A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.

The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, ß-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance.

Preoperative anxiety about spinal surgery under general anesthesia.

PURPOSE: No study has investigated preoperative anxiety about spinal surgery under general anesthesia. The purposes of this study were (1) to determine how many patients have preoperative anxiety about spinal surgery and general anesthesia, (2) to evaluate the level of anxiety, (3) to identify patient factors potentially associated with the level of anxiety, and (4) to describe the characteristics of the anxiety that patients experience during the perioperative period. METHODS: This study was performed in 175 consecutive patients undergoing laminectomy for lumbar stenosis or discectomy for herniated nucleus pulposus under general anesthesia. Demographic data, information related to surgery, and characteristics of anxiety were obtained using a questionnaire. The level of anxiety was assessed using a visual analog scale of anxiety (VAS-anxiety). Patient factors potentially associated with the level of anxiety were investigated using multiple stepwise regression analysis. RESULTS: Of 157 patients finally included in this study, 137 (87%) had preoperative anxiety (VAS-anxiety > 0). The mean VAS-anxiety score for spinal surgery was significantly higher than that for general anesthesia (4.6 ± 3.0 vs. 3.2 ± 2.7; P < 0.001). Sex and age were significant patient factors related to the level of anxiety about spinal surgery (P = 0.009) and general anesthesia (P = 0.018); female patients had a higher level of anxiety about spinal surgery, and elderly patients had a higher level of anxiety about general anesthesia. The most helpful factors in overcoming anxiety before surgery and in reducing anxiety after surgery were faith in the medical staff (48.9 %) and surgeon's explanation of the surgery performed (72.3%), respectively. CONCLUSIONS: Patients awaiting laminectomy or discectomy feared spinal surgery more than general anesthesia. This study also found that medical staff and surgeons play important roles in overcoming and reducing patient anxiety during the perioperative period.

Synthesis of (±)-spongiolactone enabling discovery of a more potent derivative.

An eleven-step synthesis of (±)-spongiolactone from 1,3-cyclohexanedione is reported that relies on a diastereoselective, nucleophile-catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated ß-lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure-activity studies that revealed a regio- and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.

Extracorporeal cardiopulmonary resuscitation in bedside echocardiography-diagnosed massive pulmonary embolism.

Acute pulmonary embolism (PE) is one of the major causes of inhospital cardiac arrest as well as out-of-hospital cardiac arrest. Bedside diagnosis of acute PE in the emergency department (ED) can be challenging, especially in a cardiac arrest setting. Even if the early diagnosis of an acute massive PE had been made, hemodynamic instability may be worsened unless obstructive shock gets resolved. We present a case of a 46-year-old woman who developed pulseless electrical activity (PEA) after complaining of weakness and dyspnea in an ambulance, presumptively diagnosed as acute PE by bedside focused echocardiography. She received thrombolytic therapy and was rescued by extracorporeal cardiopulmonary resuscitation for recurrent PEA arrest in the ED. Focused bedside echocardiography provides a rapid diagnostic adjunct, and extracorporeal cardiopulmonary resuscitation can be a valuable rescue therapy for PEA arrest from massive PE.

Neoadjuvant Cisplatin-Based Chemotherapy Followed by Selective Bladder Preservation Chemoradiotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder: Post Hoc Analysis of Two Prospective Studies.

PURPOSE: Bladder preservation chemoradiotherapy (CRT) in patients with a clinical complete response (cCR) following cisplatin-based neoadjuvant chemotherapy (NAC) is a promising treatment strategy for muscle-invasive bladder urothelial carcinoma (MIBC). A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. MATERIALS AND METHODS: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving NAC followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survival was defined as the date of commencing CRT. RESULTS: Among 76 patients, 66 had a cCR following NAC. Sixty-four patients received gemcitabine and cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. Bladder preservation CRT following NAC was generally well-tolerated, with low urinary tract symptoms being the most common late complication. With a median follow-up of 64 months, recurrence was recorded in 43 patients (57%): intravesical only (n=20), metastatic only (n=16), and both (n=7). In 27 patients with intravesical recurrence, transurethral resection, and Bacillus Calmette-Guerin treatment was given to 17 patients. Salvage cystectomy was performed in 10 patients. Median DFS was 46.3 (95% confidence interval [CI], 25.1 to 67.5) months, and the median MFS was not reached. Neither DFS nor MFS appeared to be affected by any of the baseline characteristics. However, DFS was significantly longer in patients with a cCR than in those without (hazard ratio, 0.465; 95% CI, 0.222 to 0.976). CONCLUSION: The strategy of NAC followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC. A standardized definition of cCR is needed to better assess disease status post-NAC.

Solid-solution nanocrystallite formation by high-energy milling.

Solid-solution nanocrystalline powders were prepared by the high-energy milling of Ti alloys with graphite. The B1 structure (NaCl-like structure) phases, (Ti, Cr)C and (Ti, Al)C, were formed during the milling process of Ti-Cr + graphite and Ti-Al + graphite, and the synthetic procedures were investigated in terms of the phase evolution from XRD data. The (Ti, Al)C phase was obtained after milling for 20 hr at BPR = 40:1 (under a more severe condition), while the (Ti, Cr)C phase formed after milling for 20 hr at BPR = 20:1 (a relatively soft condition). The difference in the tendency to create a solid solution with Ti in the B1 structure caused a difference in the synthetic behavior of (Ti, Al)C and (Ti, Cr)C. In other words, (Ti, Cr)C is formed earlier than (Ti, Al)C during milling because the atomic size of Cr (0.166 nm) is similar to that of Ti (0.176 nm), which leads to the straightforward formation of the solid-solution (Ti, Cr)C as compared to when (Ti, Al)C is used. As a result, the crystallite size of the (Ti, Al)C phase (2-3 nm) synthesized at a later stage becomes smaller than that of the (Ti, Cr)C phase (5 10 nm) formed at an earlier stage during milling.

Complications and revision rate compared by type of total elbow arthroplasty.

BACKGROUND: This study evaluates the long-term results, including complication and revision rates, of different types of total elbow arthroplasty (TEA) with an average follow up of 13 years. METHODS: Since 1984, a total of 84 primary TEAs have been performed in 77 patients at our institution. The patient's average age was 54.2 years. We performed unlinked TEA in 35 cases (Pritchard ERS since 1984 [n = 18], Kudo type 3 since 1991 [n = 17]), and semi-linked TEA in 49 cases (Pritchard Mark II since 1997 [n = 14], Coonrad-Morrey since 2001 [n = 35]). We assessed the patients for compliance to daily living guidelines (not to exceed 2.25 kg for repetitive lifting and 4.5 kg for single episode lifting), and followed up with them for an average of 13 years after primary TEA. We analyzed their results with regard to complication and revision rates as the type of TEA. RESULTS: The mean Mayo Elbow Performance Score (MEPS) improved from preoperative 34 points to postoperative 84 points. The active flexion-extension elbow motion increased from 25°-94° preoperative to 12°-130° postoperative. The overall complication rate was 44.0% (37/84 cases); the rate was statistically higher in the unlinked group (62.9%, 22/35 cases) than in the semi-linked group (30.6%, 15/49 cases). The overall revision rate was 27.4% (23/84 cases); the rate was higher in the unlinked group (34.3%, 12/35 cases) than in the semi-linked group (22.4%, 11/49 cases). CONCLUSION: Semi-linked TEA has better outcomes than unlinked TEA with respect to complication and revision rates; but continuous efforts to develop a new TEA design for longevity, improved cementing technique, and supporting activities of daily living are needed to reduce complication and revision rates in the future.

Rapid consolidation of nanostuctured TiCu compounds.

TiCu nanopowder was produced using an electrical wire explosion method and subsequently consolidated into dense nanostuctured TiCu by a high frequency induction heated sintering method. The consolidation was accomplished by the combination of an induced current and a high mechanical pressure within two minutes. This process results in very quick densification to near the theoretical density and prohibits grain growth in nano-structured materials. The grain sizes and mechanical properties of the sintered TiCu were investigated.

Differences in prognostic factors between early and advanced gastric cancer.

BACKGROUND/AIMS: The aim of this study was to assess any differences in the prognostic factors affecting long term survival in early gastric cancer (EGC) and advanced gastric cancer (AGC). METHODOLOGY: The prognostic factors affecting long term survival between EGC and AGC were evaluated. RESULTS: Based on the result of multivariate analysis, the variables related with poor prognosis in patient with EGC were ages of more than 60 (p=0.003, Relative risk [RR]:2.683) and more than 7 lymph nodes with metastasis (p=0.001, RR:12.129). The relevant variables in AGC were the presence of more than 7 lymph nodes with metastasis (p=0.002, RR:2.491), lymphovascular invasion (p=0.038, RR:1.476) and tumor depth (serosa ; p<0.001, RR:3.493, adjacent structure; p=0.005, RR:3.013). CONCLUSIONS: The prognostic factors affecting long term survival are a little different between the patients with EGC and AGC. Age of more than 60 years is one of the prognostic factors affecting long term survival in patients with EGC, but not with AGC. In AGC, lymphovascular invasion and tumor depth are prognostic factors but not in EGC.

How can a single rescuer adequately deliver tidal volume with a manual resuscitator? An improved device for delivering regular tidal volume.

OBJECTIVES: A bag-valve mask (BVM) device is used as one of the first-line pieces of equipment in emergency situations. However, cardiopulmonary support providers do not recognise the exact tidal volume during procedures, and squeezing methods of BVM may not deliver the same tidal volume each time. To supply a regular and sustained tidal volume, adequate finger points were marked on the surface of a BVM. METHODS: In this study, a total of 83 volunteers participated and practised conventional BVM and volume-marked bag-valve mask (VBVM) procedures. The VBVM is simply a conventional BVM with an imaginary axis grid, drawn to guide the placement of the fingers. The VBVM method provides a constant volume of approximately 500-600 ml; the bag is squeezed until the thumb and the middle finger touch slightly. The results were then statistically analysed. RESULTS: The tidal volume delivered by the studied VBVM method is more accurate than the conventional BVM method (421.87±95.19 ml vs 534.21±24.22 ml, p<0.001). There was no statistical correlation except age between the results and the participants' training level or physical characteristics in the study. CONCLUSIONS: As the conventional BVM method cannot deliver a regular and sustained tidal volume, the authors invented the VBVM method. This method delivered a volume of 500-600 ml with more stability each time, which can improve the outcome of emergency patients.

Total synthesis of (-)-belactosin C and derivatives via double diastereoselective tandem mukaiyama aldol lactonizations.

[reaction: see text] The enantioselective synthesis of (-)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama aldol-lactonizaton (TMAL) process. One approach involved a distal double diastereoselective TMAL reaction with a dipeptide glyoxamide, whereas a second approach involved amide coupling of a dipeptide with a beta-lactone carboxylic acid, obtained via the TMAL process employing a chiral silyl ketene acetal. Notable improvements in diastereoselectivity were achieved in a proximal double diastereoselective TMAL process.

Relationship between Initial Telomere Length, Initial Telomerase Activity, Age, and Replicative Capacity of Nucleus Pulposus Chondrocytes in Human Intervertebral Discs: What Is a Predictor of Replicative Potential?

There is evidence that telomere length (TL), telomerase activity (TA), and age are related to the replicative potential of human nucleus pulposus chondrocytes (NPCs). However, it has not yet been established if any of these factors can serve as predictors of the replicative potential of NPCs. To establish predictors of the replicative potential of NPCs, we evaluated potential relationships between replicative capacity of NPCs, initial TL (telomere length at the first passage), initial TA (telomerase activity at the first passage), and age. Nucleus pulposus specimens were obtained from 14 patients of various ages undergoing discectomy. NPCs were serially cultivated until the end of their replicative lifespans. Relationships among cumulative population doubling level (PDL), initial TL, initial TA, and age were analyzed. Initial TA was negatively correlated with age (r = -0.674, P = 0.008). However, no correlation between initial TL and age was observed. Cumulative PDL was also negatively correlated with age (r = -0.585, P = 0.028). Although the cumulative PDL appeared to increase with initial TL or initial TA, this trend was not statistically significant. In conclusion, age is the sole predictor of the replicative potential of human NPCs, and replicative potential decreases with age. Initial TL and initial TA are not predictors of replicative potential, and can serve only as reference values.

A new method for the identification and quantification of magnetite-maghemite mixture using conventional X-ray diffraction technique.

The electrical explosion of Fe wire in air produced nanoparticles containing the binary mixture of magnetite (Fe(3)O(4)) and maghemite (γ-Fe(2)O(3)). The phase identification of magnetite and maghemite by the conventional X-ray diffraction method is not a simple matter because both have the same cubic structure and their lattice parameters are almost identical. Here, we propose a convenient method to assess the presence of magnetite-maghemite mixture and to further quantify its phase composition using the conventional peak deconvolution technique. A careful step scan around the high-angle peaks as (511) and (440) revealed the clear doublets indicative of the mixture phases. The quantitative analysis of the mixture phase was carried out by constructing a calibration curve using the pure magnetite and maghemite powders commercially available. The correlation coefficients, R(2), for magnetite-maghemite mixture was 0.9941. According to the method, the iron oxide nanoparticles prepared by the wire explosion in this study was calculated to contain 55.8 wt.% maghemite and 44.2 wt.% magnetite. We believe that the proposed method would be a convenient tool for the study of the magnetite-maghemite mixture which otherwise requires highly sophisticated equipments and techniques.

One Year Follow-up Result of Doppler-guided Hemorrhoidal Artery Ligation and Recto-Anal Repair in 97 Consecutive Patients.

PURPOSE: Doppler-guided hemorrhoidal artery ligation and recto-anal repair (DG-HAL & RAR) is known for low recurrence, high patient satisfaction, and less postoperative pain. The purpose of this study is to analyze the 1-year follow-up results in patients who underwent a DG-HAL & RAR and to establish the benefits of the procedure. METHODS: Among the hemorrhoid patients who were admitted to our hospital from March 2008 to May 2010 and who underwent a DG-HAL & RAR, 97 patients who were followed up for a year were investigated. Recurrence, complications, admission period, difference in preoperative and postoperative pain, operation time, and time to return to daily activities were investigated. RESULTS: The average admission period was 1.6 ± 1.1 days. Pain at postoperative day 7 showed no significant difference from preoperative pain (P > 0.05). The operation time was 34.0 ± 7.3 minutes on average, and return to daily activities was timed at 2.3 ± 2.0 days postoperatively. At the one year follow-up, no serious complications were noted, and preoperative symptoms recurred only in 14 patients (14.4%). CONCLUSION: In most patients with hemorrhoids, excluding those with severe prolapsed hemorrhoids, less pain, no serious complications, and good long-term outcome can be expected from a DG-HAL & RAR.