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Supplemental Material, sj-pdf-1-tct-10.1177_15330338211004914 for Prognostic Value of Site-Specific Metastases and Therapeutic Roles of Surgery and Chemotherapy for Patients With Metastatic Renal Pelvis Cancer: A SEER Based Study by Wei-Kang Chen, Zhi-Gang Wu, Yun-Bei Xiao, Qin-Quan Wang, Dong-Dong Yu, Jian Cai and Chao-Feng Zhou in Technology in Cancer Research & Treatment

Additional file 4. Flow-chart of the participants’ selection.

Additional file 2. The specific plan of diagnosis and treatment. BP, blood pressure. PSA, prostate-specific antigen. TRUS, transrectal ultrasonography. MRI, magnetic resonance imaging.

Additional file 1. Abnormal appearances in patients’ MRI. The blue arrow points to the seminal vesicle cyst; the red arrow points to the stone in the right seminal vesicle. MRI, magnetic resonance imaging.

Additional file 3. Flowchart of the surgery. For each key step in the surgery, “positive or negative” findings together with further guidance of the next move are listed in the flowchart.

Background Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy. Methods Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey. Results H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with IC50 values at 10–20 nM. In vivo, H-Zt/g4-MMAE inhibited pancreatic cancer xenograft growth with tumoristatic concentrations at 1~3 mg/kg bodyweight. Significantly, H-Zt/g4-MMAE eradicated tumors across multiple xenograft models regardless their chemoresistant and metastatic statuses. Moreover, H-Zt/g4-MMAE inhibited and eradicated xenografts mediated by pancreatic cancer stem-like cells and by primary cells from patient-derived tumors. Toxicologically, H-Zt/g4-MMAE is well tolerated in mice up to 60 mg/kg. In cynomolgus monkey, H-Zt/g4-MMAE up to 30 mg/kg had a manageable and reversible toxicity profile. Conclusions H-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future. Electronic supplementary material The online version of this article (10.1186/s40425-019-0525-0) contains supplementary material, which is available to authorized users.

Additional file 6: Table S1. Efficacy of H5B14-Mediated RON Internalization in Comparison with Other Anti-RON mAbs.

Additional file 5: Figure S5. Effect of H5B14-based ADCs on mouse bodyweight. Female athymic nude mice (five mice per group) were injected with H5B14-MMAe or H5B14-DCM at 40, 60, 80, and 100â mg/kg in a single dose through the tail vein, respectively. Animals were monitored daily for activity, responsiveness, food consumption, and others. Individual mice were weighted every day to reach an average bodyweight for each group. All animals were sacrificed at the end of the study.

Additional file 3: Figure S3. Stability of H5B14-based ADCs in PBS. H5B14-MMAE and H5B14-DCM at 10 μg/ml were incubated with 1 ml PBS at room temperature for 28 days. Samples were collected at different time intervals and analyzed by HIC. Individual peaks with different numbers of MMAE or DCM conjugated to H5B14 were marked as P0 to P6. The average DAR combining P2, P4, and P6 for both ADCs were calculated accordingly [1–3].

Additional file 4: Figure S4. The concentration-dependent effect of H5B14-based ADCs on cell viability. A panel of fifteen cancer cell lines expressing variable levels of RON was used as the model. Cells at 8000 cells per well in a 96-well plate in triplicate were treated with different amounts of H5B14-MMAE (A) or H5B14-DCM (B) for 72â h. Cell viability was determined by the MTT assay. Zt/g4-MMAE or Zt/g4-DCM were used for comparison.

Additional file 2: Figure S2. Interaction of H5B14 with RONs from different species. Stable NIH3T3 cells expressing human, monkey, or mouse RON were incubated in duplicate with different amounts of H5B14 followed by goat anti-human IgG coupled with FITC. Immunofluorescent intensities from individual samples were determined by flow cytometric analysis. Results are shown as the percentages of H5B14 specific binding to RON. The binding affinity (IC50) was calculated using the GraphPad Prism 7 software.

Tables S1. Pathological and Biological Features of Primary PDAC Cell Lines from Patient-Derived Xenograft Tumors*. Table S2. Adverse Effects of H-Zt/g4-MMAE on blood leukocyte and erythrocytes in Cynomolgus monkey. Table S3. Effect of H-Zt/g4-MMAE in vivo on various enzymatic activities in blood samples collected from cynomolgus monkeys. (PDF 663 kb)

Figure S1. Immune reactivity of H-Zt/g4 to RON in multiple tissues from human and cynomolgus monkey. Figure S2. Effect of H-Zt/g4-MMAE on eradication of RON-expressing cells in PDAC xenograft tumors. Figure S3. Induction in vitro by H-Zt/g4-MMAE of death of PDAC stem-like cells. Figure S4. Effect of H-Zt/g4-MMAE on elimination of RON-expressing cells in PSC + 24/44/ESA cell-mediated xenografts. Figure S5A. Cell surface RON expression by a panel of primary PDX cell lines. Figure S5B. Induction of cell surface RON internalization by H-Zt/g4. Figure S5C. Effect of H-Zt/g4-MMAE on viability of primary PDAC cell lines derived from patient’ tumors. Figure S6. Histological examination of multiple organs and/or tissues from cynomolgus monkey treated with H-Zt/g4-MMAE. Figure S7. Histological examination of multiple organs and/or tissues from cynomolgus monkey treated with H-Zt/g4-MMAE. (PDF 2315 kb)

Additional file 1: Figure S1. Schematic representation of procedures for generation of mouse mAbs specific to the RON PSI domain. (A) Structure and sequence of the human RON PSI domain. A peptide containing 43 amino acids from Gly526 to Pro568 corresponding to the entire PSI domain was presented. (B) The synthetic peptide conjugated to KLH was used for mouse immunization. Individual hybridomas cell lines were obtained through classical methods for mouse mAb production. The mAbs specific to the RON PSI domain such as PCM5B14 were verified by ELISA, immunoprecipitation, and immunofluorescence analyses.

Eugauria albidentata (Hampson, 1897) (Figs 2, 5) Cataclysta albidentata Hampson, 1897. Trans. Ent. Soc. Lond., 1897: 153. Type-locality: Java. Eugauria compactalis Snellen, 1901. Tijdschr. Ent., 43: 291, pl. 181, fig.12. Type-locality: Java. Eugauria albidentata: Speidel & Mey, 1999. Tijdschr. Ent., 142: 138. Diagnosis. The species is different from others by the inner edge of the inner and larger white patch on the forewing slightly incurved. In male genitalia, the basal half of the valval costa is strongly scleorized, the broad sacculus bears an apical harpe, and the transtilla is small and papilla-like. Descriptions. Adults. Wing span of male 12 mm. Head, thorax and abdomen dark fuscous; labial palpi upturned, dark fuscous on sides, length about 2 times of diameter of compound eyes, 2nd slender and 3rd segment pointed; maxillary palpi upturned; proboscis relatively short. Forewing dark fuscous; a dark spot at upper angle of cell; a larger white patch at postmedial area, extending from costa to Cu 1, its inner edge slightly incurved; a smaller crescent white patch at outside of the apical yellow band; a yellow band between the white patches; cilia dark fuscous. Hindwing dark fuscous; a black spot at middle of cell; anal angle with an incision; submarginal band with 5 connected black eye spots, eye spots with a silvery spot centrally; cilia dark fuscous. Male genitalia. Uncus slender, pointed at apex; gnathos slender, as long as uncus, apex pointed, with dorsal teeth; tegumen with inverted V-shaped ridge dorsally; valva broadened form base to distal; costa with basal half strongly sclerotized, middle portion projected upwards; transtilla small papilla-like; sacculus broad and sclerotized, with a spine-like apical harpe; vinculum long; saccus large, rounded; juxta plate-like; aedeagus slender and sclerotized. Female genitalia. Unknown. Biology. This species feeds on the ferns of Nephrolepis Schott (Yen, Solis & Goolsby, 2004). A life cycle lasts no more than 20 days (Yen, per. comm.). Host plants. Nephrolepis sp. Material examined. 1♂, Taiwan, Kuei-shan Is. (24.8ºN, 121.9ºE), 27 May 1999, Hsiau-Yue Wang (Ny1016); 1♂, Taiwan, Yilan, Fushan (24.7ºN, 121.7ºE), 620 m, 12 April 2008, Fu-Qiang Chen, deposited in IZCAS. Distribution. China (Taiwan); Java., Published as part of Wu, Zhi-Gang, Chen, Fu-Qiang & Wu, Chun-Sheng, 2015, Review of the genus Eugauria Snellen (Lepidoptera: Crambidae: Musotiminae) in China, with descriptions of two new species, pp. 470-475 in Zoological Systematics 40 (4) on page 472, DOI: 10.11865/zs.20150405, http://zenodo.org/record/7176362, {"references":["Hampson, G. F. 1897. On the classification of two subfamilies of moth of the family Pyralidae: the Hydrocampinae and Scoparianae. Transaactions of the Entomological Society of London, 1897: 127 - 240.","Snellen, P. C. T. 1901. Aanteekeningen over Pyraliden. Tijdschrift voor Entomologie, 43: 265 - 310."]}

Wu, Zhi-Gang, Chen, Fu-Qiang, Wu, Chun-Sheng (2015): Review of the genus Eugauria Snellen (Lepidoptera: Crambidae: Musotiminae) in China, with descriptions of two new species. Zoological Systematics 40 (4): 470-475, DOI: 10.11865/zs.20150405, URL: http://zoobank.org/1fce6f5c-375a-47cc-b2a9-3fcbfaf55177

To solve the Riccati equation of LQ control problem, the computation of interval mixed variable energy matrices is the first step. Taylor expansion can be used to compute the matrices. According to the analogy between structural mechanics and optimal control and the mechanical implication of the matrices, a computational method using state transition matrix of differential equation was presented. Numerical examples are provided to show the effectiveness of the present approach.

This report describes the safety and efficacy of the procedure for percutaneous injection of medical-grade polyurethane elastomer (MPU) to form plugs in the vas deferens. The injection of 0.16-0.22 ml MPU in 53 men resulted in occlusion and azoospermia in 85% of the men after 12 months; 96% achieved azoospermia by 2 years. The success rate of the method and the rate of sperm suppression to azoospermia depended on the shapes of the plugs; this was determined by palpation after insertion. There were few complications and the results are discussed in terms of the reversibility potential of this method.In China, physicians performed percutaneous injection of medical-grade polyurethane (MPU) in 53 men at the National Research Institute for Family Planning in Beijing and followed them for 2 years to evaluate the safety and efficacy of MPU vas occlusion. The injection of 1% procaine solution was used to kill residual spermatozoa in the distal reproductive tract. 1 year and within-subject fructose levels did not fluctuate greatly. 85% of the men reached azoospermia within 1 year after vas occlusion. 96% were azoospermic at 18 months. 2 men still had spermatozoa in the semen after 2 years (8-48 million ml-1). Both MPU plugs in most men (74%) had a regular shape. All of these men reached azoospermia by 18 months. 91% of the 11 men who had 1 regular and 1 irregular shaped MPU plug reached azoospermia by 18 months. This percentage fell to 67% for the 3 men whose MPU plugs were both irregular. The physicians had removed irregularly shaped MPU plugs in 5 men earlier and the elastomer filled the vas lumen and the surrounding vas surface. Recanalization did not occur in these 5 patients. 1 man with MPU vas occlusion developed a hematoma. 3 men experienced hemaspermia within 2 weeks after vas occlusion, but medication made it disappear within 4 weeks. Injection of 1% procaine solution may have damaged the seminal vesicles, resulting in the hemaspermia. Longterm complications did not occur.

In this paper, the problem of output feedback stabilization is considered for a class of switched delay systems under asynchronous switching. When the switching signal of the switched controller involves delay, by constructing a novel Lyapunov functional which is allowed to increase during the running time of active subsystems with the mismatched controller, sufficient conditions for exponential stability are developed for a class of switching signals based on the average dwell time method. Moreover the stabilizing output feedback controllers are designed. Finally, an example is given to demonstrate the feasibility and effectiveness of the proposed design techniques. Refereed/Peer-reviewed