Development and validation of a predictive model for spinal fracture risk in osteoporosis patients.

Background: Spinal osteoporosis is a prevalent health condition characterized by the thinning of bone tissues in the spine, increasing the risk of fractures. Given its high incidence, especially among older populations, it is critical to have accurate and effective predictive models for fracture risk. Traditionally, clinicians have relied on a combination of factors such as demographics, clinical attributes, and radiological characteristics to predict fracture risk in these patients.

Multi-step parallel synthesis enabled optimization of benzofuran derivatives as pan-genotypic non-nucleoside inhibitors of HCV NS5B.

In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with <10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876.

Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC).

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

Profiling and Application of Photoredox C(sp)-C(sp) Cross-Coupling in Medicinal Chemistry.

Recent visible-light photoredox catalyzed C(sp)-C(sp) cross-coupling provides a novel transformation to potentially enable the synthesis of medicinal chemistry targets. Here, we report a profiling study of photocatalytic C(sp)-C(sp) cross-coupling, both decarboxylative coupling and cross-electrophile coupling, with 18 pharmaceutically relevant aryl halides by using either Kessil lamp or our newly developed integrated photoreactor. Integrated photoreactor accelerates reaction rate and improves reaction success rate.

Chemoselective Peptide Modification via Photocatalytic Tryptophan β-Position Conjugation.

Targeting tryptophan is a promising strategy to achieve high levels of selectivity for peptide or protein modification. A chemoselective peptide modification method via photocatalytic tryptophan β-position conjugation has been discovered. This transformation has good substrate scope for both peptide and Michael acceptor, and has good chemoselectivity versus other amino acid residues.

Which Combination Treatment Is Better for Spinal Metastasis: Percutaneous Vertebroplasty With Radiofrequency Ablation, 125I Seed, Zoledronic Acid, or Radiotherapy?

Background: Percutaneous vertebroplasty (PVP) can not only alleviate pain but also restore mechanical stability with injection of bone cement, whereas it exhibits a poor effect on antitumor activity. But through combinations with other therapies, it may be possible to achieve the maximum effect in clinical treatment. Thus, this study is designed to assess the clinical efficacy of PVP separately combined with 4 ways for spinal metastasis (SM) treatment.

A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions.

Photocatalysis for organic synthesis has experienced an exponential growth in the past 10 years. However, the variety of experimental procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chemical energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation.

Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores.

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone.

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors.

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SAr reaction.

Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis.

MicroRNA-375 functions as a tumor suppressor in osteosarcoma by targeting PIK3CA.

Osteosarcoma has become one of the most common primary malignant bone tumors in childhood and adult. Numerous studies have demonstrated that aberrant microRNA (miRNA) expression is involved in human disease including cancer. To date, the potential miRNAs regulating osteosarcoma growth and progression are not fully identified yet.

Organic chemistry. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules.

At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized.

[Clinical application of Wallis interspinous dynamic stabilization in treating adjacent segment degeneration (ASD) after lumbar spinal fusion].

Objective: To evaluate therapeutic effects of Wallis interspinous dynamic stabilization in treating ASD after lumbar spinal fusion.

Methods: Totally 40 patients (included 16 males and 24 females, aged 25 to 60 years old) with degenerative disc disease were treated with posterior interbody fusion. Among them, 20 cases (treatment group) were treated with posterior interbody fusion combined with Wallis interspinous dynamic stabilization, while other 20 cases (control group) only treated with posterior interbody fusion.

Predictive potential of glutathione S-transferase polymorphisms for prognosis of osteosarcoma patients on chemotherapy.

Objective: To evaluate the predictive value of glutathione S-transferase (GST) gene polymorphisms for the prognosis of osteosarcoma patients receiving chemotherapy.

Methods: A total of 159 patients were included in our study between January 2005 and December 2007., with follow-up until January 2012.

Comparison between two pedicle screw augmentation instrumentations in adult degenerative scoliosis with osteoporosis.

Background: The operative treatment of adult degenerative scoliosis combined with osteoporosis increase following the epidemiological development. Studies have confirmed that screws in osteoporotic spines have significant lower-screw strength with more frequent screw movements within the vertebra than normal spines. Screws augmented with polymethylmethacrylate (PMMA) or with autogenous bone can offer more powerful corrective force and significant advantages.

Learning curve of computer-assisted navigation system in spine surgery.

Background: Spine surgery using computer-assisted navigation (CAN) has been proven to result in low screw misplacement rates, low incidence of radiation exposure and excellent operative field viewing versus the conventional intraoperative image intensifier (CIII). However, as we know, few previous studies have described the learning curve of CAN in spine surgery.

Methods: We performed two consecutive case cohort studies on pedicel screw accuracy and operative time of two spine surgeons with different experience backgrounds, A and B, in one institution during the same period.

Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis.

Trytophan Hydroxylase Type I (TPH1), most abundantly expressed in the gastrointestinal tract, initiates the synthesis of serotonin by catalyzing hydroxylation of tryptophan in the presence of biopterin and oxygen. We have previously described three series of novel, periphery-specific TPH1 inhibitors that selectively deplete serotonin in the gastrointestinal tract. We have now determined co-crystal structures of TPH1 with three of these inhibitors at high resolution.

Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors.

Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. Here we describe the discovery of substituted triazines as a novel class of tryptophan hydroxylase inhibitors.

Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter.

The mammalian proline transporter (PROT) is a high affinity Na(+)/Cl(-)-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic synaptic terminals and may play an important role in the regulation of excitatory neurotransmission.

Probable risk factors for postoperative delirium in patients undergoing spinal surgery.

Postoperative delirium and its risk factors had been widely reported in several kinds of surgeries; however, there is only one known article relative to postoperative delirium in spinal surgery. We retrospectively examined the incidence of postoperative delirium and the probable risk factors in patients undergoing spinal surgery in our hospital, with the same aged non-delirium patients as controls, over a 6-month period. Studies about postoperative delirium were reviewed and referenced for variable factors collecting in our study.