The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is ...necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 μg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Alginate-hyaluronic acid (ALG-HA) composite injectable microbeads with 100–250μm average size distribution were prepared by a spraying method into a CaCl2 solution.•Rat bone marrow stem cells ...(RBMSCs) were also considered to encapsulate in ALG-HA microbeads.•Encapsulated cells were found to release at 7days post-injection and display excellent viability and proliferation.•In vivo biocompatibility was examined by the injection of ALG-HA microbeads without encapsulating cell into subscapular area of kidney.
In this study, alginate (ALG) and alginate-hyaluronic acid (ALG-HA) injectable microbeads, with the purpose of delivering stem cells for tissue engineering, were prepared by a spraying method into a CaCl2 solution that shows high porosity for the exchange of nutrition and waste. In addition, the size distribution and surface morphology was investigated using optical and scanning electron microscopy, respectively. The chemical structural properties of the ALG-HA microbeads were examined by Fourier transform infrared spectroscopy. The biocompatibility of ALG and ALG-HA microbeads was examined in vitro. Rat bone marrow stem cells were encapsulated in microbeads to investigate cell release, cell viability, proliferation, and secretion of growth factors such as VEGF and PDGF. Growth factors were released for the 21day experimental period. Cells were found to be released from the microbeads after 7days. Furthermore, the in vivo biocompatibility of ALG-HA microbeads was examined using microbeads without cell encapsulation in the kidney capsule, in order to assess the foreign body reaction and inflammatory response, for 14days. The desired in vivo response to ALG-HA microbeads hydrogel makes it an exquisite candidate for subcapsular cell and drug delivery to kidney tissue.
Background There is a growing body of evidence that a pathological diagnosis is necessary for small (<3 cm in diameter), asymptomatic, hypoechoic, subepithelial tumors (SETs) originating from the ...muscularis propria on EUS. However, the diagnostic efficacy of current tissue sampling techniques appears to be limited. Objective To evaluate the diagnostic yield and safety of endoscopic partial resection using the unroofing technique (EPR-UT) in a subset of patients. Design A prospective case series. Setting A single tertiary-care referral center. Patients Between August 2007 and March 2009, 16 patients with hypoechoic SETs of <3 cm in diameter, originating from the muscularis propria on EUS (14 gastric and 2 esophageal lesions), underwent EPR-UT. Interventions The overlying mucosa was removed by using the unroofing technique using a conventional snare with electrical current to expose the tumor sufficiently. Next, the exposed tumor was partially resected by snaring. Main Outcome Measurements The diagnostic yield and safety of this method. Results EPR-UT provided specimens that were sufficient for a diagnosis and the assessment of risk for malignancy in 15 out of 16 cases (diagnostic yield 93.7% 95% CI, 80.4%-100.0%). The pathological diagnoses were leiomyoma (7 of 15, 46.6%), GI stromal tumor (6 of 15, 40.0%), aberrant pancreas (1 of 15, 6.6%), and well-differentiated neuroendocrine carcinoma (1 of 15, 6.6%). Six cases with GI stromal tumor were classified as very low risk for malignant potential (mitotic index <5/50 high-power fields). Procedural blood oozing was relatively common (9 of 16, 56.0% 95% CI, 33.0%-77.0%); however, this minor complication was easily controlled by argon plasma coagulation. There were no procedure-related major complications (0 of 16, 0% 95% CI, 0.0%-23.0%). Limitations Single-center, noncomparative study with small sample size. Conclusion EPR-UT appears to be simple, safe, and effective for determining the definite pathological diagnosis and assessing malignant potential of small, hypoechoic SETs originating from the muscularis propria on EUS.
BACKGROUND/AIMDeubiquitinating enzyme 3 (DUB3) is a member of the ubiquitin-specific proteases family involved in regulating cell proliferation, invasion, and apoptosis. However, the biological role ...and clinicopathological significance of DUB3 expression have not been elucidated in non-small cell lung cancer (NSCLC).PATIENTS AND METHODSWe evaluated the expression of DUB3 by immunohistochemistry using tissue microarrays and assessed the clinicopathologic significance of DUB3 expression levels in 187 patients with NSCLC, including its two major subtypes (93 cases of adenocarcinoma and 72 cases of squamous cell carcinoma).RESULTSIn adenocarcinoma, we observed that DUB3 expression had an effect on tumor size (p=0.030), vessel invasion (p=0.038), T stage (p=0.014), and tumor recurrence (p=0.002). Kaplan-Meier curves with log-rank test showed that high DUB3 expression was correlated with significantly more favorable clinical outcomes compared to those of the low expression group in adenocarcinoma (p=0.013). Multivariate analysis of disease-free survival also demonstrated that DUB3 expression is an independent prognostic factor in lung adenocarcinoma (p=0.017). Additionally, we identified the correlation between DUB3 and the expression of large tumor suppressor kinase 1 expression, a core protein of the Hippo pathway.CONCLUSIONDUB3 could function as a tumor suppressor by regulating the Hippo pathway in lung adenocarcinoma and can be considered a powerful predictive factor and therapeutic target.
Ampullary adenoma is a common indication for endoscopic papillectomy. Ampullary neuroendocrine tumor(NET) is a rare disease for which complete surgical resection is the treatment of choice. However, ...because of the morbidity and mortality associated with surgical resection, endoscopic papillectomy is increasingly used in selected cases of low grade, with no metastasis and no invasion of the pancreatic or bile duct. Also, confirmed and complete endoscopic resection of ampullary NET accompanied by adenoma has not been reported to date. We report herein a rare case of an ampullary NET accompanied with adenoma, which was successfully and completely resected via endoscopic papillectomy. Prior to papillectomy, this case was diagnosed as an ampullary adenoma.
A variety of synthetic materials are currently in use as bone substitutes, among them a new calcium phosphate-based multichannel, cylindrical, granular bone substitute that is showing satisfactory ...biocompatibility and osteoconductivity in clinical applications. These cylindrical granules differ in their mechanical and morphological characteristics such as size, diameter, surface area, pore size, and porosity. The aim of this study is to investigate whether the sizes of these synthetic granules and the resultant inter-granular spaces formed by their filling critical-sized bone defects affect new bone formation characteristics and to determine the best formulations from these individual types by combining the granules in different proportions to optimize the bone tissue regeneration. We evaluated two types of multichanneled cylindrical granules, 1 mm and 3 mm in diameter, combined the granules in two different proportions (wt%), and compared their different mechanical, morphological, and in vitro and in vivo biocompatibility characteristics. We assessed in vitro biocompatibility and cytotoxicity using MC3T3-E1 osteoblast-like cells using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and confocal imaging. In vivo investigation in a rabbit model indicated that all four samples formed significantly better bone than the control after four weeks and eight weeks of implantation. Micro-computed tomography analysis showed more bone formation by the 1 mm cylindrical granules with 160 ± 10 µm channeled pore and 50% porosity than the other three samples (p<.05), which we confirmed by histological analysis.
AIM:To evaluate the technical feasibility of a modified tapered metal tip and low profile introducer for onestep endoscopic ultrasound(EUS)-guided biliary drainage(EUS-BD)in a new experimental ...biliary dilatation porcine model.METHODS:A novel dedicated device for one-step EUS-guided biliary drainage system(DEUS)introducer has size 3F tapered catheter with size 4F metal tip for simple puncture of the intestinal wall and liver parenchyma without graded dilation.A self-expandable metal stent,consisting of both uncovered and nitinol-covered portions,was preloaded into DEUS introducer.After establishment of a biliary dilatation model using endoscopic hemoclips or band ligation with argon plasma coagulation in 9 mini-pigs,EUS-BD using a DEUS was performed following 19-G needle puncture without the use of fistula dilation devices.RESULTS:One-step EUS-BD was technically successful in seven pigs7/9(77.8%)as intention to treatwithout the aid of devices for fistula dilation from the high body of stomach or far distal esophagus to the intrahepatic(n=2)or common hepatic(n=5)duct.Primary technical failure occurred in two cases that did not show adequate biliary dilatation.In seven pigs with a successful bile duct dilatation,the technical success rate was 100%(7/7 as per protocol).Median procedure time from confirmation of the dilated bile duct to successful placement of a metallic stent was 10 min(IQR;8.9-18.1).There were no immediate procedure-related complications.CONCLUSION:Modified tapered metal tip and low profile introducer may be technically feasible for onestep EUS-BD in experimental porcine model.
Background Endoscopic treatment of a pedunculated submucosal tumor (SMT) has not been well established. In particular, endoscopic cautery snare resection of a large pedunculated SMT is discouraged ...because of the increased risk of bowel perforation. Objective To report the clinical outcome of endoloop ligation for the treatment of various pedunculated SMTs with a clip-marking technique. Design Prospective evaluation of 10 patients who, between June 2005 and May 2006, received endoloop ligation with a clip-marking technique. Setting At a tertiary-care, academic medical center. Patients Ten patients with various pedunculated SMTs with either symptomatic lesions or large-sized lesions (>4 cm). Main Outcome Measurements Clinical procedural success, reported adverse events. Results Nine cases were successfully treated, with tumor removal within 4 weeks. In contrast, only 1 patient needed a second session of loop ligation. Only 6 specimens were retrieved. There were no procedure-related complications, such as bleeding or perforation. Limitations Retrieval by the patient of a specimen from stool was possible in only 60% of cases; a limited number of 10 patients; by oncology standards, not the correct treatment for nonlipomatous lesions, which limits its application to surgical risk candidates. Conclusions Endoloop ligation of large pedunculated SMTs seemed to be technically feasible and appeared to be safe in this case series. Further controlled clinical trials have to be conducted before application of this technique to a large submucosal lipoma or other SMTs in surgical high-risk candidates can be generally recommended.
Background Submucosal injection is essential to performing EMR easily, and various solutions have been proposed to create a long-lasting submucosal fluid cushion. Objective To assess the efficacy of ...a fibrinogen mixture (FM) as a submucosal injection solution. Design A prospective, randomized, controlled trial. Setting At a tertiary care, academic medical center. Patients A total of 72 patients with early gastric neoplasm were randomly assigned to receive EMR with submucosal injection of normal saline solution (NS) or a FM. Intervention We performed EMR only with a conventional method. Main Outcome Measurements En bloc resection rate, complete resection rate, complications, and other procedure-related outcomes. Results No significant differences were observed between the 2 groups (the FM group vs the NS group) in the rates of en bloc resection (80.6% vs 88.9%), complete resection rate (86.1% vs 80.6%), and recurrence rate (3% vs 6.1%). Mean procedure time was significantly shorter in the FM group vs the NS group (11.39 ± 3.07 minutes vs 13.93 ± 3.26 minutes; P < .05). Mean submucosal injection volume of the FM group was significantly less than that of the NS group (9.81 ± 2.26 mL vs 14.32 ± 2.35 mL; P < .05). Also, additional submucosal injection to maintain elevation of the lesion was less frequently required in the FM group than in the NS group (5.6% vs 33.3%; P < .05). Limitations The main limitations were the method of EMR (only included the conventional method) and the size of lesions (<30 mm), because a long-lasting submucosal fluid cushion was more important in the dissection method and larger tumors. Conclusions The FM is a reliable submucosal injection solution for conventional EMR.
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