bluuebunny/crossref_metadata_2025 huggingface dataset:
Perinucleolar Compartment Prevalence Has an Independent Prognostic Value for Breast Cancer
Authors: Kamath Rajesh V. , Thor Ann D. , Wang Chen , Edgerton Susan M. , Slusarczyk Alicja , Leary D.J. , Wang J. , Wiley E.L. , Jovanovic B. , Wu Q. , Nayar R. , Kovarik P. , Shi F. , Huang Sui
Published: June 2022

The perinucleolar compartment (PNC) is a multicomponent nuclear structure enriched with RNAs transcribed by RNA pol III and RNA binding proteins. Studies in cultured cells showed an association between PNC and transformed phenotype. To evaluate the relationship between structure and malignancy in vivo, we examined PNC prevalence (the percentage of cells containing at least one PNC) in normal and cancerous paraffin-embedded breast tissues using immunohistochemistry against a PNC-associated protein. Five hundred nuclei in the most active area of each sample were scored for PNC prevalence. The results show that PNC prevalence significantly correlates with the progression of breast cancer (by the criteria of staging). PNC prevalence in primary tumors, lymph nodes, and distant metastases shows a stepwise increase from a median of 23% in primary tumors to ∼100% in distant metastases. In addition, univariate and multivariate (controlling for tumor size and grade) analyses show that early-stage patients with invasive ductal carcinomas containing a higher PNC prevalence have a significantly poorer prognosis. These findings link PNC prevalence with the progression of breast cancer in vivo and suggest that PNC-containing cells have metastatic advantages. These findings also show the potential of PNC prevalence as a prognostic marker for breast cancer.
Inactivation of Imprinted Genes Induced by Cellular Stress and Tumorigenesis
Authors: Pantoja Cristina , de los Ríos Laura , Matheu Ander , Antequera Francisco , Serrano Manuel
Published: June 2022

Cellular proliferation under stressful conditions may result in permanent genetic and epigenetic changes. Using primary mouse embryonic fibroblasts, we have completed a screening test to identify gene expression changes triggered when cells proliferate under stress. In this manner, we have discovered a novel phenomenon that consists of the rapid and coordinated silencing of genes subject to imprinting, including Cdkn1c, Igf2, H19, Ndn1, Grb10, and Meg3. This generalized silencing of imprinted genes is independent of the stress-responsive tumor suppressors p53, p19Arf, and p16Ink4a, and it is also independent of the oxidative culture conditions and the stress response known as “mouse embryonic fibroblast senescence”. In the case of Cdkn1c and H19, their silencing is associated with unscheduled de novo methylation of the normally expressed allele at their corresponding CpG island promoters, thus resulting in biallelic methylation. Finally, we provide evidence for frequent de novo methylation of Cdkn1c in a variety of murine cancer types. Altogether, our data support the concept that silencing of imprinted genes, including methylation of Cdkn1c, constitutes an epigenetic signature of cellular stress and tumorigenesis.
Oncogenic Transformation of Human Mammary Epithelial Cells by Autocrine Human Growth Hormone
Authors: Zhu Tao , Starling-Emerald B. , Zhang Xin , Lee Kok-Onn , Gluckman Peter D. , Mertani Hichem C. , Lobie Peter E.
Published: June 2022

The human growth hormone (hGH) gene is expressed in the normal human mammary epithelial cell and its expression increases concomitant with the acquisition of proliferative lesions. Herein we demonstrate that autocrine production of hGH in human mammary carcinoma cells dramatically enhances anchorage-independent growth in a Janus kinase 2–dependent manner. Forced expression of the hGH gene in immortalized human mammary epithelial cells increased proliferation, decreased apoptosis, altered the cellular morphology and resulted in oncogenic transformation. Autocrine hGH was therefore sufficient to support anchorage-independent growth of immortalized human mammary epithelial cells and tumor formation in vivo. Moreover, autocrine hGH disrupted normal mammary acinar architecture with luminal filling and deregulated proliferation in three-dimensional epithelial cell culture. Autocrine hGH utilized homeobox A1 to govern the transcriptional program required for autocrine hGH–stimulated oncogenic transformation of human mammary epithelial cells, including transcriptional up-regulation of c-Myc, cyclin D1, and Bcl-2. Forced expression of a single orthotopically expressed wild-type gene is therefore sufficient for oncogenic transformation of the immortalized human mammary epithelial cell.
Cell Cycle Checkpoints, DNA Damage/Repair, and Lung Cancer Risk
Authors: Wu Xifeng , Roth Jack A. , Zhao Hua , Luo Sherry , Zheng Yun-Ling , Chiang Silvia , Spitz Margaret R.
Published: June 2022

Given that defects in cell cycle control and DNA repair capacity may contribute to tumorigenesis, we hypothesized that patients with lung cancer would be more likely than healthy controls to exhibit deficiencies in cell cycle checkpoints and/or DNA repair capacity as gauged by cellular response to in vitro carcinogen exposure. In an ongoing case-control study of 155 patients with newly diagnosed lung cancer and 153 healthy controls, we used the comet assay to investigate the roles of cell cycle checkpoints and DNA damage/repair capability in lung tumorigenesis. The median γ-radiation-induced and benzo(a)pyrene diol epoxide–induced Olive tail moments, the comet assay parameter for measuring DNA damage, were significantly higher in the case group (5.31 and 4.22, respectively) than in the control group (4.42 and 2.83, respectively; P < 0.001). Higher tail moments of γ-radiation and benzo(a)pyrene diol epoxide–induced comets were significantly associated with 2.32- and 4.49-fold elevated risks, respectively, of lung cancer. The median γ-radiation-induced increases of cells in the S and G2 phases were significantly lower in cases (22.2% and 12.2%, respectively) than in controls (31.1% and 14.9%, respectively; P < 0.001). Shorter durations of the S and G2 phases resulted in 4.54- and 1.85-fold increased risks, respectively, of lung cancer. Also observed were joint effects between γ-radiation-induced increases of S and G2 phase frequencies and mutagen-induced comets. In addition, we found that in controls, the S phase decreased as tail moment increased. This study is significant because it provides the first molecular epidemiologic evidence linking defects in cell cycle checkpoints and DNA damage/repair capacity to elevated lung cancer risk.
Characterization of γ-Aminobutyric Acid Type A Receptor–Associated Protein, a Novel Tumor Suppressor, Showing Reduced Expression in Breast Cancer
Authors: Klebig Christiane , Seitz Susanne , Arnold Wolfgang , Deutschmann Nicole , Pacyna-Gengelbach Manuela , Scherneck Siegfried , Petersen Iver
Published: June 2022

Frequent allelic loss of the chromosomal region 17p13 in breast cancer has suggested that more tumor suppressor genes, besides p53, are located in this region. By doing suppression subtractive hybridization to detect differentially expressed genes between the breast cancer cell line CAL51 and a nontumorigenic microcell hybrid CAL/17-1, we identified the gene for the γ-aminobutyric acid type A (GABAA) receptor associated protein (GABARAP), located on 17p13.1. GABARAP displayed high expression levels in the microcell hybrid CAL/17-1 but only weak expression in CAL51 and other breast cancer cell lines tested. Furthermore, we observed large vesicles in CAL/17-1 by immunofluorescence staining, whereas no signal could be detected in the tumor cell line. GABARAP mRNA expression and protein expression were significantly down-regulated in invasive ductal and invasive lobular carcinomas compared with normal breast tissue measured by semiquantitative reverse transcription–PCR and immunohistochemistry, respectively. We assessed that neither mutations in the coding region of the gene nor hypermethylation of CpG islands in the promoter region are responsible for loss of gene expression in CAL51; however, 5-aza-2′-deoxycytidine treatment was effective in gene up-regulation, suggesting a methylation-dependent upstream effect. Stable transfection of GABARAP into CAL51 resulted in an increase of gene expression and remarkably influenced the ability of colony formation in soft agar and the growth rate in vitro and, moreover, suppressed the tumorigenicity of the cells in nude mice. In summary, our data suggest that GABARAP acts via a vesicle transport mechanism as a tumor suppressor in breast cancer.
Bone Morphogenic Proteins Are Overexpressed in Malignant Melanoma and Promote Cell Invasion and Migration
Authors: Rothhammer Tanja , Poser Ina , Soncin Fabrice , Bataille Frauke , Moser Markus , Bosserhoff Anja-Katrin
Published: June 2022

Malignant melanoma cells are known to have altered expression of growth factors compared with normal human melanocytes. These changes probably favor tumor growth and progression and influence the tumor environment. The induction of transforming growth factor β1 (TGF-β1), TGF-β2, and TGF-β3 expression in malignant melanoma has been reported before, whereas the expression of related bone morphogenic protein (BMP) molecules has not been analyzed in melanomas until now. Here, we show that BMP4 and BMP7 are up-regulated in nine melanoma cell lines, whereas BMP2 is overexpressed in only two of the analyzed cell lines. Immunohistochemistry of primary and metastatic melanoma also shows increased BMP4 and BMP7 expression compared with nevi. Promoter studies reveal that expression is controlled at the transcriptional level. The transcription factor Ets-1 was identified as a positive regulator for BMP4 expression. In order to determine the functional relevance of BMP expression in malignant melanoma, chordin-expressing cell clones and antisense BMP4 cell clones were generated. The clones in which BMP4 activity and expression are reduced show no changes in proliferation or in attachment-independent growth when compared with controls. However, a strong reduction of migratory and invasive properties was observed in these cells, suggesting that BMP4 promotes melanoma cell invasion and migration and therefore has an important role in the progression of malignant melanoma.
A Functional Common Polymorphism in a Sp1 Recognition Site of the Epidermal Growth Factor Receptor Gene Promoter
Authors: Liu Wanqing , Innocenti Federico , Wu Michael H. , Desai Apurva A. , Dolan M. Eileen , Cook Edwin H. , Ratain Mark J.
Published: June 2022

The epidermal growth factor receptor (EGFR) plays a prominent role in cell growth and development. Its regulation in humans is complex and incompletely understood. In this study, 12 new polymorphisms were discovered in the 5′-regulatory region of EGFR gene and 2 common single nucleotide polymorphisms (−216G/T and −191C/A) were found in the essential promoter area, one of which is located in a Sp1 recognition site (−216). Transient transfection in human cancer and primary cell lines showed significantly different promoter activity between the two most common haplotypes (−216G-191C and −216T-191C). The replacement of G by T at position −216 increases the promoter activity by 30%. A transient transfection assay in the Sp1-deficient cell line (Schneider cell line 2) showed a strong dependence of EGFR promoter activity on Sp1 and confirmed the effect of the aforementioned polymorphisms. Electrophoretic mobility shift assay also showed a significantly higher binding efficiency of nuclear protein or pure Sp1 protein to the T allele compared with the G allele. We then investigated the allelic imbalance of EGFR transcription in fibroblast cell lines with heterozygous genotype at −216G/T but C/C homozygous genotype at −191C/A. The expression of mRNA carrying T-C haplotype was significantly stronger compared with that of G-C haplotype (P < 0.02). Thus, we successfully showed that a common polymorphism in the EGFR promoter was associated with altered promoter activity and gene expression both in vitro and in vivo. Our findings have implications for cancer etiology and therapy and may also be relevant to the inherited susceptibility of other common diseases.
Calcium Sensing Receptor in Human Colon Carcinoma: Interaction with Ca2+ and 1,25-Dihydroxyvitamin D3
Authors: Chakrabarty Subhas , Wang Hongmei , Canaff Lucie , Hendy Geoffrey N. , Appelman Henry , Varani James
Published: June 2022

Recent studies show that the human parathyroid calcium sensing receptor (CaSR) is expressed in human colon epithelium and functions to regulate epithelial proliferation and differentiation. In this study, we show that the cells of the colon crypt acquire CaSR expression as they differentiate and migrate towards the apex of the crypt. CaSR expression was weak in colon carcinomas with a more-differentiated histologic pattern, whereas CaSR expression was undetectable in less-differentiated tumors. We found that Ca2+ and/or 1,25(OH)2D3 stimulated CaSR promoter activity and CaSR protein expression in the human colon carcinoma CBS cells, which possessed a functional CaSR. Both agents concomitantly induced a series of changes in the CBS cells that influence proliferation and differentiation, but cellular responses to the two agents were not identical. Ca2+ strongly induced E-cadherin expression and inhibited the expression of the nuclear transcription factor, TCF4. 1,25(OH)2D3 was weaker in its effect on E-cadherin and was not able to inhibit TCF4 expression. 1,25(OH)2D3 was as strong or stronger than Ca2+ in its induction of the cyclin-dependent kinase inhibitors, P21 and p27. It is concluded that CaSR may function in the colon to regulate epithelial differentiation and that loss of CaSR expression may be associated with abnormal differentiation and/or malignant progression. Extracellular Ca2+ and 1,25(OH)2D3 are potential candidates involved in regulating CaSR expression in the colon and the chemopreventive actions of Ca2+ and 1,25(OH)2D3 in colon cancer may be mediated, in part, through the CaSR.
Polymorphisms in DNA Base Excision Repair Genes ADPRT and XRCC1 and Risk of Lung Cancer
Authors: Zhang Xuemei , Miao Xiaoping , Liang Gang , Hao Bingtao , Wang Yonggang , Tan Wen , Li Yi , Guo Yongli , He Fuchu , Wei Qingyi , Lin Dongxin
Published: June 2022

Adenosine diphosphate ribosyl transferase (ADPRT) and X-ray repair cross-complementing 1 (XRCC1) are two major DNA base excision repair (BER) proteins and act interactively in stimulating and executing BER processes. Polymorphisms of ADPRT Val762Ala and XRCC1 Arg399Gln have been associated with altered protein function and BER activity. This case-control study examined the contribution of these two polymorphisms, alone and in combination, or in interaction with smoking, to the risk of developing lung cancer. We estimated the risk of lung cancer associated with these polymorphisms in 1,000 cases and 1,000 cancer-free controls using logistic regression models. Subjects having the ADPRT Ala/Ala genotype had an odds ratio (OR) of 1.68 [95% confidence interval (95% CI), 1.27-2.23] compared with those having the Val/Val genotype. A greater than multiplicative joint effect between the ADPRT polymorphism and smoking was observed. The ORs (95% CI) of the Ala/Ala genotype for nonsmokers and smokers who smoked ≤16, 16 to 28, or >28 pack-years were 1.13 (0.79-1.62), 1.35 (0.68-2.70), 2.46 (1.35-4.51) or 17.09 (8.15-35.83), respectively (P trend test < 0.001). Gene-gene interaction of ADPRT and XRCC1 polymorphisms increased risk of lung cancer in a supermultiplicative manner (OR for the presence of both ADPRT 762Ala/Ala and XRCC1 399Gln/Gln genotypes, 5.91; 95% CI, 2.09-16.72), although the XRCC1 polymorphism itself was not associated with the risk. In conclusion, the ADPRT Val762Ala polymorphism plays an important role in smoking-related lung cancer and the XRCC1 Arg399Gln polymorphism may serve as a risk modifier.
Premature Senescence Is a Primary Fail-safe Mechanism of ERBB2-Driven Tumorigenesis in Breast Carcinoma Cells
Authors: Trost Tatjana M. , Lausch Ekkehart U. , Fees Stephan A. , Schmitt Steffen , Enklaar Thorsten , Reutzel Dirk , Brixel Lili R. , Schmidtke Peter , Maringer Marko , Schiffer Ilka B. , Heimerdinger Carolin K. , Hengstler Jan G. , Fritz Gerhard , Bockamp Ernst O. , Prawitt Dirk , Zabel Bernhard U. , Spangenberg Christian
Published: June 2022

The receptor tyrosine kinase ERBB2 plays a central role in the development of breast cancer and other epithelial malignancies. Elevated ERBB2 activity is believed to transform cells by transmitting mitogenic and antiapoptotic signals. Here we show that tightly regulated overexpression of oncogenic ERBB2 in human breast carcinoma cells does not stimulate proliferation but provokes premature senescence, accompanied by up-regulation of the cyclin-dependent kinase inhibitor P21WAF1/CIP1. A similar effect was caused by retrovirus-mediated overexpression of oncogenic ERBB2 in low-passage murine embryonic fibroblasts. In contrast to previous observations based on constitutively overexpressing cell lines, P21 induced by tetracycline-regulated ERBB2 localizes to the nucleus in arrested cells. P21 up-regulation seems to be independent of the P53 tumor suppressor protein, and senescence-associated phenotypic alterations are reversed by specific inhibition of P38 mitogen-activated protein kinases. Functional inactivation of P21 by antisense oligonucleotides is sufficient to prevent cell cycle arrest as well as the senescent phenotype, thereby identifying the P21 protein as the key mediator of hypermitogenic cell cycle arrest and premature senescence in breast carcinoma cells. Our results may thus indicate that premature senescence represents an inherent anticarcinogenic program during ERBB2-driven mammary tumorigenesis. We propose a multistep model for the process of malignant transformation by ERBB2 wherein secondary lesions either target P21 or downstream effectors of senescence to bypass this primary fail-safe mechanism.
Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species
Authors: Laurent Alexis , Nicco Carole , Chéreau Christiane , Goulvestre Claire , Alexandre Jérôme , Alves Arnaud , Lévy Eva , Goldwasser Francois , Panis Yves , Soubrane Olivier , Weill Bernard , Batteux Frédéric
Published: June 2022

Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H2O2), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H2O2 is controlled by catalase. N-acetylcysteine, which decreases H2O2 levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H2O2 concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H2O2 levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.
Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank
Authors: Atkins Janice L. , Pilling Luke C. , Torti Suzy V. , Torti Frank M. , Kuchel George A. , Melzer David
Published: June 2022

Background:

In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence, but risks for other cancers in male and female homozygotes are unclear.

Methods:

451,143 UK Biobank European ancestry participants (aged 40–70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than nonmelanoma and liver cancer) and common incident cancers [bladder, blood (with subanalyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, esophageal, ovarian, pancreatic, prostate and stomach] in those with p.C282Y and p.H63D genotypes, compared with participants without HFE mutations.

Results:

Male p.C282Y homozygotes (n = 2,890, 12.1% with baseline diagnosed hereditary hemochromatosis) had increased incidence of prostate cancer [6.8% vs. 5.4% without mutations; HR = 1.32; 95% confidence interval (CI), 1.07–1.63; P = 0.01; Bonferroni adjusted P = 0.17] during follow-up. In life table estimates from ages 40 to 75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%; 95% CI, 1.3–6.8). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex.

Conclusions:

In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (nonliver) cancers.

Impact:

Replication of results in other large community genotyped cohorts are needed to confirm if clinical monitoring for prostate cancer is necessary in p.C282Y homozygous males.
Abstract 6295: Grape seed procyanidins inhibit cell proliferation & induce apoptosis in both human breast & liver cancer cell lines
Authors: Alneanaey Rana Hamed , Taha Nabil , Lebda Mohammed , Hashem Aml , Sultan Ahmed
Published: June 2022

As a potential anticancer agent, grape seed procyanidins (GSPs) have been shown to be effective in treating and preventing various cancer types, but the mechanistic inhibitory effect at cellular and molecular levels in most of the cancer types remains unclear. The objective of the present study was to investigate the potential influence of GSPs on both liver and breast cancers. The anticancer efficacy of GSPs was investigated in vitro, using two human cancer cell lines; human hepatocellular carcinoma (HepG2) and human breast carcinoma, Zr-75-1.The potential influence of extracted GSPs was examined on cell proliferation, clonogenic assays, morphological alteration, and western blot was used to analyze the expression of oncogenic signaling pathways of STAT3, β-catenin, T-ERK, and pERK, Bax, Bcl-2, mutant-p53, and caspase enzyme activity assay was measured by caspase colorimetric assay.Our data showed that GSPs treatment inhibits both cellular viability and proliferation in a concentration-and time-dependent fashion in both breast and liver cancer cell lines after 48h. Furthermore, mechanistic studies showed that GSPs induced late apoptosis by 72% that was associated with cell morphological changes, histone release from fragmented DNA, caspase-3 activation in a dose-dependent manner after 48h. Furthermore, GSPs down-regulated pERK, STAT3, β-catenin, and mutant p53 levels as well as increased p21and Bax, pro-apoptotic signal, in both breast and liver cancer cells as determined by western blot analysis. All in all, our findings suggest that GSPs inhibit breast and liver cancer cells proliferation and induce cell apoptosis by suppressing the oncogenic signaling pathways that play a role in cancer progression which in turn introduce GSPs as a promising phytochemical for cancer treatment.

Citation Format: Rana Hamed Alneanaey, Nabil Taha, Mohammed Lebda, Aml Hashem, Ahmed Sultan. Grape seed procyanidins inhibit cell proliferation & induce apoptosis in both human breast & liver cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6295.
Abstract SY11-02: Long-read sequencing reveals complex patterns of wraparound transcription in polyomaviruses
Authors: DeCaprio James A. , Nomburg Jason , Meyerson Matthew
Published: June 2022

Polyomaviruses (PyV) are ubiquitous pathogens that can cause devastating human diseases. Due to the small size of their genomes, PyV utilize complex patterns of RNA splicing to maximize their coding capacity. Despite the importance of PyV to human disease, their transcriptome architecture is poorly characterized. Here, we compare short- and long-read RNA sequencing data from eight human and non-human PyV. We provide a detailed transcriptome atlas for BK polyomavirus (BKPyV), an important human pathogen, and the prototype PyV, simian virus 40 (SV40). We identify pervasive wraparound transcription in PyV, wherein transcription runs through the polyA site and circles the genome multiple times. Comparative analyses identify novel, conserved transcripts that increase PyV coding capacity. One of these conserved transcripts encodes superT, a T antigen containing two RB-binding LxCxE motifs. We find that superT-encoding transcripts are abundant in PyV-associated human cancers. Together, we show that comparative transcriptomic approaches can greatly expand known transcript and coding capacity in one of the simplest and most well-studied viral families.

Citation Format: James A. DeCaprio, Jason Nomburg, Matthew Meyerson. Long-read sequencing reveals complex patterns of wraparound transcription in polyomaviruses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY11-02.
Abstract SY27-03: Using the cancer dependency map
Authors: Hahn William C.
Published: June 2022

Although molecular profiling of human tumors is now routine, the use of this data to guide therapy remains limited to a subset of patients. In particular, pediatric cancers often harbor a signature molecular alteration but few other mutations. To complement genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed both genome scale RNAi and CRISRP-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. These studies now allow us to define a Cancer Dependency Map. Using these datasets and approaches, we have defined new categories of potential cancer targets, identify synthetic lethal candidates in pediatric and adult cancers and have developed a method to systematically identify molecular pleiotropy. These approaches promise to further operationalize precision cancer medicine.

Citation Format: William C. Hahn. Using the cancer dependency map [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY27-03.
Abstract SY41-03: Cancer specific amino acid metabolism
Authors: Maddocks Oliver
Published: June 2022

The growth & proliferation of cancer cells is fundamentally dependent on metabolic processes, and tumours frequently display altered metabolism compared with healthy tissues. To sustain enhanced growth, and to resist stresses associated with cancer treatments, cancer cells become highly dependent on the uptake of exogenous nutrients, particularly amino acids. Amino acid metabolism supports tumour growth and survival in numerous ways, particularly in the provision of anabolic precursors for macromolecule (e.g. protein and DNA) synthesis, as well as stress responsive antioxidant pathways (e.g. glutathione/GSH synthesis). We have shown that uptake of exogenous serine and glycine is key nutrient dependency for many cancer cells, simultaneously supporting THF-dependent one carbon metabolism and GSH synthesis. More recently we have defined a role for immune-regulated IDO1 dependent tryptophan metabolism as an alternative one-carbon source for nucleotide synthesis, underlining the potential flexibility of tumour metabolism. The sensitivity of certain cancer cells to cysteine starvation is well established, and multiple mechanisms contribute to cysteine withdrawal sensitivity, including transsulfuration activity and methylation reactions. We have recently defined a role for methionine driven polyamine metabolism in sensitising cells to cysteine starvation, particularly in the context of MTAP gene deletion. Improved understanding of cancer specific amino acid metabolism is defining genetically driven metabolic vulnerabilities that can be therapeutically exploited by a combination of diet and small molecules.

Citation Format: Oliver Maddocks. Cancer specific amino acid metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY41-03.
A Case of Autosomal Recessive Woolly Hair/Hypotrichosis with Alternation in Severity: Deterioration and Improvement with Age
Authors: Matsuno Naoko , Kunisada Makoto , Kanki Haruhisa , Simomura Yutaka , Nishigori Chikako
Published: June 2022

Autosomal recessive woolly hair/hypotrichosis (ARWH/H) is a nonsyndromic hair abnormality characterized by sparse, short and curly hair (WH/H). We report the case of a 3-year-old female, with no consanguineous ancestry, who exhibited WH/H. Normal hair was observed at birth, but severe hair loss had developed within the first 6 months; however, her hair density had improved somewhat by age 3. Light microscopy showed hair shaft invaginations, and polarized light microscopy suggested complete medullary disruption of the hair. Direct sequence analysis of peripheral blood showed a homozygous missense mutation in exon 6 of the lipase H gene (LIPH: c.736T>A, p.Cys246Ser), and the exact same mutation was found in the heterozygous state in both parents. The initial deterioration followed by improvement with age observed in this case suggests that the clinical course of ARWH/H may vary among patients with the same mutation in LIPH detected in this case, indicating that additional factors may influence the effect of LIPH on hair development.
A Rare Case of Breast Malignancy in an Adolescent Woman: Lessons Learned from Diagnosis and Management
Authors: Fehr Célina Alexandra , Went Philip , Maranta Martina , Cathomas Richard
Published: June 2022

Introduction: Primary breast malignancy in adolescent women is very rare and differs in several aspects from findings in adult women. Case Presentation: A young woman aged 16 years presented with a locally aggressive breast tumor. The patient received cisplatin-based chemotherapy followed by tumor resection assuming a diagnosis of germ cell tumor. Four months later, she developed locally recurrent disease and underwent a mastectomy. No definite diagnosis was agreed upon despite intensive pathological workup. Subsequent management consisted of follow-up only and the patient remains in complete remission 9 years later. Conclusion: This case demonstrates the difficulty of diagnosis and management of rare malignancies in adolescents, and highlights the importance of international and interdisciplinary collaboration in diagnosis and clinical decision-making.
A Review of New-Onset Ventricular Arrhythmia after Left Ventricular Assist Device Implantation
Authors: Shi Jianwei , Yu Xinyi , Liu Zhigang
Published: June 2022

Introduction: Heart failure (HF) is a severe and terminal stage of various heart diseases. Left ventricular assist devices (LVADs) are relatively mature and have contributed to the treatment of end-stage HF. Ventricular arrhythmia (VA) is a common complication after LVAD implantation, including ventricular tachycardia and ventricular fibrillation, both of which may cause abnormal circulation. Methods: A literature search was conducted in the PubMed database, “Ventricular Arrhythmia” OR “VA” OR “Arrhythmia” OR “Ventricular Tachycardia,” OR “Ventricular Fibrillation” AND “LVAD” OR “Left Ventricular Assist Device” OR “Heart Assist Device” as either keywords or MeSH terms, the authors screened the titles and abstracts of the articles. Eventually, 12 original research articles were retrieved. Results: The 0.83 [95% CI: 0.77, 0.89] of patients were male. A whole of 53% [95% CI: 0.25, 0.81] of VA patients had a history of atrial fibrillation and 61% [95% CI: 0.52, 0.69] had a history of VA. 39% [95% CI: 0.29, 0.49] of the participants had no prior history of VA and experienced new VA following CF-LVAD implantation. Following CF-LVAD implantation, 59% [95% CI: 0.51, 0.67] of patients developed early VA (VA ≤30 days). The 30-day mortality rate of patients was 4% [95% CI: 0.01, 0.07]. And overall mortality was 28% [95% CI: 0.15, 0.41]. The reported incidence of VA after LVAD implantation is not identical in different medical centers and ranges from 20% to 60%. The mechanism of VA after LVAD implantation is summarized as primary cardiomyopathy-related, device mechanical stimulation, myocardial scarring, ventricular displacement, electrolyte regulation, and other processes. Conclusions: A preoperative VA history is considered a predictor of VA following LVAD implantation in most studies. Multiple mechanisms and factors, such as prevention of “suction events,” ablation, and implantable cardioverter defibrillator, should be considered for the prevention and treatment of postoperative VA in patients requiring long-term VAD treatment. This study provides a reference for the clinical application of LAVD and the prevention of postoperative VA after LVAD implantation. Future multicenter prospective studies with uniform patient follow-up are needed to screen for additional potential risk factors and predictors. These studies will help to define the incidence rate of VA after LAVD implantation. As a result, we provide guidance for the selection of preventive intervention.
Clinical and Histopathological Features of the Differentiated Type of Early Gastric Cancer with an Unclear Lateral Demarcation
Authors: Nagai Kengo , Hayashi Yoshito , Uema Ryotaro , Inoue Takanori , Kimura Keiichi , Sakatani Akihiko , Yoshii Shunsuke , Tsujii Yoshiki , Shinzaki Shinichiro , Iijima Hideki , Takehara Tetsuo
Published: June 2022

Introduction: Magnifying endoscopy with narrow-band imaging (M-NBI) is useful for determining lateral demarcation of early gastric cancers; however, this is sometimes difficult. Features related to an unclear lateral demarcation remain unknown. We evaluated the clinical and histopathological features of early gastric cancers with unclear lateral demarcation on M-NBI. Methods: This single-center, retrospective, cohort study analyzed early gastric cancer treated by endoscopic submucosal dissection between January 2013 and August 2015. We evaluated the clinicopathological and immunohistochemical features using anti-p53, anti-Ki-67, anti-MUC5AC, anti-MUC6, anti-MUC2, and anti-CD10 antibody staining. We compared the lateral demarcation between the demarcation clear (DC) and the demarcation unclear (DU) lesions by using M-NBI. Results: A total of 224 differentiated adenocarcinomas (DU group: 18 lesions; DC group: 206 lesions) were analyzed. A history of successful Helicobacter pylori eradication was significantly more frequent in the DU group (p = 0.001). We examined the tissues of 72 lesions (DU group: 18 lesions, DC group: 54 lesions [randomly selected]) immunohistochemically. The nonneoplastic superficial epithelium was observed more frequently in the DU group as compared to in the DC group (p = 0.006). Additionally, compared to the DC group, the DU group showed a significantly higher expression of the gastric phenotype markers (p = 0.023) and had lower p53 scores (p < 0.001) and Ki-67 labeling indexes (p = 0.029). Multivariate analysis revealed the nonneoplastic superficial epithelium and a low p53 score as the significant independent variables associated with an unclear lateral demarcation on M-NBI. Conclusions: The nonneoplastic superficial epithelium and a low p53 score were associated with difficulties in determining the lateral demarcation in early gastric cancers on M-NBI.
ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis
Authors: Lu Li-Chun , Deantonio Cecilia , Palu Cintia C. , Lee Yi-Hsuan , Mitchell Laura S. , Cowan Marianne , Corser Matthew , Sherry Lorcan , Cheng Ann-Lii , Quaratino Sonia , Shao Yu-Yun , Sainson Richard C.A. , Hsu Chih-Hung
Published: June 2022

Introduction: Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC). Methods: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed. Results: A total of 142 patients (male:female = 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low α-fetoprotein level (<20 ng/mL) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p < 0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS+Foxp3+ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3− cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p = 0.030), suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teffs. Conclusion: An increased abundance of ICOS+ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC.
Reference Database of Inner Retinal Layer Thickness and Thickness Asymmetry in Healthy Thai Adults as Measured by the Spectralis Spectral-Domain Optical Coherence Tomography
Authors: Choovuthayakorn Janejit , Chokesuwattanaskul Susama , Phinyo Phichayut , Hansapinyo Linda , Pathanapitoon Kessara , Chaikitmongkol Voraporn , Watanachai Nawat , Kunavisarut Paradee , Patikulsila Direk
Published: June 2022

Introduction: The study aimed to determine a reference database of the thickness and intraocular thickness asymmetry of total retina, retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) in healthy Thai subjects measured by the Spectralis spectral-domain optical coherence tomography. Methods: This cross-sectional study recruited the healthy subjects age ≥18 years, having spherical refraction within ±6 diopters and cylindrical refraction ±3 diopters, from a hospital’s personnel and the people visiting the ophthalmology department. Only 1 eye of each subject was randomly selected for an analysis. Macular images were obtained using posterior pole thickness scan protocol over a 24° × 24° area at the center of the fovea. The automated retinal thickness segmentation values of total retina and three inner retinal layers were calculated for the mean and the mean intraocular thickness difference between superior and inferior retinal hemispheres. The influence of age, gender, and axial length on thickness and thickness asymmetry of individualized retinal layer was evaluated. Results: 252 subjects were included in study with a mean (SD) age of 46.7 (15.8) years, and 120 (47.6%) were males. According to the Early Treatment Diabetic Retinopathy Study map, the inner ring area was the thickest location of the total retina (range; 326.0–341.5 µm), GCL (range; 47.7–52.7 µm), and IPL (range; 39.9–42.1 µm), whereas the thickest location of RNFL was at the outer ring area (range; 18.8–47.5 µm). For posterior pole intraocular thickness asymmetry, the greatest mean ± SD difference was observed for total retina (9.0 ± 2.2 µm), followed by RNFL (9.9 ± 3.2 µm) and GCL (2.7 ± 0.6 µm), and the lowest mean difference was noted for IPL (2.4 ± 0.5 µm). The thickness and thickness asymmetry of each retinal layer were variably influenced by age, gender, and axial length; however, these factors had a minimal influence on the thickness asymmetry maps of GCL and RNFL. Conclusion: The reference database of the macular thickness and thickness asymmetry from this study would be beneficial in determining physiologic variations of the OCT parameters in the healthy Thai population.
Expression of Signal Transducer and Activator of Transcription-3 in Androgenetic Alopecia: A Case-Control Study
Authors: Hassan Akmal Saad , Al-dhoun Mohammad Qassim , Shaker Olfat Gamil , AlOrbani Aya M.
Published: June 2022

Background: Signal transducer and activator of transcription (STAT)-3 belongs to a group of latent transcription factors phosphorylated and activated by several protein tyrosine kinases, including members of Janus kinases (JAKs) family. It has been implicated that the JAK-STAT pathway activation could promote quiescence in the hair cycle, and topical treatment of mouse and human skin with JAK inhibitors was shown to result in rapid hair growth. Objective: Our aim was to assess the tissue expression of STAT3 in patients with androgenetic alopecia and correlate it with disease severity and clinical parameters. Methods: Twenty-five androgenetic alopecia patients who served as both cases and controls were included in this study. Full clinical examination was done and tissue STAT3 gene expression was then measured by real-time polymerase chain reaction. Results: Scalp tissue affected by androgenetic alopecia shows significantly higher STAT3 gene expression levels compared to unaffected (androgen independent) areas (p < 0.001), but no statistically significant relation was found between tissue STAT3 expression level and severity of hair loss (p = 0.660). Limitations: Limited sample size. Conclusion: This study demonstrated an upregulation in STAT3 gene expression in androgenetic alopecia. Further studies are needed to assess the possible role of the JAK-STAT pathway in the pathogenesis of androgenetic alopecia.
Expansão da Fronteira Agropecuária e Desmatamento na Região de Alta Floresta/MT: alternativas para o desenvolvimento sustentável.
Authors: Paulo Carla Moura de , Cintra Lydia Minhoto , Cunha Lucas Muzio Vieira , Otta Debora Vendramin , Engelmann Eduardo
Published: June 2022

A fronteira, mais que um limite fixo traçado em um mapa, é um espaço que guarda especificidades e revela-se excepcionalmente dinâmico e contraditório. Historicamente, o avanço da fronteira agropecuária sobre as áreas florestais da Amazônia Legal resulta em destruição da biodiversidade e conflitos agrários. Como consequência direta deste processo está o desmatamento, cuja principal força encontra-se na pecuária. Por isso, é necessário encontrar saídas capazes de colocar um freio na destruição, por meio de iniciativas e atividades econômicas que se reproduzam em uma outra lógica, que não esteja exclusivamente centrada na venda da madeira, na expansão da monocultura e no estímulo à pecuária. Assim, este artigo tem como objetivo apresentar algumas proposições que aliam desenvolvimento econômico e conservação ambiental para a região do município de Alta Floresta, ao norte do estado de Mato Grosso, localizado em área de fronteira agropecuária.
Privações da Vida Cotidiana do Autismo na Cidade: desafios às políticas públicas
Authors: Machado Márcia Francisca Lombo , Ansara Soraia
Published: June 2022

ResumoEste artigo apresenta dados que evidenciam as questões da cidade na correlação de forças para obtenção de políticas públicas para pessoas com autismo. Trazendo parte de uma pesquisa que investigou a relação da vida cotidiana com a participação das famílias dos autistas na tomada de decisões para a democratização dos espaços e serviços, o estudo articula a discussão sobre saúde e intersetorialidade à cidade e à constituição da cidadania. A investigação revelou que a urgência em prover os itens fundamentais ao desenvolvimento dos filhos com autismo se confronta com as discrepâncias do espaço urbano provocando rupturas na vida cotidiana e concorrendo contra a organização coletiva e o engajamento das famílias na gestão de políticas públicas da cidade, limitando a participação política em soluções efetivas às suas demandas. Palavras-chave: participação; políticas públicas; direito à cidade; famílias de autistas; cidadania. AbstractThis paper presents data that highlight the city's issues in the correlation of forces to obtain public policies for people with autism. Bringing part of a research that investigated the relationship of daily life with the participation of autistic families in decision making for the democratization of spaces and services, the study articulates the discussion on health care and “intersectoriality” (in the sense of global vision and cooperation among sectors).to the city and to the constitution of citizenship. The investigation revealed that the urgency to provide the essential items for the development of children with autism is confronted with the discrepancies of the urban space causing ruptures in daily life and competing against the collective organization and the engagement of the families in the management of public policies of the city, restricting the political participation for effective solutions to their demands. Keywords: participation; public policy; right to the city; autistic families; citizenship.   Resumen Este artículo presenta datos  de un estudio que investigó la relación de la vida cotidiana con la participación de familias autistas en la toma de decisiones para la democratización de espacios y servicios destacando los problemas de la ciudad en la correlación de fuerzas para obtener políticas públicas para personas con autismo. De esta manera, el  estudio articula la discusión sobre salud e "intersectorialidad" a la gestión de la ciudad y a la constitución de la ciudadanía. La investigación reveló que la urgencia de proporcionar los elementos esenciales para el desarrollo de niños con autismo se contrapone a las discrepancias del espacio urbano causando rupturas en la vida cotidiana de las familias, creando dificultades para su organización colectiva e intervención en la gestión de las políticas públicas de la ciudad, restringiendo la participación política a soluciones efectivas a sus demandas. Palabras-chave: participación; políticas públicas; derecho a la ciudad; familias de autistas; ciudadanía