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. However, these models often lack precision and fail to include all potential risk factors. There is a need for a more comprehensive, statistically robust prediction model that can better identify high-risk individuals for early intervention. AIM: To construct and validate a model for forecasting fracture risk in patients with spinal osteoporosis. METHODS: The medical records of 80 patients with spinal osteoporosis who were diagnosed and treated between 2019 and 2022 were retrospectively examined. The patients were selected according to strict criteria and categorized into two groups: Those with fractures (n = 40) and those without fractures (n = 40). Demographics, clinical attributes, biochemical indicators, bone mineral density (BMD), and radiological characteristics were collected and compared. A logistic regression analysis was employed to create an osteoporotic fracture risk-prediction model. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the model's performance. RESULTS: Factors significantly associated with fracture risk included age, sex, body mass index (BMI), smoking history, BMD, vertebral trabecular alterations, and prior vertebral fractures. The final risk-prediction model was developed using the formula: (logit [P] = -3.75 + 0.04 × age - 1.15 × sex + 0.02 × BMI + 0.83 × smoking history + 2.25 × BMD - 1.12 × vertebral trabecular alterations + 1.83 × previous vertebral fractures). The AUROC of the model was 0.93 (95%CI: 0.88-0.96, P < 0.001), indicating strong discriminatory capabilities. CONCLUSION: The fracture risk-prediction model, utilizing accessible clinical, biochemical, and radiological information, offered a precise tool for the evaluation of fracture risk in patients with spinal osteoporosis. The model has potential in the identification of high-risk individuals for early intervention and the guidance of appropriate preventive actions to reduce the impact of osteoporosis-related fractures.

Biomechanical evaluation of a short-rod technique for lumbar fixation surgery.

Objective: The purpose of this study was to analyze the stability and instrument-related complications associated with fixation of the lumbar spine using the Short-Rod (SR) technique. Methods: Using finite element analysis, this study assessed the stability of a bilateral lumbar fixation system when inserting the pedicle screws at angles of 10°, 15°, and 20° to the endplate in the sagittal plane. Using the most stable construct with a screw angle, the model was then assessed with different rod lengths of 25, 30, 35, and 45 mm. The optimal screw inclination angle and rod length were incorporated into the SR model and compared against traditional parallel screw insertion (pedicle screws in parallel to the endplate, PPS) in terms of the stability and risk of instrument-related complications. The following parameters were evaluated using the validated L4-L5 lumbar finite element model: axial stiffness, range of motion (ROM), stress on the endplate and facet joint, von-Mises stress on the contact surface between the screw and rod (CSSR), and screw displacement. Results: The results showed that the SR model with a 15° screw inclination angle and 35 mm rod length was superior in terms of construct stability and risk of complications. Compared to the PPS model, the SR model had lower stiffness, lower ROM, less screw displacement, and lower stress on the facet cartilage, the CSSR, and screws. However, the SR model also suffered more stress on the endplate in flexion and lateral bending. Conclusion: The SR technique with a 15° screw inclination and 35 mm rod length offers good lumbar stability with a low risk of instrument-related complications.

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. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties.

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.

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. STUDY QUESTION: Which combination treatment is better for spinal metastasis, percutaneous vertebroplasty with radiofrequency ablation, I seed, zoledronic acid or radiotherapy? STUDY DESIGN: A total of 169 patients with SM were retrospectively recruited and randomly assigned to 4 groups to receive 4 different ways separately: 49 patients (group A) received PVP plus I seed, 51 (group B) received PVP plus radiofrequency ablation (RFA), 38 (group C) underwent PVP plus zoledronic acid (ZA), and 31 (group D) underwent PVP plus radiotherapy (RT). MEASURES AND OUTCOMES: All of them underwent routine examinations before operation. Visual analog scale (VAS), World Health Organization (WHO) Pain Relief, and ODI were applied to evaluate pain relief and motor function. RESULTS: PVP plus RT achieved the best efficacy in relieving pains, with the highest WHO Pain Relief (P < 0.05). The PVP plus RFA exhibited lowest ODI, suggesting the best outcome after treatment (P < 0.05). The PVP plus I showed the lowest VAS score, but it was the worst to improve the routine exercise ability and relieve pains from patients. The PVP plus ZA presented higher VAS and ODI (P < 0.05). CONCLUSIONS: PVP combined with I seed exhibited the best clinical efficacy in terms of VAS, PVP combined with RT was the best choice in terms of WHO Pain Relief, and PVP combined with RFA showed the best effect in terms of ODI for the treatment of SM.

Profiling and Application of Photoredox C(sp3)-C(sp2) Cross-Coupling in Medicinal Chemistry.

Recent visible-light photoredox catalyzed C(sp3)-C(sp2) cross-coupling provides a novel transformation to potentially enable the synthesis of medicinal chemistry targets. Here, we report a profiling study of photocatalytic C(sp3)-C(sp2) 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. Cross-electrophile coupling gives higher success rate with broad substrate scope on alkyl halides than that of the decarboxylative coupling. In addition, a successful application example on a discovery program demonstrates the efficient synthesis of medicinal chemistry targets via photocatalytic C(sp3)-C(sp2) cross-coupling by using our integrated photoreactor.

Chemoselective Peptide Modification via Photocatalytic Tryptophan ß-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 ß-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. The endogenous peptides, glucagon and GLP-1 amide, were both successfully conjugated at the tryptophan ß-position. Insulin was studied as a nontryptophan control molecule, resulting in exclusive B-chain C-terminal-selective decarboxylative conjugation. This transformation provides a novel approach toward peptide modification to support the discovery of new therapeutic peptides, protein labeling and bioconjugation.

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. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chemistry settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.

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. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.

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. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

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 SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

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. Herein, we showed that miR-375 was frequently downregulated in osteosarcoma tissue and cell lines compared to normal human colon tissues. Overexpression of miR-375 resulted in decreased expression of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) at both mRNA and protein levels. We found that miR-375 overexpression markedly suppressed cell proliferation in vitro. And inhibition of miR-375 promotes osteosarcoma growth. Mechanistic studies showed that PIK3CA was a potential target of miR-375 and it mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. Taken together, our results demonstrate that miR-375 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA in osteosarcoma.

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. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.

[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. JOA score and VAS score were compared after inserted Wallis interspinous dynamic stabilization at 1 month and 3 years, and changes of intervertebral disc height of adjacent segment and cross-sectional area of the canal were tested and compared. RESULTS: All patients were followed up from 3 to 5 years with an average of 3.6 years. All injuries were healed at stage I and the pain were released after treatment. There were no significant meaning in JOA score and VAS score at 1 month after treatment between two groups (P>0.05), while had meaning at 3 years (P<0.05). There were no statistical significane in intervertebral disc height of adjacent segment and cross-sectional area of the canal at 1 month after treatment (P>0.05), while had statistical meaning at 3 years (P<0.05). CONCLUSION: There is no difference in immediate effects between two groups. Both of them can obtain good results for effective decompression. Medial-term effectiveness of treatment group is obviously better than control group, which depends on Wallis interspinous dynamic stabilization to plays good biology effects and effective accelerate adjacent degeneration caused by lumbar 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. Genotyping was based upon the duplex polymerase-chain-reaction with the PCR-CTPP method. RESULTS: At the time of diagnosis, 15.4% of the patients presented with metastasis, while 22.3% developed metastasis during follow-up. At the time of final analysis on January 2012, the median follow-up was 45.5 months. Patients with null GSTM1 and GSTT1 had a higher event free survival rate than non-null genotype, but no significant association was found between the two genotypes and prognosis of osteosarcoma. Individuals with GSTP1 Val/Val genotype tended to live shorter than with the IIe/IIe genotype, and we found a significantly higher risk of death from osteosarcoma (adjusted HR=2.35, 95% CI=1.13-4.85). CONCLUSION: The GSTP1 gene polymorphism may have an important role in the prognosis of osteosarcoma patients with chemotherapy. Further analyses with larger samples and more genes encoding metabolizing and DNA repair enzymes are warranted.

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. METHODS: A retrospective analysis was conducted on 31 consecutive patients with degenerative lumbar scoliosis combined with osteoporosis who had surgery from December 2000. All had a minimum of 2-year follow-up. All patients had posterior approach surgery. 14 of them were fixed with pedicle screw by augmentation with polymethylmethacrylate (PMMA) and the other 17 patients with autogenous bone. Age, sex and whether smoking were similar between the two groups. Surgical time, blood loss, blood transfusion, medical cost, post surgery ICU time, hospital day, length of oral pain medicines taken, Pre-and postoperative Oswestry disability index questionnaire and surgical revision were documented and compared. Preoperative, postoperative and final follow up Cobb angle, sagittal lumbar curve, correction rate, and Follow up Cobb loss were also compared. RESULTS: No significant differences were found between the autogenous bone group and polymethylmethacrylate group with regards to all the targets above except for length of oral pain medicines taken and surgery cost. 2 patients were seen leakage during operation, but there is neither damage of nerve nor symptom after operation. No revision was needed. CONCLUSION: Both augmentation pedicle screw with polymethylmethacrylate (PMMA) and autogenous bone treating degenerative lumbar scoliosis combined with osteoporosis can achieve a good surgical result. Less oral pain medicines taken are the potential benefits of polymethylmethacrylate augmentation, but that is at the cost of more medical spending.

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. Lumbar pedicel screw cortical perforation rate and operative time of the same kind of operation using CAN were analyzed and compared using CIII for the two surgeons at initial, 6 months and 12 months of CAN usage. RESULTS: CAN spine surgery had an overall lower cortical perforation rate and less mean operative time compared with CIII for both surgeon A and B cohorts when total cases of four years were included. It missed being statistically significant, with 3.3% versus 4.7% (P = 0.191) and 125.7 versus 132.3 minutes (P = 0.428) for surgeon A and 3.6% versus 6.4% (P = 0.058), and 183.2 versus 213.2 minutes (P = 0.070) for surgeon B. In an attempt to demonstrate the learning curve, the cases after 6 months of the CAN system in each surgeon's cohort were compared. The perforation rate decreased by 2.4% (P = 0.039) and 4.3% (P = 0.003) and the operative time was reduced by 31.8 minutes (P = 0.002) and 14.4 minutes (P = 0.026) for the CAN groups of surgeons A and B, respectively. When only the cases performed after 12 months using the CAN system were considered, the perforation rate decreased by 3.9% (P = 0.006) and 5.6% (P < 0.001) and the operative time was reduced by 20.9 minutes (P < 0.001) and 40.3 minutes (P < 0.001) for the CAN groups of surgeon A and B, respectively. CONCLUSIONS: In the long run, CAN spine surgery decreased the lumbar screw cortical perforation rate and operative time. The learning curve showed a sharp drop after 6 months of using CAN that plateaued after 12 months; which was demonstrated by both perforation rate and operative time data. Careful analysis of the data showed CAN is especially useful for less experienced surgeon to reduce perforation rate and intraoperative time, although further comparative studies are anticipated.

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. Analysis of the structural data showed that each of the three inhibitors fills the tryptophan binding pocket of TPH1 without reaching into the binding site of the cofactor pterin, and induces major conformational changes of the enzyme. The enzyme-inhibitor complexes assume a compact conformation that is similar to the one in tryptophan complex. Kinetic analysis showed that all three inhibitors are competitive versus the substrate tryptophan, consistent with the structural data that the compounds occupy the tryptophan binding site. On the other hand, all three inhibitors appear to be uncompetitive versus the cofactor 6-methyltetrahydropterin, which is not only consistent with the structural data but also indicate that the hydroxylation reaction follows an ordered binding mechanism in which a productive complex is formed only if tryptophan binds only after pterin, similar to the kinetic mechanisms of tyrosine and phenylalanine hydroxylase.