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The drug discovery and development process is a long and expensive one, costing over 1 billion USD on average per drug and taking 10-15 years. To reduce the high levels of attrition throughout the process, there has been a growing interest in applying machine learning methodologies to various stages of drug discovery and development in the recent decade, especially at the earliest stage – identification of druggable disease genes. In this paper, we have developed a new tensor factorisation model to predict potential drug targets (genes or proteins) for treating diseases. We created a three-dimensional data tensor consisting of 1,048 gene targets, 860 diseases and 230,011 evidence attributes and clinical outcomes connecting them, using data extracted from the Open Targets and PharmaProjects databases. We enriched the data with gene target representations learned from a drug discovery-oriented knowledge graph and applied our proposed method to predict the clinical outcomes for unseen gene target and disease pairs. We designed three evaluation strategies to measure the prediction performance and benchmarked several commonly used machine learning classifiers together with Bayesian matrix and tensor factorisation methods. The result shows that incorporating knowledge graph embeddings significantly improves the prediction accuracy and that training tensor factorisation alongside a dense neural network outperforms all other baselines. In summary, our framework combines two actively studied machine learning approaches to disease target identification, namely tensor factorisation and knowledge graph representation learning, which could be a promising avenue for further exploration in data-driven drug discovery.

PROteolysis TArgeting Chimeras (PROTACs) use the ubiquitin–proteasome system to degrade a protein of interest for therapeutic benefit. Advances made in targeted protein degradation technology have been remarkable, with several molecules having moved into clinical studies. However, robust routes to assess and better understand the safety risks of PROTACs need to be identified, which is an essential step toward delivering efficacious and safe compounds to patients. In this work, we used Cell Painting, an unbiased high-content imaging method, to identify phenotypic signatures of PROTACs. Chemical clustering and model prediction allowed the identification of a mitotoxicity signature that could not be expected by screening the individual PROTAC components. The data highlighted the benefit of unbiased phenotypic methods for identifying toxic signatures and the potential to impact drug design.

To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermiaand ovarian failure, the association of preclinical reflexes abnormalwith clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivitywith clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitroscreening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitrosafety panels.

Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post‐MI cardiac dysfunction. We have used an in vitro human induced pluripotent stem cell‐derived CPC model to screen a 10,000‐compound library containing molecules representing different target classes and compounds reported to modulate the phenotype of stem or primary cells. The primary readout of this phenotypic screen was proliferation as measured by nuclear count. We identified retinoic acid receptor (RAR) agonists as potent proliferators of CPCs. The CPCs retained their progenitor phenotype following proliferation and the identified RAR agonists did not proliferate human cardiac fibroblasts, the major cell type in the heart. In addition, the RAR agonists were able to proliferate an independent source of CPCs, HuES6. The RAR agonists had a time‐of‐differentiation‐dependent effect on the HuES6‐derived CPCs. At 4 days of differentiation, treatment with retinoic acid induced differentiation of the CPCs to atrial cells. However, after 5 days of differentiation treatment with RAR agonists led to an inhibition of terminal differentiation to cardiomyocytes and enhanced the proliferation of the cells. RAR agonists, at least transiently, enhance the proliferation of human CPCs, at the expense of terminal cardiac differentiation. How this mechanism translates in vivo to activate endogenous CPCs and whether enhancing proliferation of these rare progenitor cells is sufficient to enhance cardiac repair remains to be investigated. An image‐based phenotypic screen, using a readout of nuclear count to measure proliferation, identified retinoic acid receptor agonists as potent proliferators of induced pluripotent stem cell‐derived cardiac progenitor cells. The cardiac progenitor cells retained their progenitor phenotype following proliferation and the retinoic acid receptor agonists did not proliferate human cardiac fibroblasts, the major cell type in the heart.

Emerging technologies in shoulder arthroplasty, such as 3-dimensional planning software and real-time intraoperative navigation, are now available for surgeons to perform more accurate placement of the glenoid component without malposition or perforation. Using these tools, the surgeon can visualize the version, inclination, and containment of the implant and determine whether augmented components would be necessary. This review provides an updated investigation of the present literature to elucidate the role of computer navigation in modern shoulder arthroplasty.

Venous thoracic outlet syndrome (vTOS) usually results from compression of the subclavian vein classically as a result of narrowing of the costoclavicular space. We report 2 rare cases of soft tissue neoplasms resulting in apparent vTOS. The first case is a 46-year-old female with a 2-year history of intermittent unilateral shoulder pain, who was initially diagnosed with intervertebral disk herniation. Cervical fusion was performed; however, her symptoms progressed and she additionally developed paresthesias and venous congestion. Computed tomography (CT) angiogram demonstrated a 13-cm-encapsulated mass within the subscapularis muscle compressing the axillary vein. Radiological findings suggested lipoma. She subsequently underwent complete resection via a transaxillary approach with extension along the lateral border of the latissimus. Final pathology confirmed an intramuscular lipoma. The second case is a 21-year-old female who presented with acute onset of unilateral chest wall pain, palpable nodularity, and venous congestion. CT chest showed pulmonary embolism and an anterior chest wall mass. An initial attempt at resection was aborted due to proximity of the mass to the subclavian vein. The mass enlarged on serial imaging, measuring 3.8 cm in greatest dimension. Additionally, tumor thrombus was seen, and a subsequent ultrasound-guided biopsy was positive for high-grade synovial sarcoma. Positron emission tomography scan showed a pulmonary nodule that was resected thoracoscopically with pathology confirming metastatic synovial sarcoma. Subsequently, she underwent neoadjuvant chemoradiation followed by successful resection of the chest wall mass. An extended infraclavicular approach with a secondary transaxillary incision was utilized to achieve adequate exposure and margins. Final pathology was consistent with preoperative biopsy. Venous reconstruction was not needed. Although rare, an extrinsic mass as a cause of apparent TOS should be in the differential diagnosis. Surgical approach is based on tumor type, location, and proximity to the neurovascular bundle.

While mechanisms of cytotoxicity and cytostaticity have been studied extensively from the biological side, relatively little is currently understood regarding areas of chemical space leading to cytotoxicity and cytostasis in large compound collections. Predicting and rationalizing potential adverse mechanism-of-actions (MoAs) of small molecules is however crucial for screening library design, given the link of even low level cytotoxicity and adverse events observed in man. In this study, we analyzed results from a cell-based cytotoxicity screening cascade, comprising 296 970 nontoxic, 5784 cytotoxic and cytostatic, and 2327 cytostatic-only compounds evaluated on the THP-1 cell-line. We employed an in silicoMoA analysis protocol, utilizing 9.5 million active and 602 million inactive bioactivity points to generate target predictions, annotate predicted targets with pathways, and calculate enrichment metrics to highlight targets and pathways. Predictions identify known mechanisms for the top ranking targets and pathways for both phenotypes after review and indicate that while processes involved in cytotoxicity versus cytostaticity seem to overlap, differences between both phenotypes seem to exist to some extent. Cytotoxic predictions highlight many kinases, including the potentially novel cytotoxicity-related target STK32C, while cytostatic predictions outline targets linked with response to DNA damage, metabolism, and cytoskeletal machinery. Fragment analysis was also employed to generate a library of toxicophores to improve general understanding of the chemical features driving toxicity. We highlight substructures with potential kinase-dependent and kinase-independent mechanisms of toxicity. We also trained a cytotoxic classification model on proprietary and public compound readouts, and prospectively validated these on 988 novel compounds comprising difficult and trivial testing instances, to establish the applicability domain of models. The proprietary model performed with precision and recall scores of 77.9% and 83.8%, respectively. The MoA results and top ranking substructures with accompanying MoA predictions are available as a platform to assess screening collections.

Purpose Several bioabsorbable and metal options are available for internal fixation of an unstable osteochondritis dissecans (OCD) lesion, but currently there are little data on outcomes with metal headless compression screws in the adult knee. The purpose of this study was to determine (1) the radiographic healing rates, (2) midterm clinical outcomes, and (3) comparison between healed and unhealed OCD fragments after use of headless metal compression screws for the treatment of unstable OCD lesions in the knees of skeletally mature patients.Methods Retrospective chart review for all skeletally mature patients who presented with unstable femoral condyle OCD lesions of the knee was conducted. All patients underwent open or arthroscopic reduction and internal fixation using headless metal compression screws. Preoperative and postoperative radiographs were reviewed with healing defined as radiographic evidence of union of the OCD progeny fragment with the condyle. Clinical outcome data were collected retrospectively using 3 validated outcome scores: International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Marx.Results Twenty-two knees in 22 patients with a mean age of 21 years (range= 14-37 years) were followed for an average of 8.7 years (range = 2-22 years). Metal, headless, cannulated compression screws were used in all 22 cases. At a mean of 31 months postoperatively (range = 2-262), fragment union was observed in 18 knees (82%). The remaining 4 knees (18%) required loose fragment excision and hardware removal at a mean of 9 months (range = 2-16 months) postoperatively. Mean postoperative Marx score was 7 (range = 0-16), the mean postoperative IKDC score was 85 (range = 62-100), and mean KOOS scores included KOOS Pain (93; range = 69-100), KOOS Symptoms (86; range = 71-100), KOOS ADL (98; range = 90-100), KOOS Sports (82; range = 50-100), and KOOS QOL (76; range = 50-100).Conclusion Headless metal compression screws provide a satisfactory union rate for treatment of unstable OCD lesions of the femoral condyles in skeletally mature patients. Patients achieving union have good knee function, maintain satisfactory activity levels, and have superior knee outcomes compared with those that failed to heal after fixation at mid to long-term follow-up.

Consistent with the career development issues that black* people encounter, it is likely that black human resource developers face unique career development issues versus human resource developers in general. However, an exhaustive search did not find research that has focused specifically on the career development process of black human resource development professionals. Therefore, the purpose of this study was to describe the career experiences of black human resource developers. A qualitative study was conducted of 10 black human resource developers. Interviewing was the primary data collection method and the data were analyzed using the constant comparative method. The results of this study indicate that the respondents experienced similar career challenges to other black workers. Based on the results, we posit that because of racial prejudice and discrimination, black human resource developers serve as outsiders within traditional work organizations and become skilled at using bicultural strategies for managing various aspects of their lives.

Consistent with the career development issues that black* people encounter, it is likely that black human resource developers face unique career development issues versus human resource developers in general. However, an exhaustive search did not find research that has focused specifically on the career development process of black human resource development professionals. Therefore, the purpose of this study was to describe the career experiences of black human resource developers. A qualitative study was conducted of 10 black human resource developers. Interviewing was the primary data collection method and the data were analyzed using the constant comparative method. The results of this study indicate that the respondents experienced similar career challenges to other black workers. Based on the results, we posit that because of racial prejudice and discrimination, black human resource developers serve as outsiders within traditional work organizations and become skilled at using bicultural strategies for managing various aspects of their lives.

Purpose: Extracorporeal irradiation (ECI) has been used selectively in the management of primary malignant bone tumors since 1996. We report our techniques for ECI and the short-term oncologic and orthopedic outcomes. Methods and Materials: Sixteen patients with primary malignant bone tumors were treated with ECI from 1996 to 2000. The median age was 14 years. The histologic diagnoses were Ewing's sarcoma (11), osteosarcoma (4) and chondrosarcoma (1). The treated sites were femur (7), tibia (4), humerus (2), ilium (2), and sacrum (1). Following induction chemotherapy in Ewing's sarcomas and osteosarcoma, en bloc resection of the tumor and tumor-bearing bone was performed. A single dose of 50 Gy was delivered to the bone extracorporeally using either a linear accelerator (9 cases) or a blood product irradiator (7 cases). The orthopedic outcome was recorded using a standard functional scale. Results: At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis. For the 10 patients with follow-up greater than 18 months, the functional outcomes were graded good to excellent. Conclusion: The short-term oncologic and orthopedic results are encouraging and suggest that ECI provides a good alternative for reconstruction in limb conservative surgery in selected patients. This technique should only be used in a multidisciplinary setting, where careful follow-up is available to assess the long-term outcomes.

There are relatively few reports concerning management of the musculoskeletal problems of children with renal failure. From a population group of 124 children with renal failure treated at The Children's Hospital, Camperdown, 16 were referred for management of skeletal problems. These problems included genu valgum, slipped capital femoral epiphysis, ankle valrus, procurvatum of the tibia, osteonecrosis, osteochondritis dissecans, “brown tumors,” gout, and pathological fracture. The methods of management of these problems are discussed.

N- p-fluorobenzyl-2-chlorobenzimidazole was treated under hyperbaric conditions with a variety of primary and secondary amines. The resulting S NAr reaction proceeded smoothly to produce excellent yields of adducts in most cases. This methodology provides rapid access to astemizole, norastemizole and related analogues.

Two children with rhabdomyosarcoma who developed slipped capital femoral epiphyses following pelvic irradiation are described. Previous case reports are summarised, and the relevant orthopedic implications of the disorder discussed.

The understanding of the mechanism-of-action (MoA) of compounds and the prediction of potential drug targets play an important role in small-molecule drug discovery. The aim of this work was to compare chemical and cell morphology information for bioactivity prediction. The comparison was performed using bioactivity data from the ExCAPE database, image data (in the form of CellProfiler features) from the Cell Painting data set (the largest publicly available data set of cell images with ∼30,000 compound perturbations), and extended connectivity fingerprints (ECFPs) using the multitask Bayesian matrix factorization (BMF) approach Macau. We found that the BMF Macau and random forest (RF) performance were overall similar when ECFPs were used as compound descriptors. However, BMF Macau outperformed RF in 159 out of 224 targets (71%) when image data were used as compound information. Using BMF Macau, 100 (corresponding to about 45%) and 90 (about 40%) of the 224 targets were predicted with high predictive performance (AUC > 0.8) with ECFP data and image data as side information, respectively. There were targets better predicted by image data as side information, such as β-catenin, and others better predicted by fingerprint-based side information, such as proteins belonging to the G-protein-Coupled Receptor 1 family, which could be rationalized from the underlying data distributions in each descriptor domain. In conclusion, both cell morphology changes and chemical structure information contain information about compound bioactivity, which is also partially complementary, and can hence contribute to in silicoMoA analysis.

A new technique of using 99mTc bone scan to assess partial closure of the growth plate is described. The site and degree of osseous fusion can be obtained by using the apex view. The technique has the potential of assessing serially the growth of a plate before and after surgery.

From 1984 to 1995, 19 patients with cubitus varus resulting from supracondylar humeral fractures underwent lateral closing-wedge osteotomies at The Royal Alexandra Hospital for Children. As the indication for osteotomy in all cases was the cosmetically unacceptable cubitus varus, we reviewed the cosmetic results. Seventeen patients were available for review. Subjective reports from patients and parents, as well as objective clinical assessment by one of the authors, were used to assess these results. According to our grading system, 12 (76%) patients had excellent results. These patients and their parents were satisfied with the cosmetic results, and there was no clinical evidence of a bony prominence over the lateral condylar region or an unsightly operative scar. One patient had a poor result with a lateral bony prominence and an unsightly scar, both of which were clinically obvious. We report that lateral closing osteotomies in children who have not yet reached skeletal maturity produce excellent cosmetic results.

We have previously developed a high-throughput bioengineered human cardiac organoid (hCO) platform, which provides functional contractile tissue with biological properties similar to native heart tissue, including mature, cell-cycle-arrested cardiomyocytes. In this study, we perform functional screening of 105 small molecules with pro-regenerative potential. Our findings reveal surprising discordance between our hCO system and traditional 2D assays. In addition, functional analyses uncovered detrimental effects of many hit compounds. Two pro-proliferative small molecules without detrimental impacts on cardiac function were identified. High-throughput proteomics in hCO revealed synergistic activation of the mevalonate pathway and a cell-cycle network by the pro-proliferative compounds. Cell-cycle reentry in hCO and in vivorequired the mevalonate pathway as inhibition of the mevalonate pathway with a statin attenuated pro-proliferative effects. This study highlights the utility of human cardiac organoids for pro-regenerative drug development, including identification of underlying biological mechanisms and minimization of adverse side effects.

Two children presented with recurrent swelling and pain, one in th e forearm the other in the leg, without a history of a penetrating Injury, It was difficult to arrive at a precise clinical diagnosis, X‐ray films showed periosteal thickening in the diaphysis of the adjacent long bone with some unusual features but were suggestive of infection or tumour. Other extensive investigations did not contribute to a diagnosis . This was only achieved after surgical exploration. Both children had a 3 cm length of brittle palm needle within a soft tissue cavity adjacent to the long bone. The needles were from a commonly grown palm, Phoenix canariensis. Palm needle induced pseudo‐tumour should always be considered in the differential diagnosis of bone neoplasm, particularly in childhood.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.