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Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aβ42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aβ42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aβ42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aβ42 species populated during amyloid assembly.

Supplementary Figure S1 shows circos plots including 17 PDACs of the patient cohort and a PDCM.

Supplementary Table S1 lists potentially clinically relevant somatic alterations in the PDAC patient cohort.

Supplementary Figure S1. RECQL1 and survival in ER+ or ER- breast cancer patients. Supplementary Figure S2. RECQL1-depleted MCF-7 cells exhibit sensitivity to doxorubicin. Supplementary Figure S3. RECQL1 depletion and ERα protein levels.

Supplementary Table S1: Clinicopathological characteristics in the METABRIC cohort Supplementary Table S2: Clinicopathological characteristics of Nottingham Tenovus series Supplemental Table S3: Clinicopathological characteristics of ER- cohort Supplemental Table S4: Clinicopathological characteristics of BRCA germ-line deficient cohort Supplementary Table S5: Antigens, primary antibodies, clone, source, optimal dilution and scoring system used for each immunohistochemical marker Supplementary Table S6. RecQL1 mRNA expression and breast cancer. Supplementary Table S7. RECQL1 protein levels and ER+ breast cancers. Supplementary Table S8. RECQL1 protein levels and ER- breast cancers.

RECQL1 expression and survival in ER+ or ER- breast cancers

RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (P = 0.026), which is characterized by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 [luminal A estrogen receptor–positive (ER+) subgroup; P = 0.0455] and intClust.9 (luminal B ER+ subgroup; P = 0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer–specific survival (P = 0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumor size, lymph node positivity, high tumor grade, high mitotic index, pleomorphism, dedifferentiation, ER negativity, and HER-2 overexpression (P < 0.05). In ER+ tumors that received endocrine therapy, low RECQL1 was associated with poor survival (P = 0.008). However, in ER− tumors that received anthracycline-based chemotherapy, high RECQL1 was associated with poor survival (P = 0.048). In RECQL1-depleted breast cancer cell lines, we confirmed doxorubicin sensitivity, which was associated with DNA double-strand breaks accumulation, S-phase cell-cycle arrest, and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers. Mol Cancer Ther; 16(1); 239–50. ©2016 AACR.

Supplementary patient data provides a summary on the clinical course of patient 16.

Supplementary Table (S3). Clinico-pathological characteristics of primary locally advanced triple negative breast cancer cohort (PLA-TNBC; n=110)

Hgf/c-Met signaling supports migration of cells with CEC phenotype

Supplementary Materials & Methods

Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC).Experimental Design: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed.Results: In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2–1.5; P = 0.000005] when compared with HAGE− cases. Patients who received ACT and expressed mRNA-HAGE+ were at a lower risk of death than those who were mRNA–HAGE− (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE+ had a 2-fold death risk increase (P = 0.018) compared with HAGE−.Conclusions: HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted. Clin Cancer Res; 22(4); 905–14. ©2015 AACR.

Supplementary Figure Legends

Supplementary Figure Legends 1-9 from Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome

Supplementary Figures 1-9 from Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome

Supplementary Tables 1- 9 from Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome

Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133+ tumor cells. Both viruses exerted strong antitumoral effects on human hepatocellular carcinoma growing subcutaneously or multifocally in the peritoneal cavity of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Notably, the CD133-targeted viruses were more effective in prolonging survival than the parental MV-NSe, which is currently assessed as oncolytic agent in clinical trials. Interestingly, target receptor overexpression or increased spreading kinetics through tumor cells were excluded as being causative for the enhanced oncolytic activity of CD133-targeted viruses. MV-141.7 was also effective in mouse models of orthotopic glioma tumor spheres and primary colon cancer. Our results indicate that CD133-targeted measles viruses selectively eliminate CD133+ cells from tumor tissue, offering a key tool for research in tumor biology and cancer therapy. Cancer Res; 73(2); 865–74. ©2013 AACR.

Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3K9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) marks in a well-characterized series of human breast carcinomas (n = 880). Tissue staining intensities were assessed using blinded semiquantitative scoring. Validation studies were done using immunofluorescence staining and Western blotting. Our analyses revealed low or absent H4K16ac in the majority of breast cancer cases (78.9%), suggesting that this alteration may represent an early sign of breast cancer. There was a highly significant correlation between histone modifications status, tumor biomarker phenotype, and clinical outcome, where high relative levels of global histone acetylation and methylation were associated with a favorable prognosis and detected almost exclusively in luminal-like breast tumors (93%). Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in carcinomas of poorer prognostic subtypes, including basal carcinomas and HER-2-positive tumors. Clustering analysis identified three groups of histone displaying distinct pattern in breast cancer, which have distinct relationships to known prognostic factors and clinical outcome. This study identifies the presence of variations in global levels of histone marks in different grades, morphologic types, and phenotype classes of invasive breast cancer and shows that these differences have clinical significance. [Cancer Res 2009;69(9):3802–9]

Supplementary Methods and Materials from Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome

BACKGROUND: The purpose of this review is to provide a brief history of previous attempts at developing patient screening tools and to further examine the definitions of these psychological concepts, relevance to clinical outcomes, and implications for spine surgeons during preoperative patient assessments. METHODS: A literature review was performed by 2 independent researchers to identify original manuscripts related to spine surgery and novel psychological concepts. The history of presurgical psychology screening was also studied, and definitions of frequently utilized metrics were detailed. RESULTS: Seven manuscripts were identified that utilized psychological metrics for preoperative risk assessments and correlated outcomes with these scores. The metrics most frequently used in the literature included resilience, patient activation, grit, and self-efficacy. DISCUSSION: Current literature favors resilience and patient activation as important metrics for preoperative patient screening. Available studies demonstrate significant associations between these character traits and patient outcomes. Further research is warranted to investigate the roles of preoperative psychological screening to optimize patient selection in spine surgery. CLINICAL RELEVANCE: The purpose of this review is to provide clinicians with a reference for available psychosocial screening tools and their relevance to patient selection. This review also serves to guide future research directions given the importance of this topic. LEVEL OF EVIDENCE: 4.

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Protein misfolding and aggregation into oligomeric and fibrillar structures is a common feature of many neurogenerative disorders. Single-molecule techniques have enabled characterization of these lowly abundant, highly heterogeneous protein aggregates, previously inaccessible using ensemble averaging techniques. However, they usually rely on the use of recombinantly-expressed labeled protein, or on the addition of amyloid stains that are not protein-specific. To circumvent these challenges, we have made use of a high affinity antibody labeled with orthogonal fluorophores combined with fast-flow microfluidics and single-molecule confocal microscopy to specifically detect α-synuclein, the protein associated with Parkinson's disease. We used this approach to determine the number and size of α-synuclein aggregates down to picomolar concentrations in biologically relevant samples.

Linking clinical multi-omics analyses with mechanistic studies provides opportunities to explore the pathogenesis of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective systemic therapies. All tumors exhibited outlier expression of the ALK receptor tyrosine kinase, which was partly accompanied by intragenic deletions and aberrant splicing, resulting in truncated ALK variants that were oncogenic and sensitive to ALK inhibitors. Additional recurrent alterations included CKDN2A/MTAP co-deletions, providing a rationale for therapies targeting CDK4/6 and PRMT5. Functional studies showed that FUS-TFCP2 blocks myogenic differentiation and induces transcription of ALK and a truncated form of TERT through binding outside their regular promoters. Furthermore, FUS-TFCP2 inhibited DNA double-strand break repair. Consistent with this, and unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibited marked genomic instability and signs of defective homologous recombination. DNA methylation profiling indicated a close relationship with undifferentiated sarcomas rather than rhabdomyosarcoma. Finally, we identified patients in whom overt disease was preceded by benign lesions carrying TFCP2 fusions, providing insight into stepwise sarcomagenesis and suggesting new approaches to early detection and interception.SIGNIFICANCEMost rare cancers are poorly understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. This study illustrates the potential of linking precision oncology programs with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers that could improve the clinical management of such diseases.