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1.
Cancers (Basel) ; 16(9)2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38730657

ABSTRACT

Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.

2.
Eur Urol ; 85(4): 337-345, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37246069

ABSTRACT

BACKGROUND: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk. OBJECTIVE: To identify coding genomic variants associated with predisposition to TGCT. DESIGN, SETTING, AND PARTICIPANTS: The study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We carried out exome sequencing and gene burden analysis to identify associations with TGCT risk. RESULTS AND LIMITATIONS: Gene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for truncating variants, p = 0.47 for all variants) or evidence of associations with the regions previously identified via genome-wide association studies (GWAS). When considering all significant coding variants together with genes associated with TGCT on GWAS, there were associations with three major pathways: mitosis/cell cycle (Gene Ontology identity GO:1903047: observed/expected variant ratio [O/E] 6.17, false discovery rate [FDR] 1.53 × 10-11), co-translational protein targeting (GO:0006613: O/E 18.62, FDR 1.35 × 10-10), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 × 10-4). CONCLUSIONS: To the best of our knowledge, this study is the largest to date on men with HR-TGCT. As in previous studies, we identified associations with variants for several genes, suggesting multigenic heritability. We identified associations with co-translational protein targeting, and chromosomal segregation and sex determination, identified via GWAS. Our results suggest potentially druggable targets for TGCT prevention or treatment. PATIENT SUMMARY: We searched for gene variations that increase the risk of testicular cancer and found numerous new specific variants that contribute to this risk. Our results support the idea that many gene variants inherited together contribute to the risk of testicular cancer.


Subject(s)
Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Male , Humans , Testicular Neoplasms/genetics , Testicular Neoplasms/pathology , Genetic Predisposition to Disease , Genome-Wide Association Study , Exome Sequencing , Case-Control Studies , Neoplasms, Germ Cell and Embryonal/genetics , Germ Cells/pathology
3.
Biochem Biophys Res Commun ; 680: 51-60, 2023 11 05.
Article in English | MEDLINE | ID: mdl-37717341

ABSTRACT

Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has made significant success in treating hematological malignancies, paving the way for solid tumors like prostate cancer. However, progress is impeded by a paucity of suitable target antigens. A novel carbohydrate antigen, F77, is expressed on both androgen-dependent and androgen-independent prostate cancer cells, making it a potential immunotherapy target. This study entails the generation and evaluation of a second-generation CAR against a carbohydrate antigen on malignant prostate cancer cells. Using a single chain fragment variable (scFv) from an F77-specific mouse monoclonal antibody, we created second-generation CARs with CD28 and CD137 (4-1BB) costimulatory signals. F77 expressing lentiviral CAR T cells produce cytokines and kill tumor cells in a F77 expression-dependent manner. These F77-specific CAR T cells eradicate prostate tumors in a human xenograft model employing PC3 cells. These findings validate F77 as a promising immunotherapeutic target for prostate cancer and other malignancies with this aberrant carbohydrate structure.


Subject(s)
Androgens , Prostatic Neoplasms , Male , Animals , Mice , Humans , Cell Line, Tumor , Prostatic Neoplasms/pathology , Immunotherapy, Adoptive , Carbohydrates , Cell- and Tissue-Based Therapy , Receptors, Antigen, T-Cell/genetics , Xenograft Model Antitumor Assays
5.
Int J Mol Sci ; 24(7)2023 Mar 30.
Article in English | MEDLINE | ID: mdl-37047449

ABSTRACT

Our laboratory has identified and developed a unique human-engineered domain (HED) structure that was obtained from the human Alpha-2-macroglobulin receptor-associated protein based on the three-dimensional structure of the Z-domain derived from Staphylococcal protein A. This HED retains µM binding activity to the human IgG1CH2-CH3 elbow region. We determined the crystal structure of HED in association with IgG1's Fc. This demonstrated that HED preserves the same three-bundle helix structure and Fc-interacting residues as the Z domain. HED was fused to the single chain variable fragment (scFv) of mAb 4D5 to produce an antibody-like protein capable of interacting with the p185Her2/neu ectodomain and the Fc of IgG. When further fused with murine IFN-γ (mIFN-γ) at the carboxy terminus, the novel species exhibited antitumor efficacy in vivo in a mouse model of human breast cancer. The HED is a novel platform for the therapeutic utilization of engineered proteins to alleviate human disease.


Subject(s)
Breast Neoplasms , Single-Chain Antibodies , Humans , Animals , Mice , Female , Single-Chain Antibodies/genetics , Staphylococcal Protein A/chemistry
6.
Biochem Biophys Res Commun ; 651: 39-46, 2023 04 09.
Article in English | MEDLINE | ID: mdl-36791497

ABSTRACT

Mutations in the epidermal growth factor receptor (EGFR) have been found in more than 10% of non-small cell lung cancer (NSCLC) patients in North America. The vast majority of these differences are L858R point mutations in Exon 21. Currently, monoclonal antibodies directed against the extracellular domain of EGFR or small molecule/tyrosine kinase inhibitors (TKI) are the stalwarts of NSCLC therapy. Resistance, however, gradually develops because of the T790 mutation towards first and second generation TKIs. The third generation TKI AZD9291 (Osimertinib) has a high affinity for both activating and the acquired resistant mutation (T790 M) in EGFR, with a low affinity towards wild-type EGFR. Recent research, however, suggests that the EGFR (C797S) mutation in the tyrosine kinase domain is a likely cause of resistance to AZD9291. Another significant transformation mechanism associated with this resistance is erbB2 amplification. Our laboratory has developed a small kinase inhibitor, ER121 (MW: ∼500), that inhibits the erbB2/HER2 tyrosine kinases in addition to the EGFR C797S mutations. We have identified a TKI, ER121 targeting the mutant EGFR(T790 M). Using in vitro and in vivo models, examined the efficacy of ER121 on mutant EGFR cell lines. This has enabled us to establish that ER121 is well tolerated when administered orally and produces significant inhibitory activity against human cancers generated by mutant EGFR and amplified ErbB2.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Female , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Protein Kinase Inhibitors/therapeutic use , Lung Neoplasms/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Antineoplastic Agents/therapeutic use , Mutation , Receptor, ErbB-2/genetics , ErbB Receptors/genetics , ErbB Receptors/pharmacology
7.
J Thromb Haemost ; 21(3): 652-666, 2023 03.
Article in English | MEDLINE | ID: mdl-36696211

ABSTRACT

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a serious thrombotic disorder caused by ultralarge immune complexes (ULICs) containing platelet factor 4 (PF4) and heparin that form the HIT antigen, together with a subset of anti-PF4 antibodies. ULICs initiate prothrombotic responses by engaging Fcγ receptors on platelets, neutrophils, and monocytes. Contemporary anti-thrombotic therapy for HIT is neither entirely safe nor entirely successful and acts downstream of ULIC formation and Fcγ receptor-initiated generation of thrombin. OBJECTIVES: To determine whether HIT antigen and ULIC formation and stability could be modified favorably by inhibiting PF4-heparin interactions with fondaparinux, together with blocking formation of PF4 tetramers using a humanized monoclonal anti-PF4 antibody (hRTO). METHODS: Results: The combination of fondaparinux and hRTO inhibited HIT antigen formation, promoted antigen dissociation, inhibited ULIC formation, and promoted ULIC disassembly at concentrations below the effective concentration of either alone and blocked Fcγ receptor-dependent induction of factor Xa activity by monocytic THP1 cells and activation of human platelets in whole blood. Combined with hRTO, fondaparinux inhibited HIT antigen and immune complex formation and activation through Fcγ receptors at concentrations at or below those used clinically to inhibit FXa coagulant activity. CONCLUSIONS: HIT antigen and immune complexes are dynamic and amenable to modulation. Fondaparinux can be converted from an anticoagulant that acts at a downstream amplification step into a rationale, disease-specific intervention that blocks ULIC formation. Interventions that prevent ULIC formation and stability might increase the efficacy, permit use of lower doses, shorten the duration of antithrombotic therapy, and help prevent this serious thrombotic disorder.


Subject(s)
Thrombocytopenia , Thrombosis , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Anticoagulants/adverse effects , Antigen-Antibody Complex , Fondaparinux/adverse effects , Heparin/adverse effects , Platelet Factor 4 , Receptors, IgG , Thrombosis/etiology
9.
Cancer Epidemiol Biomarkers Prev ; 31(9): 1769-1779, 2022 09 02.
Article in English | MEDLINE | ID: mdl-35700037

ABSTRACT

BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. METHODS: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. IMPACT: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.


Subject(s)
Neoplasms, Germ Cell and Embryonal , Seminoma , Testicular Neoplasms , DNA Methylation , Folic Acid , Genome-Wide Association Study , Humans , Male , Neoplasms, Germ Cell and Embryonal/genetics , Polymorphism, Single Nucleotide , Seminoma/genetics , Seminoma/metabolism , Seminoma/pathology , Testicular Neoplasms/genetics
10.
J Immunother Cancer ; 10(6)2022 06.
Article in English | MEDLINE | ID: mdl-35710296

ABSTRACT

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor. METHODS: BALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot. RESULTS: HER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75-80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways. CONCLUSIONS: HER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.


Subject(s)
Breast Neoplasms , Carcinoma , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , CD8-Positive T-Lymphocytes , Dendritic Cells , Female , Humans , Mice , Receptor, ErbB-2
11.
Soc Sci Med ; 301: 114905, 2022 05.
Article in English | MEDLINE | ID: mdl-35367908

ABSTRACT

INTRODUCTION: Experiences of illness change the physical body and embodiments, or the ways in which the world and the self are known through the body. When illness is anticipated, such as with inherited cancer predisposition syndromes, risk becomes embodied and shared in family groups. Embodied risk is experienced whether or not symptoms have manifested. To examine how individuals and families with genetic risk experience the world and understand their disease through their bodies, we employ Li-Fraumeni syndrome (LFS) as an exemplar. LFS is a rare, genetic, cancer predisposition syndrome with nearly 100% lifetime cancer risk starting from birth, limited opportunities for prevention, rigorous screening protocols, and early mortality. METHODS: Forty-five families, including 117 individuals aged 13-81 years, enrolled in the National Cancer Insitute's LFS study (NCT01443468) completed 66 open-ended interviews regarding LFS experiences. An interdisciplinary team used modified grounded theory to explore physical aspects of living with LFS in psychosocial contexts. FINDINGS: The physicality of living with LFS included constant monitoring of LFS bodies across the family to identify physical change that might indicate carcinogenesis. Cancer screening, risk reduction, and treatment acted as dually protective and invasive, and as an unavoidable features of LFS. Connections between family members with similar embodiments normalized aesthetic changes and supported coping with visible markers of difference. In some circumstances, participants objectified the body to preserve the self and important relationships. In others, intense pain or loss created thresholds beyond which the self could no longer be separated from the body to support coping. DISCUSSION: This paper focuses on Li-Fraumeni syndrome, a familial condition with a well-established genetic identity in which the body-self is experienced in relation to important others, to medical imaging, and to historical experiences with cancer. We expand on theories of embodied risk and inter-embodiment to describe experiences across disease trajectories, with attention to division and union between body, self, and other.


Subject(s)
Li-Fraumeni Syndrome , Early Detection of Cancer , Electricity , Family , Genetic Predisposition to Disease , Humans , Li-Fraumeni Syndrome/complications , Li-Fraumeni Syndrome/diagnosis , Li-Fraumeni Syndrome/genetics
12.
Am J Obstet Gynecol ; 227(1): 61.e1-61.e18, 2022 07.
Article in English | MEDLINE | ID: mdl-35216968

ABSTRACT

BACKGROUND: Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. OBJECTIVE: We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. STUDY DESIGN: Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. RESULTS: Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones. CONCLUSION: Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.


Subject(s)
Ovarian Neoplasms , Salpingo-oophorectomy , Estradiol , Female , Gonadal Steroid Hormones , Humans , Ovarian Neoplasms/prevention & control , Postmenopause , Prospective Studies
13.
J Clin Oncol ; 40(14): 1529-1541, 2022 05 10.
Article in English | MEDLINE | ID: mdl-35077220

ABSTRACT

PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.


Subject(s)
Breast Neoplasms, Male , Breast Neoplasms , Ovarian Neoplasms , Pancreatic Neoplasms , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Infant, Newborn , Male , Mutation , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/genetics , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/genetics , Risk
14.
Genet Med ; 24(1): 119-129, 2022 01.
Article in English | MEDLINE | ID: mdl-34906479

ABSTRACT

PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.


Subject(s)
Breast Neoplasms , Ovarian Neoplasms , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Genes, BRCA1 , Genes, BRCA2 , Genetic Predisposition to Disease , Genetic Testing/methods , Germ-Line Mutation/genetics , Humans , Middle Aged , Ovarian Neoplasms/genetics
15.
Article in English | MEDLINE | ID: mdl-34964002

ABSTRACT

PURPOSE: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete. MATERIALS AND METHODS: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases. RESULTS: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant. CONCLUSION: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.


Subject(s)
Urinary Bladder Neoplasms/genetics , Aged , Female , Genetic Predisposition to Disease/epidemiology , Genetic Testing/methods , Genetic Testing/statistics & numerical data , Humans , Male , Middle Aged , Risk Factors , Urinary Bladder Neoplasms/epidemiology , Exome Sequencing/methods , Exome Sequencing/statistics & numerical data
16.
Front Immunol ; 12: 750542, 2021.
Article in English | MEDLINE | ID: mdl-34675933

ABSTRACT

T regulatory cells suppress a variety of immune responses to self-antigens and play a role in peripheral tolerance maintenance by limiting autoimmune disorders, and other pathological immune responses such as limiting immune reactivity to oncoprotein encoded antigens. Forkhead box P3 (FOXP3) expression is required for Treg stability and affects functional activity. Mutations in the master regulator FOXP3 and related components have been linked to autoimmune diseases in humans, such as IPEX, and a scurfy-like phenotype in mice. Several lines of evidence indicate that Treg use a variety of immunosuppressive mechanisms to limit an immune response by targeting effector cells, including secretion of immunoregulatory cytokines, granzyme/perforin-mediated cell cytolysis, metabolic perturbation, directing the maturation and function of antigen-presenting cells (APC) and secretion of extracellular vesicles for the development of immunological tolerance. In this review, several regulatory mechanisms have been highlighted and discussed.


Subject(s)
T-Lymphocytes, Regulatory/immunology , Animals , Forkhead Transcription Factors/immunology , Humans
17.
Article in English | MEDLINE | ID: mdl-34703307

ABSTRACT

Breast cancer is a highly prevalent malignancy that shows improved outcomes with earlier diagnosis. Current screening and monitoring methods have improved survival rates, but the limitations of these approaches have led to the investigation of biomarker evaluation to improve early diagnosis and treatment monitoring. The enzyme-linked immunosorbent assay (ELISA) is a specific and robust technique ideally suited for the quantification of protein biomarkers from blood or its constituents. The continued clinical relevancy of this assay format will require overcoming specific technical challenges, including the ultra-sensitive detection of trace biomarkers and the circumventing of potential assay interference due to the expanding use of monoclonal antibody (mAb) therapeutics. Approaches to increasing the sensitivity of ELISA have been numerous and include employing more sensitive substrates, combining ELISA with the polymerase chain reaction (PCR), and incorporating nanoparticles as shuttles for detection antibodies and enzymes. These modifications have resulted in substantial boosts in the ability to detect extremely low levels of protein biomarkers, with some systems reliably detecting antigen at sub-femtomolar concentrations. Extensive utilization of mAb therapies in oncology has presented an additional contemporary challenge for ELISA, particularly when both therapeutic and assay antibodies target the same protein antigen. Resolution of issues such as epitope overlap and steric hindrance requires a rational approach to the design of diagnostic antibodies that takes advantage of modern antibody generation pipelines, epitope binning techniques and computational methods to strategically target biomarker epitopes. This review discusses technical strategies in ELISA implemented to date and their feasibility to address current constraints on sensitivity and problems with interference in the clinical setting. The impact of these recent advancements will depend upon their transformation from research laboratory protocols into facile, reliable detection systems that can ideally be replicated in point-of-care devices to maximize utilization and transform both the diagnostic and therapeutic monitoring landscape.

18.
Health Soc Work ; 46(4): 299-307, 2021 Nov 16.
Article in English | MEDLINE | ID: mdl-34618014

ABSTRACT

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome in which individuals have a significantly increased risk of developing multiple cancers throughout the life span. An LFS diagnosis may shift the individual's sense of self and tolerance of cancer risk as they engage in cancer screening and cancer prevention activities. This study examined the impact of family identity on health decision making, communication, and role function. Forty-five families completed one or more interviews during an annual, protocol-specific cancer screening study. An interdisciplinary team analyzed 66 interviews using interpretive description and modified grounding theory. Thematically, identity emerged as an evolving construct regarding self and/or family, embedded in historical and ongoing experiences with LFS. Notions of individual and shared family identities guided decision making related to healthcare and influenced interpersonal communication and role function between supportive networks and families. Alignment between individual, family, and generational identities may shape engagement in genetic testing, risk management, and family life. Medical teams that are unequipped to address the psychosocial challenges that LFS populations face may include mental health professionals on interprofessional care teams to navigate risk management and consequential familial conflict.


Subject(s)
Li-Fraumeni Syndrome , Early Detection of Cancer , Health Personnel , Humans , Li-Fraumeni Syndrome/genetics , Mass Screening
19.
Antibodies (Basel) ; 10(3)2021 Aug 16.
Article in English | MEDLINE | ID: mdl-34449551

ABSTRACT

The lack of progress in developing targeted therapeutics directed at protein-protein complexes has been due to the absence of well-defined ligand-binding pockets and the extensive intermolecular contacts at the protein-protein interface. Our laboratory has developed approaches to dissect protein-protein complexes focusing on the superfamilies of erbB and tumor necrosis factor (TNF) receptors by the combined use of structural biology and computational biology to facilitate small molecule development. We present a perspective on the development and application of peptide inhibitors as well as immunoadhesins to cell surface receptors performed in our laboratory.

20.
Article in English | MEDLINE | ID: mdl-34262338

ABSTRACT

INTRODUCTION: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triple-negative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA. METHODS: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively. RESULTS: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model. CONCLUSION: Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.

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