-h extracorporeal hemoperfusion. The normalized plasma level of high-mobility-group box chromosomal protein 1 at 12 h after the completion of hemoperfusion was significantly lower with the new column than with the control column. CONCLUSION: The newly developed polymethylmethacrylate column adsorbs high-mobility-group box chromosomal protein 1 during hemoperfusion in swine ALF model.

Prognostic significance of promoter DNA hypermethylation of the cysteine dioxygenase 1 (CDO1) gene in primary gallbladder cancer and gallbladder disease.

BACKGROUND: Aberrant promoter DNA methylation of the cysteine dioxygenase 1 (CDO1) gene is found in various human cancers and is associated with clinical outcome. In this study, we assessed for the first time the clinicopathological significance of CDO1 methylation in primary gallbladder cancer (GBC) in comparison with non-malignant gallbladder disease. METHODS: CDO1 DNA methylation was quantified using quantitative TaqMan methylation specific PCR (Q-MSP) in 99 primary GBC patients together with the 78 corresponding non-tumor tissues and 26 benign gallbladder disease (including 7 patients with xanthogranulomatous cholecystitis) who underwent surgical resection between 1986 and 2014. RESULTS: The average CDO1 TaqMeth value of primary GBCs was 23.5±26. These values were significantly higher than those of corresponding non-tumor tissues (average 8±13, p < .0001) and diseased gallbladder tissues from patients with benign gallbladder diseases (average 0.98±1.6, p < .0001). CDO1 hypermethylation is also found in xanthogranulomatous cholecystitis. Using a cut-off value of 17.7, GBC cases with CDO1 hypermethylation (n = 47) showed significantly poorer prognosis than those with CDO1 hypomethylation (n = 52) (p = 0.0023). Multivariate Cox proportional hazards analysis identified that CDO1 hypermethylation was an independent prognostic factor. Notably, CDO1 hypermethylation showed prognostic relevance, especially in stage II GBC, in which it is highly anticipated to work as a predictive marker for candidates of adjuvant therapy. CONCLUSIONS: Promoter NA methylation of CDO1 was demonstrated for the first time to be a cancer-associated methylation in primary GBC, and it has the potential to be a prognostic biomarker of GBC for high-risk patients with stage II GBC.