bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy
Authors: Hong Zhipeng , Liu Tao , Wan Lingfeng , Fa Pengyan , Kumar Pankaj , Cao Yanan , Prasad Chandra Bhushan , Qiu Zhaojun , Liu Joseph , Wang Hongbing , Li Zaibo , Wang Qi-En , Guo Peixuan , Guo Deliang , Yilmaz Ayse S. , Lu Lanchun , Papandreou Ioanna , Jacob Naduparambil K. , Yan Chunhong , Zhang Xiaoli , She Qing-Bai , Ma Zhefu , Zhang Junran
Published: March 2023

Abstract
Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacologic inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ataxia-telangiectasia mutated (ATM) activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized cross-talk between squalene metabolites, ER stress, and the DNA damage response. Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments.
Significance:
Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.
Data from Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis
Authors: Sendi Hossein , Yazdimamaghani Mostafa , Hu Mengying , Sultanpuram Nikhila , Wang Jie , Moody Amber S. , McCabe Ellie , Zhang Jiajie , Graboski Amanda , Li Liantao , Rojas Juan D. , Dayton Paul A. , Huang Leaf , Wang Andrew Z.
Published: March 2023

Abstract
Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA.
Significance:
Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.
Data from Extracellular Vesicle–Packaged CDH11 and ITGA5 Induce the Premetastatic Niche for Bone Colonization of Breast Cancer Cells
Authors: Li Xiao-Qing , Zhang Rui , Lu Hong , Yue Xiao-Min , Huang Yu-Fan
Published: March 2023

Abstract
Although most breast cancer metastases in bone cause osteolytic lesions, the osteogenic niche has commonly been described as an initiator of early-stage bone colonization of disseminated cancer cells. Tumor cell–derived extracellular vesicles (EV) have been shown to determine the organotropism of cancer cells by transferring their cargo, such as nucleic acids and proteins, to resident cells at future metastatic sites and preparing a favorable premetastatic niche. Runt-related transcription factor 2 (RUNX2) and its regulated genes have been shown to facilitate the acquisition of osteomimetic features and to enhance the bone metastatic potential of breast cancer cells. In this study, we present in vivo and in vitro evidence to clarify the role of EVs released by breast cancer cells with high RUNX2 expression in the education of osteoblasts to form an osteogenic premetastatic niche. Furthermore, different extracellular vesicular proteins were identified that mediate events subsequent to the specific recognition of tumor-derived EVs by osteoblasts via cadherin 11 (CDH11) and the induction of the osteogenic premetastatic niche by integrin α5 (ITGA5). CDH11high/ITGA5high EVs were demonstrated to be responsible for the formation of a premetastatic niche that facilitates RUNX2 high-expressing breast cancer cell colonization in bone, revealing a potential EV-based premetastatic niche blockage strategy.
Significance:
This study provides mechanistic insights into the generation of an osteogenic premetastatic niche by breast cancer–derived EVs and identifies potential EV-derived diagnostic biomarkers and targets for breast cancer bone metastasis.
Data from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Authors: Wang Xiansong , Hu Wei , Li Xiangchun , Huang Dan , Li Qing , Chan Hung , Zeng Judeng , Xie Chuan , Chen Huarong , Liu Xiaodong , Gin Tony , Wang Maggie Haitian , Cheng Alfred Sze Lok , Kang Wei , To Ka-Fai , Plewczynski Dariusz , Zhang Qingpeng , Chen Xiaoting , Chan Danny Cheuk Wing , Ko Ho , Wong Sunny Hei , Yu Jun , Chan Matthew Tak Vai , Zhang Lin , Wu William Ka Kei
Published: March 2023

Abstract
Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation.
Significance:
This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.
Data from Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma
Authors: Luo Ming-Yu , Zhou Ye , Gu Wei-Ming , Wang Cheng , Shen Ning-Xiang , Dong Jiang-Kai , Lei Hui-Min , Tang Ya-Bin , Liang Qian , Zou Jing-Hua , Xu Lu , Ma Pengfei , Zhuang Guanglei , Bi Ling , Xu Ling , Zhu Liang , Chen Hong-Zhuan , Shen Ying
Published: March 2023

Abstract
Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities.
Significance:
Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.
Data from Chemotherapy Coupled to Macrophage Inhibition Induces T-cell and B-cell Infiltration and Durable Regression in Triple-Negative Breast Cancer
Authors: Singh Swarnima , Lee Nigel , Pedroza Diego A. , Bado Igor L. , Hamor Clark , Zhang Licheng , Aguirre Sergio , Hu Jingyuan , Shen Yichao , Xu Yitian , Gao Yang , Zhao Na , Chen Shu-Hsia , Wan Ying-Wooi , Liu Zhandong , Chang Jeffrey T. , Hollern Daniel , Perou Charles M. , Zhang Xiang H.F. , Rosen Jeffrey M.
Published: March 2023

Abstract
Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful antitumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small-molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single-cell RNA sequencing characterized tumor-infiltrating lymphocytes including Th cells and antigen-presenting B cells that were highly enriched in responders to combination therapy. In one model that exhibited long-term posttreatment tumor regression, high-dimensional imaging techniques identified the close spatial localization of B220+/CD86+-activated B cells and CD4+ T cells in tertiary lymphoid structures that were present up to 6 weeks posttreatment. The transcriptional and metabolic heterogeneity of TAMs was also characterized in two closely related claudin-low/mesenchymal subtype tumor models with differential treatment responses. A murine TAM signature derived from the T12 model was highly conserved in human claudin-low breast cancers, and high expression of the TAM signature correlated with reduced overall survival in patients with breast cancer. This TAM signature may help identify human patients with claudin-low breast cancer that will benefit from the combination of cyclophosphamide and anti-CSF1R therapy. These studies illustrate the complexity of the tumor immune microenvironment and highlight different immune responses that result from rational immunotherapy combinations.
Significance:
Immunostimulatory chemotherapy combined with pharmacologic inhibition of TAMs results in durable treatment responses elicited by Th cells and B cells in claudin-low TNBC models.
Data from Dopamine Signaling Promotes Tissue-Resident Memory Differentiation of CD8+ T Cells and Antitumor Immunity
Authors: Chen Yingshi , Yan Shu-Mei , Pu Zeyu , Feng Jinzhu , Tan Likai , Li Yuzhuang , Hu Hongrong , Huang Wenjing , Lin Yingtong , Peng Zhilin , He Xin , Huang Feng , Zhang Hui , Zhang Yiwen
Published: March 2023

Abstract
Tissue-resident memory CD8+ T (TRM) cells have been associated with robust protective antitumor immune responses and improved prognosis of patients with cancer. Therefore, therapeutic strategies that modulate either the production or activity of TRM cells could be effective for treating cancer. Using a high-throughput drug screen, we showed that the neurotransmitter dopamine drives differentiation of CD8+ T cells into CD103+ TRM cells. In murine syngeneic tumor xenograft models and clinical human colon cancer samples, DRD5 served as the major functional dopamine receptor on CD8+ T cells and positively correlated with TRM cell density. DRD5 deficiency led to a failure of CD8+ T cells to accumulate in tissues, resulting in impaired TRM cell formation, reduced effector function, and uncontrolled disease progression. Moreover, dopamine treatment promoted the antitumor activity of CD8+ T cells and suppressed colorectal cancer growth in immunocompentent mouse models, and ex vivo preconditioning with dopamine enhanced the in vivo efficacy of chimeric antigen receptor (CAR)-T cells. Finally, in a patient with colorectal cancer cohort, dopamine expression was positively associated with patient survival and CD8+ T-cell infiltration. These findings suggest that dopaminergic immunoregulation plays an important role in the differentiation of CD8+ cells into CD103+ TRM cells and thereby modulates TRM-elicited antitumor immunity in colorectal cancer.
Significance:
Identification of an immunostimulatory function of dopamine signaling by promoting tissue-resident memory T-cell differentiation and sustaining T-cell effector functions reveals potential therapeutic strategies and prognostic biomarkers for colorectal cancer.
Data from Targeting BCAT1 Combined with α-Ketoglutarate Triggers Metabolic Synthetic Lethality in Glioblastoma
Authors: Zhang Bo , Peng Hui , Zhou Mi , Bao Lei , Wang Chenliang , Cai Feng , Zhang Hongxia , Wang Jennifer E. , Niu Yanling , Chen Yan , Wang Yijie , Hatanpaa Kimmo J. , Copland John A. , DeBerardinis Ralph J. , Wang Yingfei , Luo Weibo
Published: March 2023

Abstract
Branched-chain amino acid transaminase 1 (BCAT1) is upregulated selectively in human isocitrate dehydrogenase (IDH) wildtype (WT) but not mutant glioblastoma multiforme (GBM) and promotes IDHWT GBM growth. Through a metabolic synthetic lethal screen, we report here that α-ketoglutarate (AKG) kills IDHWT GBM cells when BCAT1 protein is lost, which is reversed by reexpression of BCAT1 or supplementation with branched-chain α-ketoacids (BCKA), downstream metabolic products of BCAT1. In patient-derived IDHWT GBM tumors in vitro and in vivo, cotreatment of BCAT1 inhibitor gabapentin and AKG resulted in synthetic lethality. However, AKG failed to evoke a synthetic lethal effect with loss of BCAT2, BCKDHA, or GPT2 in IDHWT GBM cells. Mechanistically, loss of BCAT1 increased the NAD+/NADH ratio but impaired oxidative phosphorylation, mTORC1 activity, and nucleotide biosynthesis. These metabolic alterations were synergistically augmented by AKG treatment, thereby causing mitochondrial dysfunction and depletion of cellular building blocks, including ATP, nucleotides, and proteins. Partial restoration of ATP, nucleotides, proteins, and mTORC1 activity by BCKA supplementation prevented IDHWT GBM cell death conferred by the combination of BCAT1 loss and AKG. These findings define a targetable metabolic vulnerability in the most common subset of GBM that is currently incurable.
Significance:
Metabolic synthetic lethal screening in IDHWT glioblastoma defines a vulnerability to ΑΚG following BCAT1 loss, uncovering a therapeutic strategy to improve glioblastoma treatment.

See related commentary by Meurs and Nagrath, p. 2354
Data from GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors
Authors: Li Yunzheng , Li Binghua , Xu Yanchao , Qian Liyuan , Xu Tiancheng , Meng Gang , Li Huan , Wang Ye , Zhang Laizhu , Jiang Xiang , Liu Qi , Xie Yuanyuan , Cheng Chunxiao , Sun Beicheng , Yu Decai
Published: March 2023

Abstract
Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and glutathione synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.
Significance:
Altered glutamine metabolism induced by GOT2 loss supports HCC growth and metastasis but confers a targetable vulnerability to glutaminase inhibitors.
Data from Quantification of Neoantigen-Mediated Immunoediting in Cancer Evolution
Authors: Wu Tao , Wang Guangshuai , Wang Xuan , Wang Shixiang , Zhao Xiangyu , Wu Chenxu , Ning Wei , Tao Ziyu , Chen Fuxiang , Liu Xue-Song
Published: March 2023

Abstract
Immunoediting includes three temporally distinct stages, termed elimination, equilibrium, and escape, and has been proposed to explain the interactions between cancer cells and the immune system during the evolution of cancer. However, the status of immunoediting in cancer remains unclear, and the existence of neoantigen depletion in untreated cancer has been debated. Here we developed a distribution pattern-based method for quantifying neoantigen-mediated negative selection in cancer evolution. The method can provide a robust and reliable quantification for immunoediting signal in individual patients with cancer. Moreover, this method demonstrated the prevalence of immunoediting in the immunotherapy-naive cancer genome. The elimination and escape stages of immunoediting can be quantified separately, where tumor types with strong immunoediting-elimination exhibit a weak immunoediting-escape signal, and vice versa. The quantified immunoediting-elimination signal was predictive of clinical response to cancer immunotherapy. Collectively, immunoediting quantification provides an evolutionary perspective for evaluating the antigenicity of neoantigens and reveals a potential biomarker for precision immunotherapy in cancer.
Significance:
Quantification of neoantigen-mediated negative selection in cancer progression reveals distinct features of cancer immunoediting and can serve as a potential biomarker to predict immunotherapy response.
Data from Accuracy of Perceived Risk of Recurrence Among Patients With Early-Stage Breast Cancer
Authors: Liu Ying , Pérez Maria , Aft Rebecca L. , Massman Kerry , Robinson Erica , Myles Stephanie , Schootman Mario , Gillanders William E. , Jeffe Donna B.
Published: March 2023

Abstract
Background: Accurate breast cancer recurrence risk perceptions might motivate health-promoting behaviors and alleviate undue anxiety. Although a few studies have examined early-stage breast cancer survivors' perceived risk of recurrence, none have assessed the accuracy of survivors' perceived risk of recurrence.

Methods: First primary ductal carcinoma in situ and early-invasive breast cancer survivors reported their perceived risk of recurrence during 6- and 12-month postsurgery interviews. We estimated the patients' 10-year risk of recurrence from published clinical trials, and for early-invasive breast cancer patients, risk of distant recurrence was based on their breast cancer–specific mortality calculated using Adjuvant! Online. Patients' perceived risk was compared with their calculated risk and categorized as “Accurate,” “Underestimated,” “Overestimated,” and “Uncertain.” Multinomial logit marginal effect models were fitted using Accurate as the reference.

Results: Only 17% of 531 patients accurately perceived their risk at 6 months, most of whom inaccurately perceived their risk at 12 months (P = 0.0143). Patients who were nonwhite [odds ratio (OR), 1.70; 95% confidence interval (95% CI), 1.12-2.56] and received radiation therapy (OR, 2.01; 95% CI, 1.07-3.77) were more likely to underestimate their risk. Patients with ductal carcinoma in situ (OR, 1.69; 95% CI, 1.08-2.70), lower social support (OR, 0.71; 95% CI, 0.53-0.95), and anxiety (OR, 1.58; 95% CI, 1.01-2.47) were more likely to overestimate their risk.

Conclusion: Few breast cancer survivors accurately perceived their risk of recurrence.

Impact: The accuracy of perceived risk may be increased by better physician-patient communications about their prognosis, provision of social support, and treatment for coexisting anxiety. Cancer Epidemiol Biomarkers Prev; 19(3); 675–80
Data from Childhood Exposure to Secondhand Smoke and Functional Mannose Binding Lectin Polymorphisms Are Associated with Increased Lung Cancer Risk
Authors: Olivo-Marston Susan E. , Yang Ping , Mechanic Leah E. , Bowman Elise D. , Pine Sharon R. , Loffredo Christopher A. , Alberg Anthony J. , Caporaso Neil , Shields Peter G. , Chanock Stephen , Wu Yanhong , Jiang Ruoxiang , Cunningham Julie , Jen Jin , Harris Curtis C.
Published: March 2023

Abstract
Background: Exposure to secondhand smoke during adulthood has detrimental health effects, including increased lung cancer risk. Compared with adults, children may be more susceptible to secondhand smoke. This susceptibility may be exacerbated by alterations in inherited genetic variants of innate immunity genes. We hypothesized a positive association between childhood secondhand smoke exposure and lung cancer risk that would be modified by genetic polymorphisms in the mannose binding lectin-2 (MBL2) gene resulting in well-known functional changes in innate immunity.

Methods: Childhood secondhand smoke exposure and lung cancer risk was assessed among men and women in the ongoing National Cancer Institute-Maryland Lung Cancer (NCI-MD) study, which included 624 cases and 348 controls. Secondhand smoke history was collected via in-person interviews. DNA was used for genotyping the MBL2 gene. To replicate, we used an independent case-control study from Mayo Clinic consisting of 461 never smokers, made up of 172 cases and 289 controls. All statistical tests were two-sided.

Results: In the NCI-MD study, secondhand smoke exposure during childhood was associated with increased lung cancer risk among never smokers [odds ratio (OR), 2.25; 95% confidence interval (95% CI), 1.04-4.90]. This was confirmed in the Mayo study (OR, 1.47; 95% CI, 1.00-2.15). A functional MBL2 haplotype associated with high circulating levels of MBL and increased MBL2 activity was associated with increased lung cancer risk among those exposed to childhood secondhand smoke in both the NCI-MD and Mayo studies (OR, 2.52; 95% CI, 1.13-5.60, and OR, 2.78; 95% CI, 1.18-3.85, respectively).

Conclusions: Secondhand smoke exposure during childhood is associated with increased lung cancer risk among never smokers, particularly among those possessing a haplotype corresponding to a known overactive complement pathway of the innate immune system. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3375–83)
Data from Ultraviolet Exposure and Mortality among Women in Sweden
Authors: Yang Ling , Lof Marie , Veierød Marit Bragelien , Sandin Sven , Adami Hans-Olov , Weiderpass Elisabete
Published: March 2023

Abstract
Background: Ecological studies have reported possible effects of sunlight on the risk of several diseases. Little evidence is available on the association between mortality and solar and artificial UV exposure by individual level from prospective studies.

Methods: The Swedish Women's Lifestyle and Health cohort study included women aged 30 to 49 years in 1991–1992. Participants completed a questionnaire and were followed-up through linkages to national registries until the end of 2006. Cox models were used to estimate adjusted HRs and 95% CIs for all-cause mortality and for cancer and cardiovascular disease (CVD) mortality.

Results: During 15 years of follow-up, among the 38,472 women included in the present study, 754 deaths occurred: 457 due to cancer and 100 due to CVD. When combining the information on sun exposure from age 10 to 39 years, women who got sunburned twice or more per year during adolescence had a reduced all-cause mortality, compared with women who had been sunburned once or less. A reduced risk for all-cause and CVD mortality was observed in women who went on sunbathing vacations more than once a year over three decades. Solarium use once or more per month for at least one decade increased the risk of all-cause mortality, when compared with women who never used a solarium.

Conclusions: Solar UV exposure was associated with reduced overall and CVD mortality, whereas artificial UV exposure was associated with increased overall and cancer mortality among Swedish women.

Impact: Moderate sun exposure may protect against cause-specific mortality. Cancer Epidemiol Biomarkers Prev; 20(4); 683–90. ©2011 AACR.
Data from Genetic Variation in VEGF Family Genes and Breast Cancer Risk: A Report from the Shanghai Breast Cancer Genetics Study
Authors: Beeghly-Fadiel Alicia , Shu Xiao-Ou , Lu Wei , Long Jirong , Cai Qiuyin , Xiang Yong-Bing , Zheng Ying , Zhao Zhongming , Gu Kai , Gao Yu-Tang , Zheng Wei
Published: March 2023

Abstract
Background: In addition to mediating aspects of physiologic and pathologic angiogenesis, the VEGF family also contributes to carcinogenesis.

Methods: We comprehensively characterized genetic variation across four VEGF family genes and evaluated associations with breast cancer risk with odds ratios (OR) and 95% CIs for participants of the two-stage case–control Shanghai Breast Cancer Genetics Study (SBCGS). Stage 1 evaluated 200 single nucleotide polymorphisms (SNP) across two VEGF ligands (VEGFA and VEGFC) and two VEGF receptors (FLT1/VEGFR1 and KDR/VEGFR2) among 2,079 cases and 2,148 controls. Five SNPs with promising associations were assessed in stage 2 among 4,419 cases and 1,851 controls.

Results: Two SNPs were consistently associated with breast cancer risk across our two study stages and were significant in combined analyses. Compared with FLT1 rs9551471 major allele homozygotes (AA), reduced risks were associated with AG (OR = 0.92, 95% CI: 0.84–1.00) and GG (OR = 0.78, 95% CI: 0.64–0.95) genotypes (Ptrend = 0.005). Compared with VEGFA rs833070 major allele carriers (CC or CT), increased risk was associated with TT genotypes (OR = 1.26, 95% CI: 1.05–1.52, P = 0.016).

Conclusion: Results from our study indicate that common genetic variation in VEGFA and FLT1 (VEGFR1) may contribute to breast cancer susceptibility.

Impact: Our findings provide clues for future studies on VEGF family genes in relation to cancer susceptibility and survival. Cancer Epidemiol Biomarkers Prev; 20(1); 33–41; ©2011 AACR.
Data from Manganese Superoxide Dismutase Polymorphism and Risk of Gastric Lesions, and Its Effects on Chemoprevention in a Chinese Population
Authors: Tu Hua-kang , Pan Kai-feng , Zhang Yang , Li Wen-qing , Zhang Lian , Ma Jun-ling , Li Ji-you , You Wei-cheng
Published: March 2023

Abstract
Background: Manganese superoxide dismutase is the primary antioxidant enzyme in the mitochondria and is involved in carcinogenesis. To investigate the association between MnSOD Val16Ala polymorphism and risk of advanced gastric lesions, and its effects on chemoprevention, a population-based study was conducted in Linqu, a high-risk area of gastric cancer in China.

Methods: Genotypes were determined by PCR-RFLP analysis in 3,355 subjects with the baseline histopathologic diagnosis in 1994, and 2,758 of these subjects received subsequent three interventions including vitamin supplementation for 7.3 years. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression model.

Results: We found an increased risk of dysplasia in subjects with the Val/Ala+Ala/Ala genotype (OR, 1.31; 95% CI, 1.02-1.68) compared with the Val/Val genotype. Stratified analysis indicated that a significantly elevated risk of intestinal metaplasia (OR, 3.40; 95% CI, 2.64-4.38) or dysplasia (OR, 4.01; 95% CI, 2.79-5.74) was found in subjects carrying the Val/Ala+Ala/Ala genotype and Helicobacter pylori infection, and an interaction between this genotype and a high serum H. pylori IgG titer (>2.94) on the risk of dysplasia was observed (Pinteraction = 0.01). Furthermore, an elevated chance for regression of gastric lesions was observed in subjects with the Val/Ala+Ala/Ala genotype and high IgG titer in an intervention trial with vitamin supplementation (OR, 2.45; 95% CI, 1.37-4.38).

Conclusions: These findings suggest that Val16Ala polymorphism may play an important role in development of advanced gastric lesions and modify the effect of vitamin supplementation on the evolution of gastric lesions.

Impact: Val16Ala polymorphism is related to gastric cancer development. Cancer Epidemiol Biomarkers Prev; 19(4); 1089–97. ©2010 AACR.
Data from Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development
Authors: Bianco-Miotto Tina , Chiam Karen , Buchanan Grant , Jindal Shalini , Day Tanya K. , Thomas Mervyn , Pickering Marie A. , O'Loughlin Melissa A. , Ryan Natalie K. , Raymond Wendy A. , Horvath Lisa G. , Kench James G. , Stricker Phillip D. , Marshall Villis R. , Sutherland Robert L. , Henshall Susan M. , Gerald William L. , Scher Howard I. , Risbridger Gail P. , Clements Judith A. , Butler Lisa M. , Tilley Wayne D. , Horsfall David J. , Ricciardelli Carmela
Published: March 2023

Abstract
Background: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis.

Methods: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions.

Results: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort.

Conclusions: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis.

Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies. Cancer Epidemiol Biomarkers Prev; 19(10); 2611–22. ©2010 AACR.
Data from Common Polymorphisms in the Adiponectin and Its Receptor Genes, Adiponectin Levels and the Risk of Prostate Cancer
Authors: Dhillon Preet K. , Penney Kathryn L. , Schumacher Fredrick , Rider Jennifer R. , Sesso Howard D. , Pollak Michael , Fiorentino Michelangelo , Finn Stephen , Loda Massimo , Rifai Nader , Mucci Lorelei A. , Giovannucci Edward , Stampfer Meir J. , Ma Jing
Published: March 2023

Abstract
Background: Adiponectin, an insulin-sensitizing adipokine, is inversely associated with adiposity and prostate cancer risk and progression. However, the role of genetic variation in the adiponectin (ADIPOQ) and receptor genes (ADIPOR1/R2) in prostate cancer is largely unknown.

Methods: In a nested case–control study of 1,286 cases and 1,267 controls within the Physicians' Health Study, we evaluated 29 common single-nucleotide polymorphisms (SNP) in ADIPOQ (n = 13), ADIPOR1 (n = 5), and ADIPOR2 (n = 11) in relation to the risk of prostate cancer. In subgroups, we also evaluated the association of genotype and circulating adiponectin levels (n = 951) and prostate tumor expression of insulin receptor (IR) and insulin-like growth factor 1 (IGF-IR) receptor (n = 181).

Results: Among the 12 tagging polymorphisms in ADIPOQ, four (rs266729, rs182052, rs822391, and rs2082940) were significantly associated (P < 0.05) with overall prostate cancer risk, with no significant difference by tumor grade or clinical stage. Two of the risk SNPs (rs266729 and rs182052) plus four other SNPs (rs16861209, rs17366568, rs3774261, and rs7639352) were also associated with plasma adiponectin levels, and three of these (rs1686109, rs17366568, and rs3774261) were also significantly associated with IR expression in prostate tumor tissue. One additional SNP was associated with IGFI-R tumor tissue expression (rs16861205). None of the 16 variants in ADIPOR1/R2 were related to cancer risk or circulating adiponectin levels.

Conclusions: Common variants in the adiponectin gene were associated with prostate cancer risk, plasma adiponectin levels, and IR or IGF-IR expression in the prostate tumor.

Impact: These genotype–phenotype associations support the biological relevance of adiponectin for prostate carcinogenesis, particularly in earlier stages of development. Cancer Epidemiol Biomarkers Prev; 20(12); 2618–27. ©2011 AACR.
Data from Expression and Cytoplasmic Localization of SAM68 Is a Significant and Independent Prognostic Marker for Renal Cell Carcinoma
Authors: Zhang Zhiling , Li Jun , Zheng Haiqing , Yu Chunping , Chen Jin , Liu Zhuowei , Li Manzhi , Zeng Musheng , Zhou Fangjian , Song Libing
Published: March 2023

Abstract
Purpose: This retrospective study aimed to examine the expression and localization of SAM68 (Src-associated in mitosis, 68 kDa) in a larger cohort of surgical specimens of renal cell carcinoma and their correlation with the progression of human renal cell carcinoma.

Experimental Design: The protein and mRNA expression levels of SAM68 in normal renal tubular epithelial cells, renal cell carcinoma cell lines, as well as nine pairs of renal cell carcinoma and matched tumor-adjacent renal tissues were examined using reverse transcription-PCR and Western blot. Moreover, SAM68 protein expression and localization in 241 clinicopathologically characterized renal cell carcinoma samples were examined by immunohistochemistry. Prognostic and diagnostic associations were examined by statistical analyses.

Results: SAM68 was markedly overexpressed in renal cell carcinoma cell lines and renal cell carcinoma tissues at both the transcriptional and translational levels. Immunohistochemical analysis revealed high SAM68 protein expression in 129 of the 241 (53.5%) paraffin-embedded archival renal cell carcinoma specimens. Moreover, there was a significant correlation between SAM68 expression and pathologic stage (P < 0.001), T classification (P = 0.003), N classification (P = 0.001), M classification (P = 0.006), and Fuhrman grade (P < 0.001). Patients with higher SAM68 expression had shorter overall survival time than patients with lower SAM68 expression, and the cytoplasmic localization of SAM68 significantly correlated with clinicopathologic grade and outcome. Multivariate analysis indicated that SAM68 protein overexpression and cytoplasmic localization were independent predictors for poor survival of renal cell carcinoma patients.

Conclusions: Our results suggest that SAM68 could represent a novel and useful prognostic marker for renal cell carcinoma. High SAM68 expression and cytoplasmic localization are associated with poor overall survival in renal cell carcinoma patients. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2685–93)
Data from PLCE1 mRNA and Protein Expression and Survival of Patients with Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma
Authors: Li Wen-Qing , Hu Nan , Burton Victoria H. , Yang Howard H. , Su Hua , Conway Catherine M. , Wang Lemin , Wang Chaoyu , Ding Ti , Xu Yi , Giffen Carol , Abnet Christian C. , Goldstein Alisa M. , Hewitt Stephen M. , Taylor Philip R.
Published: March 2023

Abstract
Background: Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival.

Methods:PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n = 132), gastric cardia adenocarcinoma (GCA, n = 62), and gastric noncardia adenocarcinoma (GNCA, n = 72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n = 303), and tumors of GCA (n = 298) and GNCA (n = 124).

Results: Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P = 0.03, probe_205112_at), as well as in GCA and GNCA tumors (P < 0.0001, each probe). Protein expression was nonsignificantly reduced in ESCC tumors (P = 0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs. lowest quartile; Ptrend = 0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; Ptrend = 0.04), but not for GNCA cases (P = 0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; Ptrend = 0.04).

Conclusions: Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression seems to be associated with cancer prognosis.

Impact: A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation. Cancer Epidemiol Biomarkers Prev; 23(8); 1579–88. ©2014 AACR.
Nitrated Polycyclic Aromatic Hydrocarbon (Nitro-PAH) Signatures and Somatic Mutations in Diesel Exhaust-Exposed Bladder Tumors
Authors: Gonzalez Nicole , Rao Nina , Dean Michael , Lee Donghyuk , Hurson Amber N. , Baris Dalsu , Schwenn Molly , Johnson Alison , Prokunina-Olsson Ludmila , Friesen Melissa C. , Zhu Bin , Rothman Nathaniel , Silverman Debra T. , Koutros Stella
Published: March 2023

Background:

Diesel exhaust is a complex mixture, including polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs (nitro-PAH), many of which are potent mutagens and possible bladder carcinogens. To explore the association between diesel exposure and bladder carcinogenesis, we examined the relationship between exposure and somatic mutations and mutational signatures in bladder tumors.

Methods:

Targeted sequencing was conducted in bladder tumors from the New England Bladder Cancer Study. Using data on 797 cases and 1,418 controls, two-stage polytomous logistic regression was used to evaluate etiologic heterogeneity between bladder cancer subtypes and quantitative, lifetime estimates of respirable elemental carbon (REC), a surrogate for diesel exposure. Poisson regression was used to evaluate associations between REC and mutational signatures.

Results:

We observed significant heterogeneity in the diesel-bladder cancer risk relationship, with a strong positive association among cases with high-grade, nonmuscle invasive TP53-mutated tumors compared with controls [ORTop Tertile vs.Unexposed, 4.8; 95% confidence interval (CI), 2.2–10.5; Ptrend < 0.001; Pheterogeneity = 0.002]. In muscle-invasive tumors, we observed a positive association between diesel exposure and the nitro-PAH signatures of 1,6-dintropyrene (RR, 1.93; 95% CI, 1.28–2.92) and 3-nitrobenzoic acid (RR, 1.97; 95% CI, 1.33–2.92).

Conclusions:

The relationship between diesel exhaust and bladder cancer was heterogeneous based on the presence of TP53 mutations in tumors, further supporting the link between PAH exposure and TP53 mutations in carcinogenesis. Future studies that can identify nitro-PAH signatures in exposed tumors are warranted to add human data supporting the link between diesel and bladder cancer.

Impact:

This study provides additional insight into the etiology and possible mechanisms related to diesel exhaust-induced bladder cancer.
Contribuições da psicologia para a reabilitação de doentes com dor músculo-esquelética
Authors: Portnoi Andréa G.
Published: March 2023

As emoções e os valores simbólicos individuais influenciam a magnitude das sensações dolorosas. A análise das estratégiasde enfrentamento, das características psicocomportamentais dos doentes, e de seus familiares e cuidadores e das característicasde seus ambientes possibilita o estabelecimento de programas de reabilitação psicodinâmicas, comportamentais, cognitivo comportamentais e psicoeducativos que muito podem contribuir para a melhora daqueles que padecem com dor.
Dor pelviperineal
Authors: Yeng Lin Tchia , Teixeira Manoel Jacobsen , Ungaretti Junior Arthur , Kaziyama Helena H. , Boguchwal Betty
Published: March 2023

Dor pelviperineal crônica é condição comum especialmente nos indivíduos do sexo feminino. Muito freqüentemente,anormalidades viscerais eventualmente identificadas aos exames complementares não justificam a sua ocorrência. Em grande número de enfermos, afecções músculo-esqueleticas, especialmente as síndromes dolorosas miofasciais do assoalho pélvico e da parede abdominal e neuropatias são a razão da ocorrência de dor pelviperineal crônica. O tratamento da dor pélvica crônica visa à remoção das causas possíveis e ao controle funcional da condição sintomática. Medicamentos analgésicos e adjuvantes, procedimentos de medicina física e de psicoterapia são freqüentemente indicados no tratamento das álgicas crônicas pelviperineais. As intervenções neuroanestésicas e neurocirúrgicas são indicadas em casos especiais.
Infecções do trato urinário
Authors: Srougi Miguel
Published: March 2023

As infecções do trato urinário representam problema de grande relevância clínica, não só pela elevada freqüência com que acometem mulheres e homens vivendo na comunidade, mas também por representar a primeira causa de infecção em pacientes hospitalizados.Na presente revisão, o autor apresenta os conceitos atuais sobre a epidemiologia, os fatores etiopatogênicos, as manifestações clínicas e os métodos de diagnóstico das infecções do trato urinário. Finaliza discutindo as controvérsias e as novas diretrizes que envolvemo tratamento e a prevenção dessas infecções.
Diagnóstico sindrômico
Authors: Biselli Paolo José , Atta José Antonio
Published: March 2023

O raciocínio clínico diagnóstico mudou muito ao longo dos anos, partindo de diagnóstico (e tratamento) de sinais e sintomas para, nos dias de hoje, fazermos diagnósticos mais precisos, visando o melhor tratamento. A partir da anamnese e usando técnicas de raciocínio diagnóstico hipotético-dedutivo ou reconhecimento de padrão (as duas mais utilizadas), procura-se, a partir de diagnósticos sindrômicos, chegar a diagnósticos etiológicos. Apesar de todo o acúmulo tecnológico dos últimos anos, a anamnese e o raciocínio diagnóstico continuam sendo os métodos mais eficazes para solucionar (ou pelo menos direcionar da melhor maneira possível) os problemas de nossos pacientes. Uma das maneiras de facilitar esse trabalho parte de diagnósticos sindrômicos para direcionar o raciocínio e a investigação. Partindo de três diagnósticos sindrômicos (insuficiência cardíaca, hepatoesplenomegalia e síndrome consumptiva) damos exemplos de como chegar ao diagnóstico etiológico, usando principalmente o raciocínio hipotético-dedutivo.
Símbolo da medicina
Authors: Nascimento Clarissa Nóbrega Gambarra , Ramos Moara de Oliveira , Lichtenstein Arnaldo
Published: March 2023

Este artigo aborda os aspectos histórico e mitológico do símbolo da medicina e a errônea difusão do caduceus de Hermes.
O cérebro, a visão tridimensional, e as técnicas de obtenção de imagens estereoscópicas
Authors: Ribas Guilherme Carvalhal , Ribas Eduardo Carvalhal , Rodrigues Junior Aldo Junqueira
Published: March 2023

Em forma de artigo de revisão, os autores tratam aqui inicialmente do desenvolvimento filogenético e dos mecanismos oculares e neurais envolvidos com a visão tridimensional estereoscópica, e a seguir descrevem mais detalhadamente as diferentes técnicas disponíveis para a obtenção, impressão, projeção e visualização em monitores de imagens estereoscópicas. O artigo termina mencionando a experiência da Disciplina de Topografia Estrutural Humana do Departamento de Cirurgia da FMUSP com o desenvolvimento de material didático estereoscópico, utilizando a técnica anaglífica para impressão e a técnica polarizada para projeção, ambas atualmente com tecnologia digital. Esquemas didáticos e imagens estereoscópicas anaglíficas ilustram o texto.
Relating CYP2B6 genotype and efavirenz resistance among post-partum women living with HIV with high viremia in Uganda: a nested cross-sectional study
Authors: Buzibye Allan , Wools-Kaloustian Kara , Olagunju Adeniyi , Twinomuhwezi Ellon , Yiannoutsos Constantin , Owen Andrew , Neary Megan , Matovu Joshua , Banturaki Grace , Castelnuovo Barbara , Lamorde Mohammed , Khoo Saye , Waitt Catriona , Kiragga Agnes
Published: March 2023

Background

We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum.

Methods

This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes.

Results

Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size.

Conclusions

There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.