Enhancement of the therapeutic efficacy of the MAP regimen using thiamine pyrophosphate-decorated albumin nanoclusters in osteosarcoma treatment.

Recent studies on osteosarcoma regimens have mainly focused on modifying the combination of antineoplastic agents rather than enhancing the therapeutic efficacy of each component. Here, an albumin nanocluster (NC)-assisted methotrexate (MTX), doxorubicin (DOX), and cisplatin (MAP) regimen with improved antitumor efficacy is presented. Human serum albumin (HSA) is decorated with thiamine pyrophosphate (TPP) to increase the affinity to the bone tumor microenvironment (TME). MTX or DOX (hydrophobic MAP components) is adsorbed to HSA-TPP via hydrophobic interactions. MTX- or DOX-adsorbed HSA-TPP NCs exhibit 20.8- and 1.64-fold higher binding affinity to hydroxyapatite, respectively, than corresponding HSA NCs, suggesting improved targeting ability to the bone TME via TPP decoration. A modified MAP regimen consisting of MTX- or DOX-adsorbed HSA-TPP NCs and free cisplatin displays a higher synergistic anticancer effect in HOS/MNNG human osteosarcoma cells than conventional MAP. TPP-decorated NCs show 1.53-fold higher tumor accumulation than unmodified NCs in an orthotopic osteosarcoma mouse model, indicating increased bone tumor distribution. As a result, the modified regimen more significantly suppresses tumor growth in vivo than solution-based conventional MAP, suggesting that HSA-TPP NC-assisted MAP may be a promising strategy for osteosarcoma treatment.

Total Syntheses of Pladienolide-Derived Spliceosome Modulators.

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.

Evaluation of Anti-Melanogenesis Activity of Enriched Pueraria lobata Stem Extracts and Characterization of Its Phytochemical Components Using HPLC-PDA-ESI-MS/MS.

The root of Pueraria lobata (Willd.) is a widely used herbal medicine worldwide, whereas the stem of the plant is discarded or used as feed for livestock. To reuse and exploit the stem of P. lobata as a resource, we investigated its potential as a skin-whitening agent. We found that the developed, enriched P. lobata stem (PLS) extract significantly inhibited melanin production in the 3-isobutyl-1-methylxanthine-induced B16/F10 cells at a concentration of 50 µg/mL. To further confirm the mechanism of the antimelanogenic effect of the enriched PLS extracts, we examined the mRNA expression of tyrosinase, which was suppressed by the extracts. To standardize and implement effective quality control of the enriched PLS extracts, its major chemical constituents were identified by high-performance liquid chromatography-photodiode array-electrospray ionization-mass spectrometry. In total, 12 constituents were identified. In silico analysis showed that the main constituents, puerarin and daidzin, had excellent binding affinities for human tyrosinase. Collectively, our results suggest that the PLS extracts could be used as anti-pigmentation agents.

Recent advances in development of hetero-bivalent kinase inhibitors.

Identifying a pharmacological agent that targets only one of more than 500 kinases present in humans is an important challenge. One potential solution to this problem is the development of bivalent kinase inhibitors, which consist of two connected fragments, each bind to a dissimilar binding site of the bisubstrate enzyme. The main advantage of bivalent (type V) kinase inhibitors is generating more interactions with target enzymes that can enhance the molecules' selectivity and affinity compared to single-site inhibitors. Earlier type V inhibitors were not suitable for the cellular environment and were mostly used in in vitro studies. However, recently developed bivalent compounds have high kinase affinity, high biological and chemical stability in vivo. This review summarized the hetero-bivalent kinase inhibitors described in the literature from 2014 to the present. We attempted to classify the molecules by serine/threonine and tyrosine kinase inhibitors, and then each target kinase and its hetero-bivalent inhibitor was assessed in depth. In addition, we discussed the analysis of advantages, limitations, and perspectives of bivalent kinase inhibitors compared with the monovalent kinase inhibitors.

Peroneal neuropathy caused by an extraneural ganglion cyst in the supracondylar area of the femur: A case report.

RATIONALE: Peroneal neuropathy is the most common type of peripheral neuropathy in the lower extremities. The peroneal nerve is usually compressed at the lateral aspect of the fibular head. Compression by ganglion cysts are one of the numerous underlying etiologies for peroneal nerve neuropathy and are most frequently located around the fibular neck and proximal tibiofibular joint. To the best of our knowledge, this is the first report of an extraneural ganglion cyst located at the level of the distal thigh that resulted in compressive peroneal neuropathy. PATIENT CONCERNS: We report a case of a 56-year-old man with sudden onset of left foot drop and gait disturbance caused by an extraneural ganglion cyst located in the popliteal fossa. DIAGNOSIS: Electrodiagnosis (EDX) suggested a peroneal nerve lesion. Subsequently, diagnostic ultrasonography (USG) revealed a cystic mass located within the left side of the supracondylar area of femur. Further magnetic resonance imaging confirmed that the mass was located at the proximal of popliteal fossa. INTERVENTIONS: Surgical excision was performed using a direct posterior approach. The cystic mass was compressing the common peroneal nerve, and was carefully and completely removed ensuring that all nerve branches were protected. OUTCOMES: A histopathologic evaluation confirmed the diagnosis of a ganglion cyst. There were no postoperative complications. Two months after the surgery, follow-up USG revealed no evidence of cyst recurrence or residual lesions. Six months after the surgery, the ankle dorsiflexor motor power improved and he experienced less pain and hypoesthesia. LESSONS: Physicians should bear in mind that the peroneal neuropathy can occur because of the ganglion cyst in the distal thigh. The thorough evaluation of EDX and USG is crucial for the early diagnosis and surgical intervention, although there is no abnormal finding around the fibular neck.

Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy.

Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.

Nicrophorusamides A and B, Antibacterial Chlorinated Cyclic Peptides from a Gut Bacterium of the Carrion Beetle Nicrophorus concolor.

Nicrophorusamides A and B (1 and 2) were discovered from a rare actinomycete, Microbacterium sp., which was isolated from the gut of the carrion beetle Nicrophorus concolor. The structures of the nicrophorusamides were established as new chlorinated cyclic hexapeptides bearing uncommon amino acid units mainly based on 1D and 2D NMR spectroscopic analysis. The absolute configurations of the amino acid residues 5-chloro-l-tryptophan, d-threo-ß-hydroxyasparagine/d-asparagine, l-ornithine, l-allo-isoleucine, d-leucine, and d-valine were determined using Marfey's method and chemical derivatization with 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate followed by LC/MS analysis. Nicrophorusamide A (1) showed antibacterial activity against several Gram-positive bacteria.

Specific Expression of Aplysia Phosphodiesterase 4 in Bag Cells Revealed by in situ Hybridization Analysis.

Phosphodiesterases (PDEs) play a key role in the regulation of cyclic adenosine monophosphate (cAMP), which in turn mediates various cellular functions including learning and memory. We previously cloned and characterized three PDE4 isoforms (ApPDE4) from Aplysia kurodai. Using reverse transcription polymerase chain reaction (RT-PCR), we found that ApPDE4 isoforms are primarily expressed in the central nervous system. However, the detailed distribution of ApPDE4 mRNA in Aplysia individual ganglions was not evident. In this study, to determine the distribution of ApPDE4 mRNAs in Aplysia ganglions, we performed in situ hybridization (ISH) using a probe targeting ApPDE4, including the PDE catalytic domain. Interestingly, we found the strongest ISH-positive signals in the symmetrical bag cell clusters of the abdominal ganglion. The R2, R14, L7, L2 and L11 neurons in the abdominal ganglion, LP1 neuron in pleural ganglion, and metacerebral (MCC) neurons were ISH-positive. Mechanosensory neurons of the sensory cluster were also stained on the ventral aspect of the right and left pleural ganglia. Taken together, we found the detailed distribution of ApPDE4 mRNA in Aplysia ganglion and support their roles in serotonin (5-HT)-induced synaptic facilitation of Aplysia mechanosensory neurons.

A 13-week repeated-dose oral toxicity and bioaccumulation of aluminum oxide nanoparticles in mice.

Because of an increase in the commercial applications of manufactured nanoparticles, the issue of potential adverse health effects of nanoparticles following intended or unintended exposure is rapidly gaining attention. In this study, we evaluated the toxicity of aluminum oxide nanoparticles (AlNPs, rod-type, 1.5, 3, and 6 mg/kg) after oral administration to mice for 13 weeks. Compared with the control group, the consumption of diet and drinking water and body weight gain decreased in the group treated with AlNPs. The group treated with 6 mg/kg AlNPs also showed a marked elevation in the count of white blood cells that associated with a significant decrease and increase to the proportion of eosinophils and lymphocytes, respectively. In addition, the secretion of IL-6 and monocyte chemotactic protein-1 increased in a dose-dependent manner in the treated groups. Furthermore, AlNPs showed the highest accumulation in the liver and kidneys compared with the control group, increased the lactate dehydrogenase level in the blood, and induced the development of a pathological lesion in the liver and kidneys. Taken together, we suggest that the target organs of rod-type AlNPs may be the liver, kidneys and the immune system, and the not-observed adverse effect level may be lower than 6 mg/kg.

Design and synthesis of a macrosphelide A-biotin chimera.

The rational design and synthesis of a biochemical probe of natural (+)-macrosphelide A, a potent cell-cell adhesion inhibitor, was completed to aid in the identification of its biological target. The key features of the synthesis include: (1) an efficient synthesis of the macrosphelide core structure using Yamaguchi-Hirao alkynylation, (2) a cross metathesis to connect a linker unit to the allyl-macrosphelide and (3) coupling of the linker-bound macrosphelide A with a chemical biotin tag.

Short-term Outcomes of Hand-Assisted Laparoscopic Surgery vs. Open Surgery on Right Colon Cancer: A Case-Controlled Study.

PURPOSE: This study was designed to evaluate short-term clinical outcomes by comparing hand-assisted laparoscopic surgery with open surgery for right colon cancer. METHODS: Sixteen patients who underwent a hand-assisted laparoscopic right hemicolectomy (HAL-RHC group) and 33 patients who underwent a conventional open right hemicolectomy (open group) during the same period were enrolled in this study with a case-controlled design. RESULTS: The operation time was 217 minutes in the HAL-RHC group and 213 minutes in the open group (P = 0.389). The numbers of retrieved lymph nodes were similar between the two groups (31 in the HAL-RHC group and 36 in the open group, P = 0.737). Also, there were no significant difference in the incidence of immediate postoperative leukocytosis, the administration of additional pain killers, and the postoperative recovery parameters. First flatus was shown on postoperative days 3.5 in the HAL-RHC group and 3.4 in the open group (P = 0.486). Drinking water and soft diet were started on postoperative days 4.8 and 5.9, respectively, in the HAL-RHC group and similarly 4.6 and 5.6 in the open group (P = 0.402 and P = 0.551). The duration of hospital stay was shorter in the HAL-RHC group than in the open group (10.3 days vs. 13.5 days, P = 0.048). No significant difference in the complication rates was shown between the two groups, and no postoperative mortality was encountered in either group. CONCLUSION: The patients with right colon cancer in the HAL-RHC group had similar pathologic and postoperative recovery parameters to those of the patients in the open group. The patients in the HAL-RHC group had shorter hospital stays than those in the open group. Therefore, hand-assisted laparoscopic right hemicolectomy for right-sided colon cancer is feasible.

Etiology of hemoptysis in children: a single institutional series of 40 cases.

PURPOSE: The aim of this study was to determine the causes of hemoptysis in a pediatric age group. METHODS: We conducted a retrospective chart review of all patients who were admitted to Samsung Medical Center between 1996 and 2008 with a chief complaint of hemoptysis. Patients with trauma or underlying bleeding tendency such as leukemia were excluded. Patients were divided into three groups according to age (0 to 5 yr, 6 to 10 yr, and 11 to 18 yr). The amount of hemoptysis was classified as mild (100 mL/day). Causes and duration of hemoptysis, disease course, and mortality were also investigated. RESULTS: A total of 40 patients (18 males and 22 females) were identified. Their median age was 6.3 yr (range, 10 months to 18 yr). Twenty-five patients manifested mild hemoptysis; moderate and massive hemoptysis were found in nine and six patients, respectively. Respiratory tract infection was the most common cause of hemoptysis. Other causes included congenital heart disease, Heiner syndrome, neoplasm in the airway, vasculitis syndrome, and bronchiectasis. In most patients (87.5%), hemoptysis disappeared during medical treatment that included antibiotics or transfusion. Hemoptysis recurred in 12 patients, and the overall mortality rate was 5%. CONCLUSIONS: The most common cause of hemoptysis in children was respiratory tract infection. Most cases had a benign course, but recurrence and mortality occurred in a minority of patients. An accurate diagnosis of the underlying etiology is essential for treatment.