Six fungal metabolites, of which five were new, including one (1) with a dioxa[4.3.3]propellane ring system, were discovered, identified, and structurally elucidated from Neosetophoma sp. (strain MSX50044); these compounds are similar to the bis-tropolone, eupenifeldin. Three of the meroterpenoids are potent cytotoxic agents against breast, ovarian, mesothelioma, and lung cancer cells with nanomolar IC50 values while not inducing mitochondrial toxicity at 12.5 μM.
A longstanding goal in science and engineering is to mimic the size, structure, and functionality present in biology with synthetic analogs. Today, synthetic globular polymers of several million molecular weight are unknown, and, yet, these structures are expected to exhibit unanticipated properties due to their size, compactness, and low inter-chain interactions. Here we report the gram-scale synthesis of dendritic polymers, mega hyperbranched polyglycerols (mega HPGs), in million daltons. The mega HPGs are highly water soluble, soft, nanometer-scale single polymer particles that exhibit low intrinsic viscosities. Further, the mega HPGs are lubricants acting as interposed single molecule ball bearings to reduce the coefficient of friction between both hard and soft natural surfaces in a size dependent manner. We attribute this result to their globular and single particle nature together with its exceptional hydration. Collectively, these results set the stage for new opportunities in the design, synthesis, and evaluation of mega polymers.
Mucoadhesive polymers are of significant interest to the pharmaceutical, medical device, and cosmetic industries. Polysaccharides possessing charged functional groups, such as chitosan, are known for mucoadhesive properties but suffer from poor chemical definition and solubility, while the chemical synthesis of polysaccharides is challenging with few reported examples of synthetic carbohydrate polymers with engineered‐in ionic functionality. We report the design, synthesis, and evaluation of a synthetic, cationic, enantiopure carbohydrate polymer inspired by the structure of chitosan. These water‐soluble, cytocompatible polymers are prepared via an anionic ring‐opening polymerization of a bicyclic β‐lactam sugar monomer. The synthetic method provides control over the site of amine functionalization and the length of the polymer while providing narrow dispersities. These well‐defined polymers are mucoadhesive as documented in single‐molecule scale (AFM), bulk solution phase (FRAP), and ex vivo tissue experiments. Polymer length and functionality affects bioactivity as long, charged polymers display higher mucoadhesivity than long, neutral polymers or short, charged polymers.
We describe an electrochemical strategy to transduce allosteric transcription factor (aTF) binding affinity to sense steroid hormones. Our approach utilizes square wave voltammetry (SWV) to monitor changes in current output as a progesterone (PRG) specific aTF (SRTF1) unbinds from the cognate DNA sequence in the presence of PRG. The sensor detects PRG in artificial urine samples with sufficient sensitivity suitable for clinical applications. Our results highlight the capability of using aTFs as the biorecognition elements to develop electrochemical point-of-care biosensors for detection of small molecule biomarkers and analytes. CONFLICT OF INTERESTKS, RB, CG, CMK, JEG, and MWG are inventors on a patent describing this technology filed by Boston University, which is available for license.
Surgery is the only potentially curative treatment for localized soft tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35-59% despite resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, doxorubicin-loaded meshes (DoM) increased overall survival four-fold compared to systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, while mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20-days post administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft tissue sarcoma.
Mucoadhesive polymers are of significant interest to the pharmaceutical, medical device, and cosmetic industries. Polysaccharides possessing charged functional groups, such as chitosan, are known for mucoadhesive properties but suffer from poor chemical definition and solubility, while the chemical synthesis of polysaccharides is challenging with few reported examples of synthetic carbohydrate polymers with engineered‐in ionic functionality. We report the design, synthesis, and evaluation of a synthetic, cationic, enantiopure carbohydrate polymer inspired by the structure of chitosan. These water‐soluble, cytocompatible polymers are prepared via an anionic ring‐opening polymerization of a bicyclic β‐lactam sugar monomer. The synthetic method provides control over the site of amine functionalization and the length of the polymer while providing narrow dispersities. These well‐defined polymers are mucoadhesive as documented in single‐molecule scale (AFM), bulk solution phase (FRAP), and ex vivo tissue experiments. Polymer length and functionality affects bioactivity as long, charged polymers display higher mucoadhesivity than long, neutral polymers or short, charged polymers.
The accuracy of a punch biopsy diagnosis of cervical neoplasia in patients with abnormal cytologic findings is assessed. Cervical punch biopsies were performed in 859 patients, and 258 had subsequent cold‐knife conizations. Invasive carcinoma was diagnosed in 189 patients by the initial cervical biopsy. Carcinoma in situ was noted in 194 patients, and this diagnosis was confirmed by conization in 75% of the cases. Pathology of a lower rank was found in 17%, microinvasion in 6%, and frank invasion in 2%. Dysplasia was diagnosed by biopsy in 246 patients. Of the cold‐knife conizations performed in 66 cases of dysplasia, 40% confirmed the dysplastic lesion, 40% revealed carcinoma in situ, 10% chronic cervicitis, 3% microinvasion and 2% invasive carcinoma. A comparative analysis of the biopsy, conization and hysterectomy findings is presented. Multiple cervical punch biopsies from properly selected sites aided by Schiller stain and including an adequate area of the squamocolumnar junction are useful as the initial diagnostic procedure in women with abnormal cytology or suspicious cervical lesions. Conization is indicated if biopsy or cytology findings raise suspicion of a higher rank of neoplasia. All patients with carcinoma in situ and severe dysplasia on biopsy must have subsequent conizations performed. The postmenopausal female with any degree of dysplasia on biopsy and patients with repeated abnormal cytologic findings despite negative biopsy results must also undergo conization.
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