Quantitative proteomics identifies TUBB6 as a biomarker of muscle-invasion and poor prognosis in bladder cancer.

Muscle-invasive urothelial carcinoma (MIUC) of the bladder shows highly aggressive tumor behavior, which has prompted the quest for robust biomarkers predicting invasion. To discover such biomarkers, we first employed high-throughput proteomic method and analyzed tissue biopsy cohorts from patients with bladder urothelial carcinoma (BUC), stratifying them according to their pT stage. Candidate biomarkers were selected through bioinformatic analysis, followed by validation. The latter comprised 2D and 3D invasion and migration assays, also a selection of external public datasets to evaluate mRNA expression and an in-house patient-derived tissue microarray (TMA) cohort to evaluate protein expression with immunohistochemistry (IHC). Our multilayered platform-based analysis identified tubulin beta 6 class V (TUBB6) as a promising prognostic biomarker predicting MIUC of the bladder. The in vitro 2D and 3D migration and invasion assays consistently showed that inhibition of TUBB6 mRNA significantly reduced cell migration and invasion ability in two BUC cell lines with aggressive phenotype (TUBB6 migration, P = .0509 and P < .0001; invasion, P = .0002 and P = .0044; TGFBI migration, P = .0214 and P = .0026; invasion, P < .0001 and P = .0001; T24 and J82, respectively). Validation through multiple public datasets, including The Cancer Genome Atlas (TCGA) and selected GSE (Genomic Spatial Event) databases, confirmed TUBB6 as a potential biomarker predicting MIUC. Further protein-based validation with our TMA cohort revealed concordant results, highlighting the clinical implication of TUBB6 expression in BUC patients (overall survival: P < .001). We propose TUBB6 as a novel IHC biomarker to predict invasion and poor prognosis, also select the optimal treatment in BUC patients.

Concise Stereoselective Total Synthesis of (-)-Hedycoropyran A.

A concise and stereoselective total synthesis of (-)-hedycoropyran A was accomplished in a substrate-controlled manner from a readily available alkene. Highlights of the synthesis include a highly diastereoselective dehydrogenative cycloetherification to construct the trans-2-aryl-6-alkyl-3,6-dihydro-2H-pyran framework and late-stage substrate-controlled trans-dihydroxylation at C(3,4).

Synthesis of 7,2'-Dihydroxy-4',5'-Dimethoxyisoflavanone, a Phytoestrogen with Derma Papilla Cell Proliferative Activity.

This paper reports a concise and scalable method for the synthesis of the phytoestrogen 7,2'-dihydroxy-4',5'-dimethoxyisoflavanone 1 via an optimized synthetic route. Compound 1 was readily obtained in 11 steps and 11% overall yield on a gram scale from commercially available 3,4-dimethoxyphenol. The key features of the synthesis include the construction of the deoxybenzoin unit through a sequence of Claisen rearrangement, oxidative cleavage, and aryllithium addition and the efficient synthesis of the isoflavanone architecture from highly functionalized 2-hydroxyketone.

Understanding interfacial segregation in polymer blend films with random and mixed side chain bottlebrush copolymer additives.

Bottlebrush polymers are complex macromolecules with tunable physical properties dependent on the chemistry and architecture of both the side chains and the backbone. Prior work has demonstrated that bottlebrush polymer additives can be used to control the interfacial properties of blends with linear polymers but has not specifically addressed the effects of bottlebrush side chain microstructures. Here, using a combination of experiments and self-consistent field theory (SCFT) simulations, we investigated the effects of side chain microstructures by comparing the segregation of bottlebrush additives having random copolymer side chains with bottlebrush additives having a mixture of two different homopolymer side chain chemistries. Specifically, we synthesized bottlebrush polymers with either poly(styrene-ran-methyl methacrylate) side chains or with a mixture of polystyrene (PS) and poly(methyl methacrylate) (PMMA) side chains. The bottlebrush additives were matched in terms of PS and PMMA compositions, and they were blended with linear PS or PMMA chains that ranged in length from shorter to longer than the bottlebrush side chains. Experiments revealed similar behaviors of the two types of bottlebrushes, with a slight preference for mixed side-chain bottlebrushes at the film surface. SCFT simulations were qualitatively consistent with experimental observations, predicting only slight differences in the segregation of bottlebrush additives driven by side chain microstructures. Specifically, these slight differences were driven by the chemistries of the bottlebrush polymer joints and side chain end-groups, which were entropically repelled and attracted to interfaces, respectively. Using SCFT, we also demonstrated that the interfacial behaviors were dominated by entropic effects with high molecular weight linear polymers, leading to enrichment of bottlebrush near interfaces. Surprisingly, the SCFT simulations showed that the chemistry of the joints connecting the bottlebrush backbones and side chains played a more significant role compared with the side chain end groups in affecting differences in surface excess of bottlebrushes with random and mixed side chains. This work provides new insights into the effects of side chain microstructure on segregation of bottlebrush polymer additives.

Intraoperative botulinum toxin injection for superficial partial parotidectomy: A prospective pilot study.

OBJECTIVES: Sialocele and salivary fistula are not serious but troublesome complications after parotidectomy. Various modalities have been introduced to prevent postoperative saliva-related complications. However, clinical trials assessing the prophylactic use of botulinum toxin (BTX) for parotidectomy have not been conducted yet. Herein, we report a pilot study investigating the safety and efficacy of intraoperative BTX (iBTX) injection in partial superficial parotidectomy (PSP). PARTICIPANTS: Patients with benign parotid tumour were prospectively recruited for this clinical trial from 2017 to 2019. The study participants underwent PSP with iBTX injection. We retrospectively reviewed the clinical information of all the consecutive patients who underwent PSP without iBTX from 2013 to 2019. These patients were divided into two groups: the iBTX group (n = 36) and the control group (n = 54). RESULTS: Permanent facial palsy was not observed in either group. Two patients (3.7%) had transient marginal palsy in the control group but none had it in the iBTX group. The incidence of sialocele was significantly lower in the iBTX group than in the control group (2.8% vs. 20.4%, P < .05). Although the incidence of salivary fistula was lower in the iBTX group than in the control group (0% vs. 7.4%), no significant difference was determined between the two groups (P = .147). Total drainage volume was significantly lower in the iBTX group than in the control group (55.0 mL vs. 116.6 mL, P < .001). CONCLUSIONS: iBTX injection may be safe and effective in reducing sialocele and postoperative drainage in PSP. It might be a useful option to prevent saliva-related complications after PSP.

Lewis Acid-Promoted Regio- and Diastereoselective Cross-Coupling of Aryl-Substituted 1,2-Diols and Boronic Acids.

A Lewis acid-promoted highly regio- and diastereoselective C(sp3)-C(sp2) cross-coupling reaction between unprotected aryl-substituted 1,2-diols and styryl-, aryl-, heteroaryl-, and polyarylboronic acids has been developed in a one-pot procedure. The regioselective opening of aryl-substituted cyclic boronic esters promoted by a Lewis acid followed by subsequent intramolecular 1,4-transfer of the carbon ligand from boron to a resonance-stabilized benzylic carbenium ion minimizing the allylic 1,3-strain in a stereoselective fashion led to the corresponding α-substituted syn-phenylethyl alcohols. The synthetic utility of the method was illustrated by a short and efficient enantioselective synthesis of cherylline diethyl ether (-)-16.

Pyrrolidine dithiocarbamate reverses Bcl-xL-mediated apoptotic resistance to doxorubicin by inducing paraptosis.

Elevated Bcl-xL expression in cancer cells contributes to doxorubicin (DOX) resistance, leading to failure in chemotherapy. In addition, the clinical use of high-dose doxorubicin (DOX) in cancer therapy has been limited by issues with cardiotoxicity and hepatotoxicity. Here, we show that co-treatment with pyrrolidine dithiocarbamate (PDTC) attenuates DOX-induced apoptosis in Chang-L liver cells and human hepatocytes, but overcomes DOX resistance in Bcl-xL-overexpressing Chang-L cells and several hepatocellular carcinoma (HCC) cell lines with high Bcl-xL expression. Additionally, combined treatment with DOX and PDTC markedly retarded tumor growth in a Huh-7 HCC cell xenograft tumor model, compared to either mono-treatment. These results suggest that DOX/PDTC co-treatment may provide a safe and effective therapeutic strategy against malignant hepatoma cells with Bcl-xL-mediated apoptotic defects. We also found that induction of paraptosis, a cell death mode that is accompanied by dilation of the endoplasmic reticulum and mitochondria, is involved in this anti-cancer effect of DOX/PDTC. The intracellular glutathione levels were reduced in Bcl-xL-overexpressing Chang-L cells treated with DOX/PDTC, and DOX/PDTC-induced paraptosis was effectively blocked by pretreatment with thiol-antioxidants, but not by non-thiol antioxidants. Collectively, our results suggest that disruption of thiol homeostasis may critically contribute to DOX/PDTC-induced paraptosis in Bcl-xL-overexpressing cells.

DDQ-Promoted Mild and Efficient Metal-Free Oxidative α-Cyanation of N-Acyl/Sulfonyl 1,2,3,4-Tetrahydroisoquinolines.

A mild and highly efficient metal-free oxidative α-cyanation of N-acyl/sulfonyl 1,2,3,4-tetrahydroisoquinolines (THIQs) has been accomplished at an ambient temperature via DDQ oxidation and subsequent trapping of N-acyl/sulfonyl iminium ions with (n-Bu)3SnCN. Employing readily removable N-acyl/sulfonyl groups as protecting groups rather than N-aryl ones enables a wide range of applications in natural product synthesis. The synthetic utility of the method was illustrated using a short and efficient formal total synthesis of (±)-calycotomine in three steps.

Pharmacokinetics of Jaspine B and Enhancement of Intestinal Absorption of Jaspine B in the Presence of Bile Acid in Rats.

We aimed to investigate the pharmacokinetics and the underlying mechanisms of the intestinal absorption, distribution, metabolism, and excretion of Jaspine B in rats. The oral bioavailability of Jaspine B was 6.2%, but it decreased to 1.6% in bile-depleted rats and increased to 41.2% (normal) and 23.5% (bile-depleted) with taurocholate supplementation (60 mg/kg). Consistent with the increased absorption in the presence of bile salts, rat intestinal permeability of Jaspine B also increased in the presence of 10 mM taurocholate or 20% bile. Further studies demonstrated that the enhanced intestinal permeability with bile salts was due to increased lipophilicity and decreased membrane integrity. Jaspine B was designated as a highly tissue-distributed compound, because it showed large tissue to plasma ratios in the brain, kidney, heart, and spleen. Moreover, the recovery of Jaspine B from the feces and urine after an intravenous administration was about 6.3%, suggesting a substantial metabolism of Jaspine B. Consistent with this observation, 80% of the administered Jaspine B was degraded after 1 h incubation with rat liver microsomes. In conclusion, the facilitated intestinal permeability in the presence of bile salts could significantly increase the bioavailability of Jaspine B and could lead to the development of oral formulations of Jaspine B with bile salts. Moreover, the highly distributed features of Jaspine B in the brain, kidney, heart, and spleen should be carefully considered in the therapeutic effect and toxicity of this compound.

Stereoselective Substrate-Controlled Asymmetric Syntheses of both 2,5-cis- and 2,5-trans-Tetrahydrofuranoid Oxylipids: Stereodivergent Intramolecular Amide Enolate Alkylation.

The concise, highly stereoselective, substrate-controlled asymmetric total syntheses of both 2,5-cis- and 2,5-trans-tetrahydrofuranoid nematocidal oxylipids from the Australian brown algae Notheia anomala have been accomplished in a stereodivergent fashion. The highly stereoselective intramolecular amide enolate alkylation strategy provides access to both stereoisomers of the 3-hydroxy-2,5-disubstituted tetrahydrofuran core of these marine natural products through chelate and nonchelate control, which is driven by the C3-hydroxy protecting group. This approach offers an optional and highly stereoelective access to any of the eight possible stereoisomers of the 2,5-disubstituted-3-oxygenated tetrahydrofuran skeleton, an important structural feature which is present in many biologically active natural products.

The synthesis and biological evaluation of desepoxyisotedanolide and a comparison with desepoxytedanolide.

The tedanolides are biologically active polyketides that exhibit a macrolactone constructed from a primary alcohol. Since polyketidal transformations only generate secondary alcohols, it has been hypothesized by Taylor that this unique lactone could arise from a postketidal transesterification. In order to probe this hypothesis and to investigate the biological profile of the putative precursor of all members of the tedanolide family, we embarked on the synthesis of desepoxyisotedanolide and its biological evaluation in comparison to desepoxytedanolide. The biological experiments unraveled a second target for desepoxytedanolide and provided evidence that the proposed transesterification indeed provides a survival advantage for the producing microorganism.

Targeted traction of impacted teeth with C-tube miniplates.

Orthodontic traction of impacted teeth has typically been performed using full fixed appliance as anchorage against the traction force. This conventional approach can be difficult to apply in the mixed dentition if the partial fixed appliance offers an insufficient anchor unit. In addition, full fixed appliance can induce unwanted movement of adjacent teeth. This clinical report presents 3 cases where impacted teeth were recovered in the mixed or transitional dentition with skeletal anchorage on the opposite arch without full fixed appliance. Instead, intermaxillary traction was used to bring the impacted teeth into position. With this approach, side effects on teeth and periodontal tissues adjacent to the impaction were minimized.

Minimally invasive plate osteosynthesis for humeral shaft fracture: a reproducible technique with the assistance of an external fixator.

BACKGROUND: Minimally invasive plate osteosynthesis (MIPO) has become a popular option for treatment of humeral shaft fractures. However, indirect reduction might risk unpromising results, with mal-alignment/mal-union or nonunion. The purpose of this study was to describe a reproducible MIPO technique that used an external fixator during the procedure as a tool for reduction and maintenance, and to assess the outcomes in patients with humeral shaft fracture. METHODS: Of 31 consecutive cases of humeral shaft fracture in 30 patients, 29 were included in this study. There were seven simple (type A) and 22 comminuted (type B or C) fractures. After the insertion of one Schanz pin on each proximal and distal humerus, a provisional reduction was achieved by connecting the pins with a monolateral external fixator. The MIPO procedure was then performed over the anterior aspect of the humerus. To evaluate the efficacy of the provisional reduction by external fixator, coronal and sagittal alignments were assessed. We also assessed bony and functional results, including complications, from this technique. RESULTS: There was no case of mal-union >10°, and mean angulation was 1.3° (range 0°-9°) in the coronal plane and 1.2° (range 0°-8°) in the sagittal plane. Twenty-eight of 29 fractures were united, including three delayed unions, with a mean union time of 19.1 weeks (range 12.3-38.4 weeks) and a mean follow-up of 20.8 months (range 13.5-31.0 months). There was one hypertrophic nonunion that healed after fixing with two additional screws. Except one patient with associated injury in the elbow, all patients recovered to pre-injury joint motion. There were two cases of postoperative radial nerve palsy that both recovered completely. We attributed them to manipulation, and not to the Schanz pins or plate fixation. CONCLUSIONS: Surgical treatment of humeral shaft fractures with external fixator-assisted reduction and MIPO resulted in excellent reductions and high union rates.

Total Synthesis and Structure Confirmation of (-)-Asimitrin, a C37 Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core.

The total synthesis and structure confirmation of the potent cytotoxic agent (-)-asimitrin (1), a C37 annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17-erythro-16,19-trans-THF 6, our direct ketone synthesis/l-Selectride reduction protocol for stereoselective introduction of the C(21)-C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23-trans-THF ring.

Stereoselective total synthesis of (3Z)- and (3E)-elatenynes.

We describe here the highly stereoselective total synthesis of the Laurencia C15 acetogenins (3Z)- and (3E)-elatenynes having a 7,12-dibromo-6,9-cis-10,13-cis adjacent bis-tetrahydrofuran (THF) core. The present synthesis features a highly stereoselective, protecting group-dependent, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 7-hydroxy-6,7-cis-6,9-cis-THF intermediate 10, deployment of the sequential ate complex (n-BuLi/DIBAL-H) reduction/Keck allylation/cross metathesis (CM) protocol for the stereoselective introduction of the C(10)-C(15) unit, a sequential Sharpless asymmetric dihydroxylation (SAD)/intramolecular Williamson etherification for the construction of the 10,13-cis-THF ring, and a modified Nakata chloromethanesulfonate-mediated SN2 displacement for the 7,12-dibromo functionality. Furthermore, our strategy based on chelate-controlled IAEA methodology would provide access to any member of the C15 adjacent bis-THF acetogenin class.

Sleep time on back as a predictor of adherence to positive airway pressure therapy.

Upper airway collapse can be effectively dealt with positive airway pressure (PAP), and patient adherence is considered as a major determining factor for success of PAP therapy. This study was performed to determine the potential factors affecting the adherence to PAP in patients with OSA by using polysomnography (PSG) parameters recorded for diagnosis of OSA. The data of 158 patients between December 2018 and July 2021 were collected. They were prescribed with PAP and used the device during the adaptation period for 90 days. They were categorized into adherent and non-adherent group according to the criteria of good adherence as use of PAP ≥ 4 h per night on 70% of nights. Demographic, clinical characteristics, and PSG results were reviewed. Among 158 patients engaged in PAP therapy, 121 patients (76.6%) met the criteria of good adherence. No significant differences were found in good adherence rate regarding demographic and clinical characteristics. None of the polysomnographic factors showed significant differences between adherent and non-adherent groups. However, the percentage of sleep time on back in the adherent group was significantly higher than non-adherent group (p = 0.041). The cut-off value was determined to be 41.45% (95% confidence interval 0.43 to 0.79) by receiver operating characteristic curve analysis and the odds ratio was calculated as 2.97. Only the percentage of sleep time on back appeared to be polysomnographic predictor for identifying good adherence to PAP therapy in OSA patients. However, the conclusions may be limited in generalization due to the small sample size.

Effects of humidity and surfaces on the melt crystallization of ibuprofen.

Melt crystallization of ibuprofen was studied to understand the effects of humidity and surfaces. The molecular self-assembly during the amorphous-to-crystal transformation was examined in terms of the nucleation and growth of the crystals. The crystallization was on Al, Au, and self-assembled monolayers with -CH(3), -OH, and -COOH functional groups. Effects of the humidity were studied at room temperature (18-20 °C) with relative humidity 33%, 75%, and 100%. Effects of the surfaces were observed at -20 °C (relative humidity 36%) to enable close monitoring with slower crystal growth. The nucleation time of ibuprofen was faster at high humidity conditions probably due to the local formation of the unfavorable ibuprofen melt/water interface. The crystal morphologies of ibuprofen were governed by the nature of the surfaces, and they could be associated with the growth kinetics by the Avrami equation. The current study demonstrated the effective control of the melt crystallization of ibuprofen through the melt/atmosphere and melt/surface interfaces.

New Insight into Rubber Composites Based on Graphene Nanoplatelets, Electrolyte Iron Particles, and Their Hybrid for Stretchable Magnetic Materials.

New and soft composites with good mechanical stretchability are constantly addressed in the literature due to their use in various industrial applications such as soft robotics. The stretchable magnetic materials presented in this work show a promising magnetic effect of up to 28% and improved magnetic sensitivity. The composites are soft in nature and possess hardness below 65. These composites were prepared by mixing silicone rubber with fillers such as graphene nanoplatelets (GNP), electrolyte-iron particles (EIP), and their hybrid via solution mixing. The final composites were cured at room temperature for 24 h and their isotropic and anisotropic properties were studied and presented. The mechanical properties under compressive and tensile strain were studied in detail. The results show that the compressive modulus was 1.73 MPa (control) and increased to 3.7 MPa (GNP) at 15 per hundred parts of rubber (phr), 3.2 MPa (EIP), and 4.3 MPa (hybrid) at 80 phr. Similarly, the mechanical stretchability was 112% (control) and increased to 186% (GNP) at 15 phr, 134% (EIP), and 136% (hybrid) at 60 phr. Thus, GNP emerges as a superior reinforcing filler with high stiffness, a high compressive modulus, and high mechanical stretchability. However, the GNP did not show mechanical sensitivity under a magnetic field. Therefore, the hybrids containing GNP and EIP were considered and an improved mechanical performance with magnetic sensitivity was noticed and reported. The mechanism involves the orientation of EIP under a magnetic field causing a magnetic effect, which is 28% for EIP and 5% for hybrid.

Highly Stereodivergent Construction of a C2-Symmetric cis,cis- and trans,trans-2,6-Dioxabicyclo[3.3.0]octane Framework by Double Intramolecular Amide Enolate Alkylation: Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene.

The highly stereoselective construction of C2-symmetric cis,cis- and trans,trans-2,6-dioxabicyclo[3.3.0]octane (fused bis-tetrahydrofuran) skeletons 4a and 4b has been accomplished via a novel stereodivergent double intramolecular amide enolate alkylation of common cyclization substrate 5 through the judicious choice of "chelate" versus crown ether-promoted "nonchelate" control. Application of this methodology has provided access to substrate-controlled concise total syntheses of (+)-laurenidificin (3) and (+)-aplysiallene (ent-2), which possess cis/cis- and trans/trans-fused bis-tetrahydrofuran cores, respectively.

Causes and management of persistent septal deviation after septoplasty.

Septoplasty is one of the most common otolaryngological surgical procedures. The causes of persistent septal deviation after primary septoplasty vary. The purpose of this study was to identify factors associated with failure of primary septoplasty, operative techniques that correct residual septal deviation, and surgical outcomes. Seventy-four adults who underwent revision septoplasty to treat persistent septal deviations were enrolled. The level of hospital in which primary septoplasty was performed, type of septal deviation, septal portion exhibiting persistent deviation, and techniques used to correct the deviation were evaluated. Outcomes were measured subjectively using a visual analog scale (VAS), and objectively using acoustic rhinometry. The first septoplasties were usually performed in primary and secondary hospitals. C-shaped deviations were more common than S-shaped ones in both the anteroposterior and cephalocaudal dimensions. The most common region of persistent septal deviation was the caudal septum (44.6%), followed by multiple sites (20.3%). The corrective techniques included excision of the remnant deviated portion (70.3%), septal cartilage traction suturing (27.0%), spreader grafting (13.5%), and cross-suturing (6.8%). The VAS score improved significantly 6 months after surgery. The minimal cross-sectional area and nasal cavity volume of the convex side increased significantly after revision septoplasty. Patients who underwent septoplasty in primary and secondary hospitals were more likely to require revision septoplasty. The caudal septum was the most common site of persistent septal deviation. Careful preoperative evaluation of the caudal septal deviation and selection of an appropriate surgical technique may reduce the need for revision septoplasty.