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"B. K. Chan"
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The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease’s molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45–65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in
IL6ST
are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.
Journal Article
In silico analysis of SARS-CoV-2 proteins as targets for clinically available drugs
The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires treatments with rapid clinical translatability. Here we develop a multi-target and multi-ligand virtual screening method to identify FDA-approved drugs with potential activity against SARS-CoV-2 at traditional and understudied viral targets. 1,268 FDA-approved small molecule drugs were docked to 47 putative binding sites across 23 SARS-CoV-2 proteins. We compared drugs between binding sites and filtered out compounds that had no reported activity in an in vitro screen against SARS-CoV-2 infection of human liver (Huh-7) cells. This identified 17 “high-confidence”, and 97 “medium-confidence” drug-site pairs. The “high-confidence” group was subjected to molecular dynamics simulations to yield six compounds with stable binding poses at their optimal target proteins. Three drugs—amprenavir, levomefolic acid, and calcipotriol—were predicted to bind to 3 different sites on the spike protein, domperidone to the Mac1 domain of the non-structural protein (Nsp) 3, avanafil to Nsp15, and nintedanib to the nucleocapsid protein involved in packaging the viral RNA. Our “two-way” virtual docking screen also provides a framework to prioritize drugs for testing in future emergencies requiring rapidly available clinical drugs and/or treating diseases where a moderate number of targets are known.
Journal Article
Ontological modeling and analysis of experimentally or clinically verified drugs against coronavirus infection
Our systematic literature collection and annotation identified 106 chemical drugs and 31 antibodies effective against the infection of at least one human coronavirus (including SARS-CoV, SAR-CoV-2, and MERS-CoV)
in vitro
or
in vivo
in an experimental or clinical setting. A total of 163 drug protein targets were identified, and 125 biological processes involving the drug targets were significantly enriched based on a Gene Ontology (GO) enrichment analysis. The Coronavirus Infectious Disease Ontology (CIDO) was used as an ontological platform to represent the anti-coronaviral drugs, chemical compounds, drug targets, biological processes, viruses, and the relations among these entities. In addition to new term generation, CIDO also adopted various terms from existing ontologies and developed new relations and axioms to semantically represent our annotated knowledge. The CIDO knowledgebase was systematically analyzed for scientific insights. To support rational drug design, a “Host-coronavirus interaction (HCI) checkpoint cocktail” strategy was proposed to interrupt the important checkpoints in the dynamic HCI network, and ontologies would greatly support the design process with interoperable knowledge representation and reasoning.
Journal Article
Republication of “Percutaneous Basal Closing Wedge Osteotomy of the First Metatarsal in the Treatment of Moderate to Severe Hallux Valgus and Its Short-Term Clinical Outcomes”
Background:
Although percutaneous surgery for the treatment of hallux valgus is popular in Europe, there is sparse English written literature documenting its efficacy. This study described the operative techniques using percutaneous basal closing wedge osteotomy of the first metatarsal in correction of moderate to severe hallux valgus (HV) and its short-term clinical outcomes. We postulated that satisfactory correction of hallux valgus (HV) angle, intermetatarsal (IM) angle, and patients’ clinical outcomes could be achieved with this technique.
Methods:
We conducted a retrospective review of 25 feet in 23 patients who underwent a percutaneous basal closing wedge osteotomy of the first metatarsal (MT1) combined with a mini-open modified McBride procedure and mini-open resection of medial eminence. Follow-up averaged 21.5 months. Radiographic outcomes included pre- and postoperative HV angle, IM angle, absolute and relative shortening of MT1, and time to union. American Orthopaedic Foot & Ankle Society (AOFAS) scores were compared between pre- and postoperatively.
Results:
The average HV angle improved from 39.4 (range, 29-58.3) degrees preoperatively to 14.7 (range, 0.1-23.2) degrees postoperatively (P < .05). IM angle improved from 14.9 (range, 6.7-22.4) degrees to 6.6 (range, 0.9-14.8) degrees (P < .05). The average absolute shortening was 3.8 (range, 0.27-12.91) mm and the relative shortening was 0.8 (range, 0.05-1.91) mm. There was no delayed union or malunion at the osteotomy site. The average AOFAS score improved from 39 (range, 12-50) to 81 (range, 70-93) (P < .05).
Conclusions:
Satisfactory hallux valgus deformity correction and patients’ outcomes were achieved with this technique. Our results are similar to results reported in other studies using open techniques. There was no malunion or delayed union of the osteotomy.
Level of Evidence:
Level IV, case series study.
Journal Article
Percutaneous Basal Closing Wedge Osteotomy of the First Metatarsal in the Treatment of Moderate to Severe Hallux Valgus and Its Short-Term Clinical Outcomes
Background:
Although percutaneous surgery for the treatment of hallux valgus is popular in Europe, there is sparse English written literature documenting its efficacy. This study described the operative techniques using percutaneous basal closing wedge osteotomy of the first metatarsal in correction of moderate to severe hallux valgus (HV) and its short-term clinical outcomes. We postulated that satisfactory correction of hallux valgus (HV) angle, intermetatarsal (IM) angle, and patients’ clinical outcomes could be achieved with this technique.
Methods:
We conducted a retrospective review of 25 feet in 23 patients who underwent a percutaneous basal closing wedge osteotomy of the first metatarsal (MT1) combined with a mini-open modified McBride procedure and mini-open resection of medial eminence. Follow-up averaged 21.5 months. Radiographic outcomes included pre- and postoperative HV angle, IM angle, absolute and relative shortening of MT1, and time to union. American Orthopaedic Foot & Ankle Society (AOFAS) scores were compared between pre- and postoperatively.
Results:
The average HV angle improved from 39.4 (range, 29-58.3) degrees preoperatively to 14.7 (range, 0.1-23.2) degrees postoperatively (P < .05). IM angle improved from 14.9 (range, 6.7-22.4) degrees to 6.6 (range, 0.9-14.8) degrees (P < .05). The average absolute shortening was 3.8 (range, 0.27-12.91) mm and the relative shortening was 0.8 (range, 0.05-1.91) mm. There was no delayed union or malunion at the osteotomy site. The average AOFAS score improved from 39 (range, 12-50) to 81 (range, 70-93) (P < .05).
Conclusions:
Satisfactory hallux valgus deformity correction and patients’ outcomes were achieved with this technique. Our results are similar to results reported in other studies using open techniques. There was no malunion or delayed union of the osteotomy.
Level of Evidence:
Level IV, case series study.
Journal Article
Biostatistics for epidemiology and public health using R
Since it first appeared in 1996, the open-source programming language R has become increasingly popular as an environment for statistical analysis and graphical output.In addition to being freely available, R offers several advantages for biostatistics, including strong graphics capabilities, the ability to write customized functions, and its.
eBook
Longitudinal Study of Bone Density and Periodontal Disease in Men
Bone loss is a feature of both periodontitis and osteoporosis, and periodontal destruction may be influenced by systemic bone loss. This study evaluated the association between periodontal disease and bone mineral density (BMD) in a cohort of 1347 (137 edentulous) older men followed for an average of 2.7 years. Participants were recruited from the Osteoporotic Fractures in Men Study. Random half-mouth dental measures included clinical attachment loss (CAL), pocket depth (PD), calculus, plaque, and bleeding. BMD was measured at the hip, spine, and whole-body, by dual-energy x-ray absorptiometry, and at the heel by ultrasound. After adjustment for age, smoking, race, education, body mass index, and calculus, there was no association between number of teeth, periodontitis, periodontal disease progression, and either BMD or annualized rate of BMD change. We found little evidence of an association between periodontitis and skeletal BMD among older men.
Journal Article
Sex Steroids, Periodontal Health, and Tooth Loss in Older Men
Sex steroids have a significant effect on skeletal biology in men, with reduced levels being associated with lower skeletal bone mass and cortical thickness. The purpose of this study was to determine if sex steroids are associated with periodontitis and tooth loss in a cohort of 1210 older dentate men followed for 3 years. Periodontal measures included attachment loss, pocket depth, gingival bleeding, and number of teeth. Baseline serum testosterone and estradiol were measured by radioimmunoassay. Severe periodontitis was common at baseline (38%), and progression occurred in 32% of the cohort. Incident tooth loss occurred in 22% of the cohort. Testosterone, estradiol, and sex hormone binding globulin (SHBG) concentrations were not related to baseline periodontal status or number of teeth. Moreover, there was no relationship between sex steroid levels and periodontitis progression or incident tooth loss. Although periodontitis, progression of periodontitis, and tooth loss are common in older men, they were not associated with sex steroids.
Journal Article
The Predictive Validity of OMPQ on the Rehabilitation Outcomes for Patients with Acute and Subacute Non-Specific LBP in a Chinese Population
Introduction
Early screening of physical and psychosocial risk factors has been advocated as a way to identify low back pain (LBP) patients who may develop chronic disability. This study evaluated the predictive validity of a Chinese version of the Orebro Musculoskeletal Pain Questionnaire (OMPQ) in identifying LBP patients at risk of developing poor return-to-work (RTW) outcomes.
Methods
Altogether 241 patients with acute or subacute non-specific LBP agreed to participate, and they were screened at baseline with OMPQ, and evaluated after discharge from physiotherapy (n = 173) with outcome measures including the Roland–Morris Disability Questionnaire (RMDQ), numerical pain score (0–10) and global recovery (0–10). At 1-year follow-up, information on RTW status as well as sick leave duration were obtained.
Results
At baseline the OMPQ had a mean score of 112.0 (SD = 26.5). The receiver operator characteristic (ROC) curves of OMPQ scores at 1-year follow-up recorded values of area under the curve of 0.693 for RTW and 0.714 for sick leave duration, which are comparable to those reported in European studies. OMPQ was the only factor that could significantly predict the RTW outcomes, compared to other variables such as the RMDQ scores.
Conclusion
The results confirmed the predictive validity of the Chinese version of OMPQ in screening LBP patients at risk of developing poor occupational outcomes, and appropriate interventions can be arranged for these high-risk individuals in the rehabilitation process.
Journal Article