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Background: Anatomical total shoulder arthroplasty (TSA) provides successful long-term outcomes but complications can occur after 10 years that require revision. Computed tomography (CT) is a useful tool for assessing radiolucent lines around the glenoid component of TSA; however, the merits of long-term post-TSA follow up with CT are unclear. The purpose of this study was to evaluate the long-term outcomes after TSA of Japanese population and to identify factors related to radiolucency around the glenoid component using CT., Methods: A retrospective review was conducted of TSA patients who had completed at least 10 years of clinical follow up. Radiographs and CT images of the affected shoulder obtained at the last follow up were evaluated for radiolucent lines around the stem and each peg, superior inclination and retroversion of the glenoid component, subluxation index, and critical shoulder angle (CSA). Shoulder ROM, Constant-Murley score and UCLA score were compared between the preoperative and last follow up period., Results: Eighteen shoulders in 16 patients met the inclusion criteria. Mean patient age was 61 years, mean follow up period was 137 months, and mean Yian CT score was 19%. CT score was significantly highest in pegs located inferiorly (p < 0.05). Mean glenoid superior inclination was 12.6°, retroversion was -0.3°, subluxation index was 46%, and CSA was 33.7°. Glenoid superior inclination was significantly lower (p = 0.007) in shoulders with possible loosening than in cases with no loosening (5.0° vs 15.6°). Mean Constant score and UCLA score improved significantly after TSA, from 25.8 to 10.7 points preoperatively to 70.1 and 28.9 points postoperatively, respectively. Mean shoulder flexion, internal rotation, and external rotation also showed improvement postoperatively., Conclusion: TSA provides good long-term outcomes. Radiolucency was present most frequently around the inferior pegs of the glenoid component. Glenoid superior inclination may affect the formation of radiolucent lines around glenoid pegs., Level of Evidence: Level IV; Case Series; Treatment study., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

The gastrointestinal stromal tumor(GIST)guidelines state that the use of neoadjuvant chemotherapy(NAC)for curable GIST is not apparent. However, NAC is performed for massive rectal GIST at our hospital to reduce surgical invasion and improve surgical results. The cases were a 39-year-old man, a 48-year-old man, and a 78-year-old man. The site was Rb in all cases, and the maximum diameters at the rectal GIST diagnosis were respectively 70 mm, 75 mm, and 60 mm, which were massive tumors. Imatinib mesylate(imatinib)was started as NAC. The duration of NAC was respectively 6, 11, and 12 months. The maximum tumor diameter on preoperative CT was smaller than before NAC, and the average reduction rate was 23%. Two cases underwent laparoscopic abdominal perineal resection, and 1 underwent laparoscopic ultra-low anterior resection and ileostomy. No perioperative complications of Clavien-Dindo classification Grade Ⅱ or higher were unsettled. All patients were in the high risk group and received imatinib as postoperative adjuvant chemotherapy. Currently, respectively 2 years and 3 months, 1 year and 2 months, and 1 year after surgery, all are alive without recurrence. NAC with imatinib has contributed to minimally invasive and radical surgery for giant rectal GIST.

Retrieval of an intracardiac catheter by using endovascular devices sometimes fails. That failure has conventionally required thoracotomy and cardiotomy, occasionally with cardiopulmonary bypass, to remove the catheter. These case reports describe a far less invasive way of extracting a foreign body from the heart, by introducing long-shaft forceps through the right internal jugular vein. In this way, one can grasp, manipulate, and remove the foreign body., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Temporary or prolonged vascular spasm can be appreciated when perivascular dissection is performed for microvascular reconstruction. Due to a lack of reliable assessment modalities, the resolution of spasm at the periphery of perforators cannot be determined by naked eyes or surgical loupes. To address this conundrum, we aimed to observe the state of perforator vessel spasm after flap elevation using video-capillaroscopy. Between November 2021 and February 2022, seven free flaps were evaluated with video-capillaroscopy to determine the incidence of vasospasm in less than 1 mm-diameter perforators. The type of perforator spasm after flap elevation was divided into six types according to the video-capillaroscopy findings: type A, no spasm/decreased pulsation (S/DP); type B, S/DP with recovery within 5 minutes; type C, S/DP requiring papaverine hydrochloride spraying and hot water treatment (PHS+HWT) resulting in recovery within 5 minutes; type D, S/DP requiring PHS+HWT resulting in recovery within 10 minutes; type E, S/DP requiring PHS+HWT resulting in recovery within 15 minutes; and type F, S/DP with no recovery of pulsation even after PHS+HWT. Twenty-five perforators were evaluated, 3.57 perforators (range, 3-4) per flap. Using our classification for perforator vessel spasms on video-capillaroscopy, observations of five perforating branches were classified as type A, seven as type B, six as type C, five as type D, and two as type E. No type F spasm was observed. With video-capillaroscopy it is possible to confirm if blood flow deterioration occurs even in areas that are difficult to determine macroscopically. Video-capillaroscopy, a noninvasive imaging modality, is a useful alternative for the intraoperative evaluation of perforator flow and spasm., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Indocyanine green, ultrasonography, and handheld Doppler can be used to evaluate blood flow at the donor and recipient site during microvascular reconstruction. However, these methods do not provide direct visualization and assessment of real-time blood flow. Video-capillaroscopy has been shown to be useful in clinical practice to assess microcirculation in rheumatologic disorders. In this report we used video-capillaroscopy to assess different tissue components involved in microvascular surgery. Seven patients who underwent head and neck oncologic microvascular reconstruction between November 2021 and February 2022 were included in this study. Video-capillaroscopy (GOKO-BscanZD, GOKO Imaging Devices Co., Ltd., Japan) was used to evaluate the donor-site and recipient-site tissue components. Optimal red blood cell movement was graded with a score of four, while no flow was graded with a score of 0. Seven myocutaneous flaps and seven recipient sites were evaluated. For the donor-site, our analysis demonstrated a significantly higher video-capillaroscopy quality for skin (3.43), adipose tissue (3.7) and perforators (3.7) when compared with muscle (0.429), muscle fascia (0.857), and de-epithelialized skin (1) ( P < 0.001). For the recipient-site, a significantly higher video-capillaroscopy quality for skin (2.7), adipose tissue (3.5), and the periosteum (2.1) was noted when compared with muscle (0) ( P < 0.001). Video-capillaroscopy efficiency is limited in the muscular component and injured (de-epithelialized) skin surface areas of flaps. Herein, we provide evidence that assessment of flap perfusion with video-capillaroscopy can be reliably achieved in the skin, periosteum, perforators, and adipose tissue. Video-capillaroscopy is expected to be applied for intraoperative real-time blood flow evaluation., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Introduction: In patients with pancreatic ductal adenocarcinoma (PDAC) in the pancreatic body (Pb) and tail (Pt), the appropriate area for lymphadenectomy is controversial. This study aimed to reevaluate the extent of lymph node (LN) metastasis in Pb- and Pt-PDAC, and to define the optimal area of LN dissection., Patients and Methods: This single-center retrospective study evaluated patients with Pb- and Pt-PDAC who underwent distal pancreatectomy with extended lymphadenectomy between 2006 and 2020. LN metastasis in >3.0% of patients were defined as new regional LN., Results: The study cohort included 135 patients with Pb-PDAC and 42 patients with Pt-PDAC. In patients with Pb-PDAC, LNs around the splenic artery (SPA) had the highest metastasis-positive rate (54.1%). LNs along the left gastric artery, common hepatic artery, celiac axis (CA), superior mesenteric artery (SMA), and splenic hilus were defined as new regional LNs. In patients with Pt-PDAC, LNs at the splenic hilum had the highest metastasis-positive rate (38.1%). The station and LN around the SPA were defined as new regional LNs in those with Pt-PDAC. Metastasis beyond the newly defined regional LNs was not associated with survival. The incidence of LN metastasis was lower in patients who received preoperative chemotherapy than in those who underwent upfront surgery in both Pb- and Pt-PDAC., Conclusion: Although it needs to be verified in future multicenter studies, LN of both the CA and SMA systems should be dissected in patients with Pb-PDAC. However, only those around the SPA and splenic hilus should be dissected routinely in those with Pt-PDAC., (© 2022 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

Background: Free tissue transfer is a common method of reconstruction for various surgical defects. Many clinical assessment methods, including flap color monitoring and capillary refill time measurements, are commonly used to assess the microcirculation of the flap, yet there is no objective tool available that can clear real-time visualization of the flap microcirculation. The purpose of this study was to use a novel videocapillaroscope to evaluate the circulation changes on free flap skin surfaces while purposely clamping pedicle vessels., Methods: Ten patients who underwent free flap transfer for head and neck cancer from November of 2019 to June of 2020 were included in the study. Videocapillaroscopic observation was performed after flap elevation, and changes in the flap skin capillary circulation with artery-controlled and vein-controlled clamping were recorded., Results: Average total surgery time was 517.91 minutes (SD, 73.3 minutes), average flap elevation time was 102.9 minutes (SD, 18.3 minutes). When the pedicle artery or vein was purposely clamped, the movement of red blood cells in blood vessels stopped; when clamps were removed after 60 seconds, the restoration of red blood cell movements was rapidly observed. When the pedicle artery was clamped, the number of visualizable blood vessels decreased and flap color became relatively white. When the pedicle vein was clamped, the number of visualizable blood vessels increased, and flap color tone had a tendency toward red., Conclusion: Novel videocapillaroscopy can be utilized for objective real-time flap monitoring by directly visualizing flap skin capillary microcirculation., Clinical Question/level of Evidence: Therapeutic, V., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Accumulating evidences suggest that M2 macrophages are involved with repair processes in the nervous system. However, whether M2 macrophages can promote axon regeneration by directly stimulating axons nor its precise molecular mechanism remains elusive. Here, the current study demonstrated that typical M2 macrophages, which were generated by IL4 simulation, had the capacity to stimulate axonal growth by their direct effect on axons and that the graft of IL4 stimulated macrophages into the region of Wallerian degeneration enhanced axon regeneration and improved functional recovery after PNI. Importantly, uPA (urokinase plasminogen activator)-uPA receptor (uPAR) was identified as the central axis underlying the axon regeneration effect of IL4 stimulated macrophages. IL4 stimulated macrophages secreted uPA, and its inhibition abolished their axon regeneration effect. Injured but not intact axons expressed uPAR to be sensitive to uPA. These results unveil a cellular and molecular mechanism underlying the macrophage related axon regeneration and provide a basis of a novel therapy for PNI., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Video-capillaroscopy is being explored as a potential tool for microsurgical flap monitoring. A detailed examination of the effect of temperature on capillary changes using video-capillaroscopy is yet to be investigated. We analyzed the video-capillaroscopy findings on different skin areas often used for flap harvest at normal body temperatures and at lower temperatures. Skin capillaries at the lateral thigh, anterior forearm, mid-axillary line, abdomen, and fingertips were observed using video-capillaroscopy in 20 healthy Japanese individuals. Further, ImageJ software was used to measure the blood vessel area and blood flow velocity, and comparisons were drawn between normal body temperature and lower body temperature states. All measures of blood vessel area and average blood flow velocity for the different anatomical regions were significantly different before and after cooling ( P < 0.001). The mean reduction rate of the vessel area was significantly different among anatomic regions ( P < 0.001). Post-hoc analysis revealed a significant difference in the vessel area reduction rate between anatomic areas ( P < 0.05); except when comparing the thigh versus finger, the forearm versus abdomen, and the mid-axillary line versus abdomen. The mean blood flow velocity was significantly different among anatomic regions ( P < 0.001). Post-hoc analysis revealed a significant difference between the thigh and forearm ( P = 0.009), the forearm and fingertip ( P = 0.001), and the abdomen and fingertip ( P = 0.004). Decreasing the skin temperature resulted in a significant vasoconstriction and reduction in capillary flow velocity. It is imperative to keep the monitored area warm during video-capillaroscopy assessment to avoid false diagnosis of vascular occlusion., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The metastasis to the ureter in colorectal cancer had been recognized at the stage of an autopsy. These days, according to the progression of diagnostic modalities, a few cases of long-time survival after curative surgery of metastatic ureteral tumor of colorectal cancer were reported. We present a case of a metastatic ureteral tumor of rectal cancer who had 32 months of recurrence-free survival after extirpation. After preoperative chemoradiotherapy, a 47-year-old man underwent laparoscopic low anterior resection and left unilateral pelvic node dissection for lower rectal cancer. He underwent several metastasectomies for recurrent tumors in the liver and lung. At the 42nd postoperative month, a contrast-enhanced CT scan showed thickening of the ureteral wall and left hydronephrosis. Transureteroscopic biopsy revealed metastatic adenocarcinoma of rectal cancer. At the 52nd postoperative month, partial ureteral resection and vesicoureteral neo-anastomosis were performed after confirming negative resection margin with rapid intraoperative pathology. He has 32 months of recurrence-free survival after metastasectomy of the left ureter. We review the literature presenting surgery of the metastatic ureteral tumor of colorectal cancer. Although it is a rare recurrence pattern, curative resection of ureteral metastasis might provide a possibility of long-time recurrence-free survival in such patients., (© 2021. Japanese Society of Gastroenterology.)

Objectives: This retrospective study explored the feasibility of neoadjuvant chemotherapy (NAC) without radiotherapy in patients with locally advanced rectal cancer (LARC)., Methods: Patients with clinical stage of T3-T4 and/or N-positive LARC patients were included. We retrospectively analyzed patients' NAC-related and perioperative outcomes., Results: The study enrolled 30 patients. mFOLFOX6 or SOX plus cetuximab was administered to 12 patients with the wild-type RAS gene and FOLFOXIRI or SOXIRI to 18 patients with mutant-type RAS. The NAC completion rate was 90.0%. All patients underwent total mesorectal excision, and 29 patients underwent combined bilateral lateral lymph node dissection. The R0 operation rate was 90.0%. Although the postoperative complication rate was 40%, no complications were associated with NAC. The response rate of NAC and the proportion of histological anti-tumor effect grade ≥ 2 were 56.7% and 46.7%, respectively., Conclusions: NAC was considered to be a safe, feasible treatment option for LARC., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2022 by The Japan Society of Coloproctology.)

Application of laparoscopic surgery(Lap)for colorectal cancer has expanded, and laparoscopic total pelvic exenteration (TPE)of locally advanced rectal cancer(LARC)invading the urogenital organs has been introduced in some institutions. In our institute, we have performed Lap TPE and posterior-TPE(PPE)in a total of 6 LARC patients so far. Here, we report the surgical technique of Lap TPE, and the associated surgical and short-term outcomes. We performed Lap TPE and Lap PPE in 3 patients each. Operation time was approximately 562 min, and the blood loss was 310 mL on an average. No patient developed postoperative complications above Clavien-Dindo Grade Ⅲ. One patient exhibited recurrence in the liver and another in peritoneum in the Lap PPE group. No recurrence was observed in the Lap TPE group(median follow-up period: 24.5 months). Although Lap TPE and PPE are difficult to perform and time consuming, it is suggested that these procedures may help reduce the intraoperative bleeding volume and shorten the length of postoperative hospital stay compared to open TPE and PPE.

A 75-year-old woman was treated with TC plus Bev for cancer of unknown primary. During treatment, she presented to the clinic with chief complaints of general malaise and anorexia. On presentation, abdominal distention and upper abdominal tenderness were noted, and sepsis was suspected. A thoracoabdominal CT scan revealed prominent intramural emphysema and mesenteric gas in the ascending colon. An emergency laparotomy was performed for suspected pneumatosis intestinalis non-obstructive intestinal ischemia. However, no intra-abdominal contamination or ischemic changes were observed intraoperatively. Histological examination revealed a small adenocarcinoma on the serous surface of the ascending colon, and immunochemical staining confirmed the diagnosis of serous adenocarcinoma as the patient's primary cancer. This report describes a case in which the patient achieved long-term survival after diagnosis. It also emphasizes the importance of identifying the subset of patients with cancer of unknown primary who have a good prognosis in order to provide appropriate treatment.

A 55-year-old man was admitted for ongoing gross hematuria and bladder tamponade. Computed tomography revealed a mass near the right sidewall of the bladder, along with massive blood clots. The patient was diagnosed as having bladder cancer based on laboratory findings and emergency clinical symptoms. Thus, emergency transurethral resection of the bladder tumor was performed. Pathological examination revealed an inflammatory myofibroblastic tumor (IMT). No tumor progression was observed during the 6-month follow-up period. Owing to its rarity, IMT has not been well characterized clinically and radiologically, and thus, it is very difficult to diagnose IMT accurately without pathological examinations., Competing Interests: Authors have no conflict of interest to declare., (© 2021 The Author.)

Background: The influence of long-term loading conditions on the articular surfaces of the glenohumeral joint can be determined by measuring stress-distribution patterns. Long-term pitching activity changes the stress distribution across the glenohumeral joint surface; however, the influence of competitive level on stress-distribution patterns remains unclear., Purpose: To use computed tomography (CT) osteoabsorptiometry (CTOAM) to evaluate the distribution of subchondral bone density across the glenohumeral joint in collegiate and professional baseball players as well as to determine the effects of pitching activity on the articular surfaces., Study Design: Descriptive laboratory study., Methods: We evaluated 73 shoulders in 50 baseball players. CT imaging data were obtained from the dominant-side shoulder of 12 professional pitchers (PP group) and 15 professional fielders (PF group). CT imaging data were also obtained from both shoulders of 12 asymptomatic collegiate pitchers (CP group) and 11 collegiate fielders (CF group). The pattern of distribution of subchondral bone density across the articular surfaces of each glenohumeral joint was assessed by CTOAM. As a measure of bone density, the mean Hounsfield units (HU) were obtained for each joint surface, and the absolute values of the dominant shoulder were compared for each group., Results: Stress-distribution patterns over the articular surfaces differed between the dominant and nondominant sides in the CP group as well as between both collegiate groups versus the PP group. In the CP group, the mean HU of the humeral head surface were greater on the nondominant versus dominant side ( P = .035). On the dominant side, the mean HU of the humeral head surface and glenoid were greater in the CP versus the PP group ( P = .001 and .027, respectively)., Conclusion: Stress distribution on the articular surface of the glenohumeral joint was affected by pitching ability and competitive level. Our analysis indicates that the traction force on the glenohumeral joint surface might be greater than compression force during pitching., Clinical Relevance: The present findings suggest that pitching activity results in low stress to the articular surfaces of the glenohumeral joint. This supports the notion that mechanical conditions play a crucial role in the etiology of disorders specific to pitching activity., Competing Interests: The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Nagiella tristalis Matsui & Naka, sp. nov. is described from Japan, based on DNA barcoding and morphological evidence. The two species previously known from Japan, N. quadrimaculalis and N. inferior , are diagnosed. Photographs of adults, including male and female genitalia of the three species, are provided., (Yuki Matsui, Hideshi Naka, Utsugi Jinbo.)

Background: The M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as intrinsic antigens in primary membranous nephropathy (MN). Complement activation via the lectin pathway in intrinsic antigen-related MN is still unclear., Methods: We retrospectively enrolled 60 primary Japanese MN patients and detected activated complement pathways by staining complement proteins in glomerular deposition. According to the findings of PLA2R and THSD7A staining in glomeruli, they were classified into intrinsic antigen-related or -unrelated MN. We evaluated clinicopathological characteristics and predictors of clinical outcomes in intrinsic antigen-related MN., Results: Thirty-nine (65%) patients had PLA2R in glomerular deposits and two (3.3%) patients had THSD7A. One of them had both PLA2R and THSD7A (double positive). Forty patients were classified into the intrinsic antigen-related group. The other 20 patients were negative for both antigens (unrelated group). The prevalence and staining intensity of mannose-binding lectin (MBL) deposits were much higher in the intrinsic antigen-related group [55% versus 20%, P < 0.010, 1.0 (interquartile range 1.0-2.0) versus 1.0 (0.0-1.0), P = 0.01, respectively]. The staining intensity of MBL in glomeruli also correlated with the IgG4 staining intensity. In intrinsic antigen-related MN, MBL staining intensity was an unfavorable predictor for remission of proteinuria [hazard ratio (HR) 0.40, P < 0.01] and renal dysfunction (HR 3.81, P = 0.01) in Cox proportional hazards analysis. Moreover, the glomerular MBL-positive group showed more severe interstitial fibrosis and worse clinical outcomes., Conclusions: Intrinsic antigen-related MN was more strongly associated with complement activation by the lectin pathway, which may contribute to a less favorable clinical outcome.

Background: Predictive factors for the development of osteoarthritis in adolescent osteochondritis dissecans (OCD) of the humeral capitellum remain unclear. The objectives of this study were to assess subchondral bone density in the radial head fovea of patients with OCD and to evaluate stress distribution in the radiocapitellar joint. The relationship between radiologic classification and stress distribution, according to multivariate ordinal regression analysis, was also investigated., Methods: Computed tomography (CT) imaging data from 54 male patients with OCD (mean age, 13.1 years) were collected. Stress in the radial head fovea was measured using CT osteoabsorptiometry. A stress map was constructed and divided into 4 sections, and percentages of high-density regions in each section were quantitatively analyzed. Multivariate ordinal regression analyses were performed of bone density, incorporating the stage, location, and size of the OCD lesion and the presence of medial elbow disturbance in the radiographic images., Results: The percentage of high-density area in the anteromedial, posteromedial, and the anterolateral sections of the radial head fovea were significantly increased compared with the posterolateral section. Multivariate ordinal regression analysis revealed that the location and size of the lesion and a history of excessive valgus stress were associated with imbalances in the radial head fovea., Conclusions: When the OCD lesion is large and located laterally and a medial epicondyle disturbance is apparent on radiographs, the risk for developing advanced radiocapitellar osteoarthritis should be considered. These findings can be useful in the decision-making process for treating OCD., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Trophectoderm vesicles (TVs) are observed in some blastocysts that penetrate cells from the zona pellucida to the outer margin. Therefore, we compared this incidence in relation to hatching, pregnancy, and miscarriage rates between conventional in vitro fertilization (c-IVF) and intracytoplasmic sperm injection (ICSI). Vitrified/warmed blastocysts (n = 112) were derived from surplus embryos. The blastocysts were then observed using time-lapse cinematography to resolve the relationship between hatching and implantation. Another study was conducted that comprised 681 embryo transfer cycles in 533 patients who received a single vitrified/warmed blastocyst from our clinic. The incidence of TV was significantly higher in embryos inseminated by ICSI compared with c-IVF [ICSI: 51/56 (91 %); c-IVF: 25/56 (45 %); P < 0.01]. The successful hatching rate was significantly lower in ICSI than in c-IVF [ICSI: 11/56 (20 %); c-IVF: 29/56 (52 %); P < 0.01]. In addition, the hatching rate was significantly lower when TVs were present (14/76; 18 %) than in non-TV embryos (26/36; 72 %) (P < 0.01). In regard to the clinical study results, no significant differences were found between the groups in the pregnancy rate (TV present group: 107/183, 58.5 %; TV absent group: 273/498, 54.8 %) and miscarriage rate (TV present group: 21/107, 19.6 %; TV absent group: 53/273, 19.4 %). In vivo, we hypothesized that hatching and hatched would occur naturally by assisting protease action in the uterus; therefore, these results suggest that the presence of TV has no effect on pregnancy rates in the clinical setting.

Backgrounds: The relationship between DNA damage and glomerular fibrosis in renal allografts remains unclear., Methods: We examined renal allograft specimens from 35 patients in which DNA double-strand breaks (DSBs) and glomerular fibrosis were detected by phospho-histone H2A.X (γ-H2AX) expression and collagen (COL) types III, IV, and VI accumulation. We also examined the in vitro relationship between DNA damage and COL accumulation by mitomycin C (MMc)-induced DNA damage in human glomerular endothelial cells (HRGEc)., Results: The γ-H2AX and COL type VI, which mainly accumulated in the subendothelial and mesangial regions, were positively correlated with the duration of the post-renal transplant (RT) period. In multiple regression analysis, the duration of the post-RT period and cg in the Banff '07 classification were identified as a significant predictor of COL type VI accumulation and γ-H2AX expression in the glomerular capillaries. In addition, the γ-H2AX-positive area was also identified as a predictor of glomerular accumulation of COL type VI. COL type VI was detected in the cytoplasm of the HRGEc, which was secreted into the supernatant after MMc stimulation with γ-H2AX expression. The number of γ-H2AX (-)/COL type VI (+) cells was inversely associated with the number of γ-H2AX (+)/COL type VI (-) cells during 24-h MMc treatment., Conclusions: Our findings suggest that the long-term RT induces DSBs and HRGEc-secreted COL type VI accumulation in the glomerular capillaries, which might progress to intractable glomerular fibrosis.

(Objective) Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with castration-resistant prostate cancer (CRPC). We retrospectively evaluated clinical efficacy and safety of enzalutamide in CRPC. (Patients and methods) We reviewed clinical records of 73 patients who had received enzalutamide for the CRPC at Showa University and affiliated 7 hospitals. Enzalutamide was given at a dose of 160 mg/day, but some patients were treated at lower dose because of there age or poor performance status. Prostrate-specific antigen (PSA) response, prior docetaxel use and the previously administered agents were evaluated retrospectively. (Results) The median patients age was 77 years, the median Gleason score was 9 and the median PSA level at baseline was 26.9 ng/ml. The patients who had prior docetaxel use were 29 (39.7%) and the median of total docetaxel dose was 460 mg/body. The median number of total prior treatments (anti-androgens, Estramustine and steroid) was 3. Twenty seven (61.4%) patients with docetaxel-naïve achieved over 50% reduction of PSA level from baseline, but only 7 (24.1%) in patients previously treated with docetaxel. The most common adverse events included fatigue (24.7%), anorexia (24.7%) and the nausea (16.4%). We found a small proportion of responders to enzalutamide experienced a PSA flare. (Conclusion) Our results of the use of Enzaltamide for CRPC were similar with previous reports. PSA flare was found in some patients with CRPC who responded to enzaltamide. It should be noted that this possible PSA flare phenomenon.

The single-step construction of various densely oxygenated carboskeletons was achieved by radical-based two- and three-component coupling reactions of sugar derivatives, without the need for light or heat. Et 3 B/O 2 -mediated decarbonylation readily converted α-alkoxyacyl tellurides to α-alkoxy carbon radicals, which intermolecularly added to glyoxylic oxime ether or enones to provide the two-component adducts. Furthermore, the three-component adducts were produced by an intermolecular aldol reaction between the aldehyde and the boron enolates generated by capture of the two-component radical intermediates by Et 3 B. This powerful coupling method serves as a novel strategy for the convergent synthesis of polyol natural products.

We previously generated a rat model that spontaneously developed small vessel vasculitis (SVV). In this study, a T cell clone reactive with rat vascular endothelial cells (REC) was established and named VASC-1. Intravenous injection of VASC-1 induced SVV in normal recipients. VASC-1 was a TCRαβ/CD3-positive CD4/CD8 double-negative T cell clone with expression of NKG2D. The cytokine mRNA profile under unstimulated condition was positive for IL-4 and IFN-γ but negative for IL-2 and IL-10. After interaction with REC, the mRNA expression of IL-2, IL-5 and IL-6 was induced in VASC-1, which was inhibited by blocking of CD1d on the REC surface. Although the protein levels of these cytokines seemed to be lower than the detection limit in the culture medium, IFN-γ was detectable. The production of IFN-γ from the VASC-1 stimulated with LPS-pre-treated REC was inhibited by the CD1d blockade on the REC. These findings indicated VASC-1 as an NKT cell clone. The NKT cell pool includes two major subsets, namely types I and II. Type I NKT cells are characterized by expression of semi-invariant TCRs and the potential to bind to marine sponge-derived α-galactosylceramide (α-GalCer) loaded on CD1d; whereas, type II NKT cells do not manifest these characteristics. VASC-1 exhibited a usage of TCR other than the type I invariant TCR α chain and did not bind to α-GalCer-loaded CD1d; therefore, it was determined as a type II NKT cell clone. The collective evidence suggested that REC-reactive type II NKT cells could be involved in the pathogenesis of SVV in rats., (© The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity is a state in which chronic low-grade inflammation persists in adipose tissues. Pro-inflammatory cytokines, including TNF-α, produced by adipose tissues have been implicated as active participants in the development of obesity-related diseases. Since TNF-α converting enzyme (TACE) is the major factor that induces soluble TNF-α, TACE has been noted as a pivotal regulator in this field. To reveal the role of TACE in adipose tissue inflammation, TACE-transgenic (TACE-Tg) and wild type (WT) mice were fed with high fat diet (HFD) or control diet for 16 weeks. At 13 weeks after the beginning of the diet, serum TNF-α and macrophage-related cytokine/chemokine levels were elevated in TACE-Tg mice fed with HFD (Tg-HFD mice), and the number of the so-called crown-like adipocyte was significantly increased in adipose tissues of Tg-HFD mice at the end of the experiment. Although macrophage infiltration was not detected in the adipose tissues at this time, fibrosis was observed around the crown-like adipocytes. These findings suggested that TACE overexpression induced macrophage infiltration and subsequent fibrosis in adipose tissues under HFD regimen. The collective evidence suggested that TACE could be a therapeutic target of HFD-induced obesity-related adipose tissue inflammation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Public knowledge-based application for paclitaxe(l PAC) has been approved for advanced or recurrent esophageal cancer. We investigated the feasibility of weekly PAC chemotherapy as a second-line or subsequent regimen for metastatic or recurrent esophageal cancer., Materials and Methods: Patients received PAC( 100 mg/m2 intravenously) on days 1, 8, 15, 22, 29, and 36 of each 8-week period. We analyzed the toxicity and efficacy in 6 patients treated with the weekly PAC chemotherapy., Results: Grade 3-4 toxicities were neutropenia, leukopenia, and anemia. Two patients had stable disease and 2 had progressive disease., Conclusion: By managing the side effects, weekly PAC therapy is considered a feasible regimen that can be administered on an outpatient basis.

Purpose: We investigated the background factors, histopathological results, and prognosis of patients with gastrointestinal neuroendocrine tumors., Materials and Methods: The medical records of 42 patients with gastrointestinal neuroendocrine tumors who were diagnosed and treated at our hospital from 2002 to 2012 were collected and retrospectively reviewed., Result: The ratio of male to female patients was 29:13; the mean age was 66.1 years. The tumors were located in the esophagus( 2 patients), stomach( 13 patients), duodenum( 9 patients), colon( 1 patient), and rectum( 18 patients). Regarding the depth of the tumor, invasion of the submucosa( SM) was observed in 26 patients; invasion of the muscularis propria( MP), in 1 patient; invasion of the subserosa( SS), in 3 patients; penetration of the serosa( SE)( AD), in 1 patient, invasion of the adjacent structures( SI)( AI), in 3 patients; and the extent of tumor invasion was unknown in 1 patient. Patients who experienced relapse had a poor prognosis, and all the patients died.

TNF-α-converting enzyme (TACE) can cleave transmembrane proteins, such as TNF-α, TNF receptors, and epidermal growth factor receptor (EGFR) ligands, to release the extracellular domains from the cell surface. Recent studies have suggested that overexpression of TACE may be associated with the pathogenesis of inflammation and fibrosis. To determine the roles of TACE in inflammation and fibrosis, TACE transgenic (TACE-Tg) mice, which overexpressed TACE systemically, were generated. As the transgene-derived TACE was expressed as an inactive form, no spontaneous phenotype developed in TACE-Tg mice. However, the transgene-derived TACE could be converted to an active form by furin in vitro and by phorbol myristate acetate (PMA) in vivo. Subcutaneous injection of PMA into mice induced inflammatory cell infiltration 1 day later and subsequent dermal fibrosis 7 days later. Interestingly, the degree of dermal fibrosis at day 7 was significantly higher in TACE-Tg mice than in wild-type mice. Correspondingly, PMA increased the expression of type I collagen in the primary culture of dermal fibroblasts derived from TACE-Tg mice. Furthermore, phosphorylated EGFR was increased in the fibroblasts by the PMA treatment. The collective findings suggest that TACE overexpression and activation in fibroblasts could shed off putative EGFR ligands. Subsequently, the soluble EGFR ligands could bind and activate EGFR on fibroblasts, and then increase the type I collagen expression resulting in induction of dermal fibrosis. These results also suggest that TACE and EGFR on fibroblasts may be novel therapeutic targets of dermal fibrosis, which is induced after diverse inflammatory disorders of the skin.

Src family tyrosine kinases (SFKs) participate in mitotic signal transduction events, including mitotic entry, cleavage furrow ingression, and cytokinesis abscission. Although SFKs have been shown to associate with the mitotic spindle, the role of SFKs in mitotic spindle formation remains unclear. Here, we show that c-Src promotes proper spindle orientation in early prometaphase. Src localizes close to spindle poles in a manner independent of Src kinase activity. Three-dimensional analyses showed that Src inhibition induced spindle misorientation, exhibiting a tilting spindle in early prometaphase. Spindle misorientation is frequently seen in SYF cells, which harbor triple knock-out mutations of c-Src, c-Yes, and Fyn, and reintroduction of c-Src but not Fyn into SYF cells rescued spindle misorientation. Spindle misorientation was also observed upon Src inhibition under conditions in which Aurora B was inhibited. Inducible expression of c-Src promoted a properly oriented bipolar spindle, which was suppressed by Src inhibition. Aster formation was severely inhibited in SYF cells upon Aurora B inhibition, which was rescued by reintroduction of c-Src into SYF cells. Furthermore, reintroduction of c-Src facilitated microtubule regrowth from cold-induced depolymerization and accelerated M phase progression. These results suggest that c-Src is involved in spindle orientation through centrosome-mediated aster formation.

Mitosis is a continuous process to separate replicated chromosomes into two daughter cells through prophase, metaphase, anaphase, and telophase. Although a number of methods have been established to synchronize cells at different phases of the cell cycle, it is difficult to synchronize cells at the specific phases, anaphase and telophase, during mitosis because of the short duration of anaphase. Here, we show that HeLa S3 cells in anaphase and in telophase are successfully enriched by treatment with a combination of low concentrations of the microtubule-depolymerizing agent nocodazole and the myosin II inhibitor blebbistatin. After 9-h release from thymidine block at G1/S phase, addition of nocodazole at 20 ng/ml but not 40 ng/ml ensures rapid release from the nocodazole arrest. Subsequently, the cells are cultured in the presence of 50 μM blebbistatin for 20 and 50 min to enrich cells in anaphase and telophase, respectively. Western blot analysis verifies down-regulation of phospho-histone H3-Ser10, phospho-Aurora A/B/C, and cyclin B1 during M-phase progression. Furthermore, we show how the electrophoretic mobility shifts of the Src-family kinases c-Yes and c-Src can change in each phase of mitosis. These results provide a useful synchronization method for biochemically examining protein dynamics during M-phase progression., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Periodic sharp wave complexes observed on an electroencephalographic recording and the presence of a 14-3-3 protein in the cerebrospinal fluid (CSF) are both included in the diagnostic criteria for the Creutzfeldt-Jakob disease (CJD) supplied by the World Health Organization; however, the presence or absence of the 14-3-3 protein in the CSF is sometimes difficult to discern on a western blot because of equivocal bands. The goal of this study was to establish a standard 14-3-3 protein assay and to determine the threshold level of a 14-3-3 protein that can be assayed by western blot. We searched for the most suitable isoform of the 14-3-3 protein to test for in protein assays, and the most sensitive antibody among four antibodies with an affinity for 14-3-3. We measured the levels of all 14-3-3 isoforms in 112 patients with CJD and in 100 patients with other diseases. We compared the performances of four different antibodies. We carried out a semi-quantitative analysis of γ-isoform levels using the LAS 3000 system, which was capable of producing a digital image from the luminescence on a western blot. We determined that the most suitable isoform of the 14-3-3 protein for conducting a standardized assay was the γ-isoform. Among the four commercially available antibodies for this protein, the most sensitive and specific was 18647 (IBL, Japan). We report the high repeatability of the detection of the 14-3-3 protein by this antibody to the γ-isoform, showing that western blot can be used for semi-quantitative analysis.

Creutzfeldt-Jakob disease (CJD) is a transmissible, fatal, neurodegenerative disease in humans. Recently, various drugs have been reported to be useful in the treatment of CJD; however, for such treatments to be useful it is essential to rapidly and accurately diagnose CJD. 124 CJD patients and 87 with other diseases causing rapid progressive dementia were examined. Cerebral spinal fluid (CSF) from CJD patients was analyzed by 2D-PAGE and the protein expression pattern was compared with that from healthy subjects. One of three CJD-specific spots was found to be fatty acid binding protein (FABP), and heart-type FABP (H-FABP) was analyzed as a new biochemical marker for CJD. H-FABP ELISA results were compared between CJD patients and patients with other diseases (n = 211). Visual readout accuracy of the Rapicheck(®) H-FABP test panel for CSF was analyzed using an independent measure of CSF H-FABP concentration. The distribution of H-FABP in the brains of CJD patients was examined by immunohistochemistry. ELISA sensitivity and specificity were 90.3% and 92.9%, respectively, and Rapicheck(®) H-FABP sensitivity and specificity were 87.9% and 96.0%, respectively. ELISA and Rapicheck(®) H-FABP assays provided comparable results for 14-3-3 protein and total tau protein. Elevated H-FABP levels were associated with an accumulation of abnormal prion protein, astrocytic gliosis, and neuronal loss in the cerebral cortices of CJD patients. In conclusion, Rapicheck(®) H-FABP of CSF specimens enabled quick and frequent diagnosis of CJD. H-FABP represents a new biomarker for CJD distinct from 14-3-3 protein and total tau protein.

We previously found that conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols), and suppressed human cancer cell growth. The aim of the present study was to evaluate the efficacy of concurrent radiation with cEPA in a human colon carcinoma cell line, HCT 116. Furthermore, we examined the most effective timing of irradiation. The post-irradiation addition of cEPA significantly enhanced HCT116 cell radiosensitivity by decreasing the expression of pols beta, delta and epsilon, increasing damaged DNA, such as DNA double-strand breaks, inhibiting clonogenic survival, and inducing apoptosis. However, cells treated by pre-irradiation addition of cEPA did not influence radiosensitive survival and radiation-induced apoptosis. cEPA inhibited the activities of pols needed for DNA repair, thereby DNA damage must be augmented by cEPA and irradiation. These results suggested that the combination of inhibitors of DNA repair-related pols/radiation could be an effective anticancer therapy.

The glycoglycerolipid, monogalactosyl diacylglycerol (MGDG), containing two alpha-linolenic acids (C18:3), was isolated from bitter melon as a potent and selective inhibitor of mammalian DNA polymerase (pol) species such as pols alpha, gamma, delta, and epsilon with IC(50) values of 17.6-37.2muM. This MGDG also suppressed the growth of six human cancer cell lines, although normal human cell lines were not affected. This compound (i.e., MGDG-C18:3-C18:3) was a stronger inhibitor than both MGDG-C18:1-C18:0 and MGDG-C18:0-C18:0. In this study, we discussed the structure-function relationship in the selective inhibition of mammalian replicative pols and human cancer cell proliferation by MGDGs.

Gnidimacrin (NSC252940) shows significant antiproliferating activity against human tumor cell lines. This compound binds to and directly activates protein kinase C (PKC). Human hepatoma HLE cells, which lose p53 function and retinoblastoma protein (Rb) expression, are resistant to gnidimacrin. However, PKC betaII gene-transfected HLE (HLE/PKC betaII) cells became sensitive to gnidimacrin, through which cdc2 inhibition and G(2)-phase arrest was caused. p21(WAF1/Cip1) induction and cdc2 reduction were observed and this reduction was abolished through the suppression of p21(WAF1/Cip1) induction by the MEK1/2 inhibitor U0126. Translocation of E2F-4 to the nucleus was also observed in the cells but not in parental HLE cells. Consequently gnidimacrin inhibited cell growth through G(2)-phase arrest not only by the p21(WAF1/Cip1)-dependent suppression of cdc2 activity, but also by subsequent transcriptional suppression of cdc2 itself. In addition, involvement of E2F-4 in cdc2 suppression through a long-lasting induction of p21(WAF1/Cip1) by gnidimacrin is suggested in HLE/PKC betaII cells.

We previously isolated a novel natural product, designated kohamaic acid A (KA-A, compound 1), as an inhibitor of the first cleavage of fertilized sea urchin eggs, and found that this compound could selectively inhibit the activities of mammalian DNA polymerases (pols). In this paper, we investigated the structure and bioactivity of KA-A and its chemically synthesized 11 derivatives (i.e., compounds 2-12), including KA-A - fatty acid conjugates. The pol inhibitory activity of compound 11 [(1S*,4aS*,8aS*)-17-(1,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-naphthalen-1-yl)heptadecanoic acid] was the strongest among the synthesized compounds, and the range of IC(50) values for mammalian pols was 3.22 to 8.76 microM; therefore, the length of the fatty acid side chain group of KA-A is important for pol inhibition. KA-A derivatives could prevent human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of mammalian pols. Since pol beta is the smallest molecule, we used it to analyze the biochemical relationship with KA-A derivatives. From computer modeling analysis (i.e., docking simulation analysis), these compounds bound selectively to four amino acid residues (Leu11, Lys35, His51 and Thr79) of the N-terminal 8-kDa domain of pol beta, and the binding energy between compound 11 and pol beta was largest in the synthesized compounds. The relationship between the three-dimensional molecular structures of KA-A-related compounds and these inhibitory activities is discussed.

Pironetin, isolated from Streptomyces sp., is a potent inhibitor of microtubule assembly and the first compound identified that covalently binds to alpha-tubulin at Lys352. We examined whether pironetin is an effective agent against human small cell lung cancer H69 cells, including two cell lines resistant to the microtubule-targeted drugs vindesine (H69/VDS) and paclitaxel (H69/Txl) that interact with beta-tubulin. Pironetin was found to be effective against these resistant cells as well as their parental cells. In addition, pironetin inhibited the growth of human leukemic K562 multidrug-resistant cells (K562/ADM), which have mdr1 gene expression, as well as the parental K562 cells. In these cell lines, including the parental and resistant cells, pironetin caused complete mitotic arrest; in addition, apoptosis inductions by 30 and 100 nM pironetin were observed. In this study, the new mitotic inhibitor, pironetin, was found to be effective not only against human tumor cell lines resistant to microtubule-targeted drugs, but also multidrug-resistant cells with mdr1 gene expression. These results suggest that pironetin is a useful agent for overcoming drug resistance in cancer chemotherapy.