Additional file 2: of Whole genome sequencing data of 1110 Mycobacterium tuberculosis isolates identifies insertions and deletions associated with drug resistance

Table S1. Test for the difference in IGR indel incidence rate between resistant and sensitive strains for each drug among 1110 MTB strains. Table S2. Function enrichment for genes with at-least-one-drug-resistant strain-specific FS mutations in more than two resistant strains. Table S3. Function enrichment for genes with frameshift mutations in the DR-TB, MDR-TB and XDR-TB groups of strains. Table S4. The 20 region markers identified according to adjusted chi-square and Fisher’s exact p-values. Table S5. The 20 identified region markers and corresponding strain numbers. Table S6. Overview of functions for 20 region markers. Table S7. Description of the 20 region markers. Table S8. The distribution of region markers in function categories. Table S9. The 83 identified point markers of FS mutations and IGR indels, showing adjusted p-values. Table S10. The 83 identified point markers of FS mutations and IGR indels, showing strain numbers. Table S11. The identified point markers located in the IGRs expressing sRNA. Table S12. Overview of the functions of the 83 point markers. Table S13. Descriptions of the functions of the 83 point markers. Table S14. The 6 point markers out of the 83 point markers exclusively occurring in resistant strains. Table S15. P-values after logistic regression for the associations between the 20 region markers and drug resistance. Table S16. P-values after logistic regressions for the associations between the 83 point markers and drug resistance. Table S17. Effect of mutations on DNA repair genes. Table S18. Region markers in the validation set overlapping with the 20 region markers. Table S19. Point markers in the validation set overlapping with the 83 point markers. Table S20. Point markers in the 62 samples in which no known drug resistance associated SNPs were found. Table S21. The incidence rate for region markers. Table S22. The incidence rate for point markers. (DOCX 193 kb

Virtual Reality and Augmented Reality in Plastic and Craniomaxillofacial Surgery: A Scoping Review

Virtual reality (VR) and augmented reality (AR) have evolved since their introduction to medicine in the 1990s. More powerful software, the miniaturization of hardware, and greater accessibility and affordability enabled novel applications of such virtual tools in surgical practice. This scoping review aims to conduct a comprehensive analysis of the literature by including all articles between 2018 and 2021 pertaining to VR and AR and their use by plastic and craniofacial surgeons in a clinician-as-user, patient-specific manner. From the initial 1637 articles, 10 were eligible for final review. These discussed a variety of clinical applications: perforator flaps reconstruction, mastectomy reconstruction, lymphovenous anastomosis, metopic craniosynostosis, dermal filler injection, auricular reconstruction, facial vascularized composite allotransplantation, and facial artery mapping. More than half (60%) involved VR/AR use intraoperatively with the remainder (40%) examining preoperative use. The hardware used predominantly comprised HoloLens (40%) and smartphones (40%). In total, 9/10 Studies utilized an AR platform. This review found consensus that VR/AR in plastic and craniomaxillofacial surgery has been used to enhance surgeons' knowledge of patient-specific anatomy and potentially facilitated decreased intraoperative time via preoperative planning. However, further outcome-focused research is required to better establish the usability of this technology in everyday practice

Additional file 3: of Whole genome sequencing data of 1110 Mycobacterium tuberculosis isolates identifies insertions and deletions associated with drug resistance

The accession numbers of the validation data set. (XLSX 79 kb

Additional file 1: Tables S1–S3, Figures S1–S5. of Discovery and characterization of a high-affinity and high-specificity peptide ligand LXY30 for in vivo targeting of α3 integrin-expressing human tumors

Methods S1–S4. (DOCX 1572 kb

Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, <i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)­oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (<b>1</b>), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of <b>1</b>. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound <b>59e</b> (AMG 458) was ultimately advanced into preclinical safety studies

Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor <b>5</b>, a structure-based approach was used to improve potency and selectivity, resulting in the identification of <b>54</b> as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound <b>54</b> demonstrated a robust PD–PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway

Selective Class I Phosphoinositide 3‑Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)­amino)-5-((4-(methylsulfonyl)­piperazin-1-yl)­methyl)­pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (<b>1</b>). In this paper, we describe the optimization of compound <b>1</b>, which led to the design and synthesis of pyridyltriazine <b>31</b>, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound <b>31</b> was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound <b>31</b> was selected for further evaluation as a clinical candidate and was designated AMG 511