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PubMed2004

The actin cytoskeleton in normal and pathological cell motility.

Cell motility is crucial for tissue formation and for development of organisms. Later on cell migration remains essential throughout the lifetime of the organism for wound healing and immune responses. The actin cytoskeleton is the cellular engine that drives cell motility downstream of a complex signal transduction cascade. The basic molecular machinery underlying the assembly and disassembly of actin filaments consists of a variety of actin binding proteins that regulate the dynamic behavior of the cytoskeleton in response to different signals. The multitude of proteins and regulatory mechanisms partaking in this system makes it vulnerable to mutations and alterations in expression levels that ultimately may cause diseases. The most familiar one is cancer that in later stages is characterized by active aberrant cell migration. Indeed tumor invasion and metastasis are increasingly being associated with deregulation of the actin system.

Actins↗
PubMed2026

Genome-wide CRISPR screens map synthetic lethal interactions across recurrent cancer driver alterations.

Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including tumor suppressor genes. We execute a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and conduct a large-scale SL analysis using data from the cancer dependency map (DepMap). We chart SL interactions across 15 driver alterations: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase-promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of biological insights and drug targets for future therapeutic development.

CP: cancer↗
PubMed2026

Viral mimicry escape as a necessary feature of malignant transformation.

Malignant transformation is driven by disruption of pathways regulating proliferation and cell fate, but these same disruptions can create a collateral vulnerability: loss of transcriptional and epigenetic control over transposable elements and other normally silenced genomic regions. Consequently, emerging cancer cells can accumulate transposable element-derived and other endogenous immunogenic nucleic acids capable of triggering antiviral responses, a process termed viral mimicry. Increasing evidence indicates that viral mimicry can eliminate precancerous cells and shape tumour evolution, positioning it as an intrinsic tumour-suppressive mechanism. Here we highlight how cancer-associated changes in DNA methylation, histone modifications, splicing and RNA processing can lead to the presence of immunogenic nucleic acids that can activate viral mimicry pathways. We outline how cancer cells suppress viral mimicry, including compensatory epigenetic repression, RNA editing, nucleic acid decay and dampening of interferon signalling to enable cancer cell growth. Finally, we highlight the evidence suggesting that escaping viral mimicry is a fundamental process for cancer initiation and progression, and suggest that viral mimicry escape is necessary for cancer transformation and a therapeutic target in combination with immunotherapies. By framing viral mimicry escape as a necessary part of cancer transformation, this Review provides a unifying conceptual model for its translational exploitation.

Journal Article↗
PubMed2006

Modification of lymphocyte DNA damage by carotenoid supplementation in postmenopausal women.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of chronic diseases related to aging such as cancer and cardiovascular disease. Carotenoids could be a part of a protective strategy to minimize oxidative damage in vulnerable populations, such as the elderly. OBJECTIVE: Our aim was to determine the protective effect of carotenoids against DNA damage. DESIGN: A randomized, double-blind, placebo-controlled intervention study was conducted. Thirty-seven healthy, nonsmoking postmenopausal women aged 50-70 y were randomly assigned to 1 of 5 groups and were instructed to consume a daily dose of mixed carotenoids (beta-carotene, lutein, and lycopene; 4 mg each), 12 mg of a single carotenoid (beta-carotene, lutein, or lycopene), or placebo for 56 d. Plasma carotenoid concentrations were analyzed by using HPLC, and lymphocyte DNA damage was measured by using a single-cell gel electrophoresis (comet) assay. RESULTS: At day 57, all carotenoid-supplemented groups showed significantly lower endogenous DNA damage than at baseline (P < 0.01), whereas the placebo group did not show any significant change. Significantly less (P < 0.05) endogenous DNA damage was found as early as day 15 in the mixed carotenoid (P < 0.01) and beta-carotene (P < 0.05) groups. CONCLUSIONS: The results indicate that carotenoid supplementation decreases DNA damage and that a combination of carotenoids (4 mg each of lutein, beta-carotene, and lycopene), an intake that can be achieved by diet, or a larger dose (12 mg) of individual carotenoids exerts protection against DNA damage.

Aged↗
PubMed2026

gMISpy: integration of complex regulatory networks and genome scale metabolic models.

MOTIVATION: Genome-scale metabolic models lack explicit regulatory mechanisms, limiting their predictive accuracy for genetic interventions. Current methods for computing genetic Minimal Cut Sets either ignore regulatory networks entirely or use simplified acyclic representations that cannot capture regulatory feedback loops, ubiquitous features critical in cellular modeling. RESULTS: We developed gMISpy, a Python package that that enables efficient computation of genetic Minimal Intervention Sets (gMISs) in integrated genome-scale metabolic and regulatory networks. gMISpy incorporates cyclic regulatory logic into our previous computational framework using layered Boolean networks and BoNesis framework, resulting in a more accurate modeling of how regulatory interactions affect metabolic genes. Benchmarking across four different regulatory networks with Human-GEM showed consistent improvements in prediction accuracy, with Matthews correlation coefficient gains ranging from 2.50% to 14.42%. Validation against cancer data from DepMap and Project Score confirmed that cyclic integration reduces false positives and better captures biological vulnerabilities compared to acyclic approaches. AVAILABILITY AND IMPLEMENTATION: https://github.com/PlanesLab/cyclic-gMISpy.

Software↗
PubMed2004

Household water source and the risk of childhood brain tumours: results of the SEARCH International Brain Tumor Study.

BACKGROUND: The period in utero is a time of increased vulnerability. Offspring of pregnant women exposed to carcinogenic substances in drinking water may be more likely to develop cancer. We examined whether household water source and the presence of nitrates or nitrites in residential water were associated with increased risks of childhood brain tumours (CBT). METHODS: We used data from a multicentre, case-control study with maternal information on residential water source, and nitrate/nitrite levels of tap water measured by dipstick. Subjects included 836 CBT cases and 1485 controls from five countries. RESULTS: The risks of CBT associated with reliance on well water (versus public water) during pregnancy varied widely, with significantly increased risks noted in two (of seven) regions and a decreased risk observed in one region. CBT risk did not increase with increasing nitrate levels. However, our results based on tap water tested in the pregnancy residences suggest the risk of astrocytoma may be associated with increasing levels of nitrite (odds ratio [OR] = 4.3, 95% CI: 1.4, 12.6 for nitrite levels of 1-<5 mg/l nitrite ion; OR = 5.7, 95% CI: 1.2, 27.2 of nitrite > or =5 mg/l). CONCLUSIONS: These results should be interpreted with caution because women's recollection of water sources may have contained inaccuracies, and nitrate and nitrite measurements, available for only a portion of subjects, were often obtained years after the pregnancies occurred. However, our results suggest a need for closer evaluation of well water content in some regions and the possibility that a nitrite-related water exposure may be associated with CBT.

Astrocytoma↗
PubMed2001

Alu repeat sequences are present in increased proportions compared to a unique gene in plasma/serum DNA: evidence for a preferential release from viable cells?

Small amounts of DNA circulate freely in plasma or serum, but the mechanism of release is not known. To determine if DNA is actively excreted from viable cells, we utilized real-time PCR to measure the proportion of Alu repeat sequences compared to the beta-globin gene in serum and lymphocyte DNA in 27 cancer patients and 22 healthy controls. The proportion of Alu compared to beta-globin was significantly greater in serum DNA than in lymphocyte DNA both in control subjects (p = 0.003) and in cancer patients (p < 0.001). Overall, the proportion was similar in cancer and control patients (p = 0.79). Further experiments showed that the beta-globin gene was not more vulnerable to degradation by nuclease action than Alu sequences. Our results lead us to conclude that active DNA release is likely to play a significant role in the origin of circulating DNA.

Base Sequence↗
PubMed1999

Power and the teaching of medical ethics.

This paper argues that ethics education needs to become more reflective about its social and political ethic as it participates in the construction and transmission of medical ethics. It argues for a critical approach to medical ethics and explores the political context in medical schools and some of the peculiar problems in medical ethics education.

Codes of Ethics↗
PubMed2000

Human variability and susceptibility to trichloroethylene.

Although humans vary in their response to chemicals, comprehensive measures of susceptibility have generally not been incorporated into human risk assessment. The U.S. EPA dose-response-based risk assessments for cancer and the RfD/RfC (reference dose-reference concentration) approach for noncancer risk assessments are assumed to protect vulnerable human subgroups. However, these approaches generally rely on default assumptions and do not consider the specific biological basis for potential susceptibility to a given toxicant. In an effort to focus more explicitly on this issue, this article addresses biological factors that may affect human variability and susceptibility to trichloroethylene (TCE), a widely used halogenated industrial solvent. In response to Executive Order 13045, which requires federal agencies to make protection of children a high priority in implementing their policies and to take special risks to children into account when developing standards, this article examines factors that may affect risk of exposure to TCE in children. The influence of genetics, sex, altered health state, coexposure to alcohol, and enzyme induction on TCE toxicity are also examined.

Biotransformation↗
PubMedDate not supplied

Attitudes toward risk factor behavior of relatives of cancer patients.

BACKGROUND: Targeted health promotion requires an identifiable subpopulation which is accessible, at increased risk, receptive to input, and receptive to change. Relatives of recently diagnosed cancer patients may meet these criteria and have not previously been investigated as recipients of preventive education regarding smoking and diet. METHODS: This study investigates these factors, beliefs regarding perceived susceptibility to cancer, and attitudes toward behavior change in 101 relatives of 50 patients with smoking-related cancers, breast cancer, and other diet-related cancers. Congruence of attitudes between patients and relatives, another possible factor in changing health behaviors, also was assessed. RESULTS: Access to relatives of patients was very high, as was their willingness to discuss these issues (99% of relatives contacted participated in the survey). Relatives' ratings of relevant risk factors were generally higher than those of patients; ratings of their own vulnerability were moderate. Within diagnostic groups, there was high concordance of belief between patients and relatives for certain types of risk, such as heredity for breast cancer (r = 0.81) and smoking for smoking-related cancers (r = 0.52), but not for dietary factors. CONCLUSIONS: The high level of access suggests that relatives may be receptive to discussing issues of behavior risk and change. They are at least as aware as patients of cancer risk factors. Spontaneous behavior change was very low. They may therefore be good candidates for targeted health promotion regarding cancer risk.

Adult↗
PubMed2025

GE-IA-NAM: gene-environment interaction analysis via imaging-assisted neural additive model.

MOTIVATION: Gene-environment (G-E) interaction analysis is crucial in cancer research, offering insights into how genetic and environmental factors jointly influence cancer outcomes. Most existing G-E interaction methods are regression-based, which may lack flexibility to capture complex data patterns. Recent advances have investigated deep neural network-based G-E models. However, these methods may be more vulnerable to information deficiency due to challenges such as limited sample size and high dimensionality. Apart from genetic and environmental data, pathological images have emerged as a widely accessible and informative resource for cancer modeling, presenting its potential to enhance G-E modeling. RESULTS: We propose the pathological imaging-assisted neural additive model for G-E analysis (GE-IA-NAM). The flexible and interpretable additive network architecture is adopted to account for individualized effects associated with genetic factors, environmental factors, and their interactions. To improve G-E modeling, an assisted-learning strategy is investigated, which adopts a joint analysis to integrate information from pathological images. Simulations and the analysis of lung and skin cancer datasets from The Cancer Genome Atlas demonstrate the competitive performance of the proposed method. AVAILABILITY AND IMPLEMENTATION: Python code implementing the proposed method is available at https://github.com/Mr-maoge/NAM-IA-GE. The data that support the findings in this article are openly available in TCGA (The Cancer Genome Atlas) at https://portal.gdc.cancer.gov/.

Gene-Environment Interaction↗
PubMed2000

Breast cancer patients' experiences of patient-doctor communication: a working relationship.

The traumas of diagnosis and treatment for breast cancer are well researched and generally addressed in care. While women with breast cancer continue to identify the need for better communication with physicians, studies to date have not investigated how the process of communication between physicians and women with breast cancer actually unfolds. This phenomenological study therefore explored how women with breast cancer experience patient-physician communication to gain a greater understanding of effective approaches. Interviews of a purposeful sample of 11 women within 6 months of initial diagnosis or recurrence of breast cancer were audiotaped, transcribed verbatim and analyzed using inductive interpretation. Themes and patterns of positive and negative experiences emerged. All experiences began with the woman's feeling of vulnerability. In positive experiences, information sharing and relationship building were inextricably linked components of a working relationship which was at the same time affective, behavioural and instrumental. This experience, in turn, influenced the woman's experience of control and mastery of the illness experience, and their experience of learning to live with breast cancer. Findings illuminate the importance of comprehensively patient-centred, working relationships. Several specific techniques to enhance effective communication are identified.

Adult↗
PubMed1992

L-histidinol in experimental cancer chemotherapy: improving the selectivity and efficacy of anticancer drugs, eliminating metastatic disease and reversing the multidrug-resistant phenotype.

Human cancer chemotherapy is limited by two major problems: the failure of commonly used anticancer drugs to act against tumor cells in a specific manner and the ability of malignant cells to resist killing by antineoplastic agents. Experimentally, both of these problems can be solved by using L-histidinol in combination with conventional anticancer drugs. A structural analogue of the essential amino acid L-histidine and an inhibitor of protein biosynthesis. L-histidinol improves the selectivity and the efficacy of a variety of cancer drugs in several transplantable murine tumors. Furthermore, L-histidinol circumvents the drug-resistant traits of a variety of cancer cells, including those showing multidrug resistance. This review will summarize these properties of L-histidinol, present new evidence on its ability to increase the vulnerability of both drug-sensitive and drug-resistant human leukemia cells to various anticancer drugs, and show that, in addition to inhibiting protein synthesis, L-histidinol acts as an intracellular histamine antagonist. The establishment of a connection between the latter mechanism and the capacity to modulate anticancer drug action has resulted in a clinical trial in the treatment of human cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2026

Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis.

Ferroptosis↗
PubMedDate not supplied

Struggling with paradoxes: the process of spiritual development in women with cancer.

PURPOSE/OBJECTIVES: To examine the process of spiritual development in women diagnosed with cancer within five years of initial treatment. DESIGN: Exploratory, qualitative. SETTING: Outpatients in the mid-central and southwestern United States. SAMPLE: 10 Caucasian women, ages 45-70, who completed initial treatment, were not undergoing treatment for recurrence, and were within five years of diagnosis for breast or ovarian cancer or non-Hodgkin's lymphoma. METHODS: Data collected during two semistructured interviews, coded and analyzed using grounded theory techniques. Frame of reference--symbolic interactionism. MAIN RESEARCH VARIABLES: Developmental processes of spirituality; responses to diagnosis, treatment, and survival of cancer. FINDINGS: Diagnosis of cancer threatened the meaning of the women's lives, resulting in a sense of disintegration. This problem was resolved through the basic social psychological process of Struggling With Paradoxes, a three-phase process of Deciphering the Meaning of Cancer for Me, Recognizing Human Limitations, and Learning to Live with Uncertainty. In phase I, the paradoxes focused on the possibility of death, distress, vulnerability, and maintaining connection. In phase II, the paradoxes involved confronting death, asking difficult questions, and letting go of ultimate control of their lives. In phase III, the paradoxes centered on uncertainty, redefining meaning, and identifying spiritual growth. Reintegration occurred over time, although when threatened by the possibility of recurrence, disintegration resurfaced for a time. CONCLUSIONS: Findings emphasize not only the importance of spirituality, but also that spiritual experience is individualized and developmental in nature. Spiritual growth occurs over time following the diagnosis of cancer and is not necessarily related to age. IMPLICATIONS FOR NURSING PRACTICE: Spiritual concerns may be painful for patients to address; spiritual caregiving requires an acknowledgment of need by the woman with cancer and a caring, sensitive caregiver. Nurses should be aware of the phases of spiritual development so that interventions can be designed to address individual needs that may vary over time.

Adaptation, Psychological↗
PubMedDate not supplied

The existential plight in cancer: significance of the first 100 days.

The Existential Plight in cancer is a poorly recognized but significant period. It starts with the definite diagnosis and continues for two to three months into the illness, approximately 100 days. The chief signs are the predominance of life/death concerns, e-en over worries about health or physical symptoms. One hundred and twenty newly diagnosed cancer patients were interviewed, tested, and followed from about ten days after diagnosis at four to six week intervals until three to four months had elapsed. Plight was analyzed from the viewpoint of coping strategies, resolution of problems, vulnerability, total mood disturbance, and predominant concerns. Patients who had higher emotional distress during this period had many regrets about the past, were pessimistic, came from a multiproblem family, and had marital problems. The widowed or divorced had higher vulnerability, as did patients who anticipated little or no support from significant others. Although vulnerability increased with advanced staging and many symptoms, at the time of diagnosis psychosocial distress crossed diagnostic and prognostic boundaries, enabling investigation to predict within limits those patients who will cope effectively or fail to cope with cancer and its ramifications.

Adaptation, Psychological↗
PubMed2026

TRIM49 Deficiency Stabilizes a Galectin-3/EGR1 Transcriptional Complex That Drives Invasiveness of Gastric Adenocarcinoma.

UNLABELLED: Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, tripartite motif-containing protein 49 (TRIM49), was identified as a potent suppressor of cancer invasiveness. In two thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, in which TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multiorgan metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely because of the failure to undergo TRIM49-mediated polyubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a proinvasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying proinvasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a proinvasive galectin-3/EGR1 transcriptional complex was exploited by TRIM49-deficient GAC to fuel tissue invasion, representing an Achilles' heel that is potentially targetable to prevent metastasis. SIGNIFICANCE: A proinvasion galectin-3/EGR1 transcriptional complex is a therapeutic vulnerability in the highly invasive TRIM49-deficient gastric adenocarcinoma, which can be disrupted by the oral galectin-3 inhibitor GB1107 to prevent cancer spreading.

Stomach Neoplasms↗
PubMed2006

[Age differences in psychosocial resources and psychological well-being of cancer patients at the start of chemotherapy].

It has been suggested that older patients would have fewer resources than younger patients. We assessed psychosocial resources in 361 recently diagnosed cancer patients. Older patients had a stronger internal health-related locus of control but also less hope than younger patients. No age differences were found for self-esteem and perceived social support. In addition, older patients reported lower levels of negative and positive affect. Curative-intended therapy and social support were associated with a more positive affect only in younger patients, whereas hope was only related to older patients' psychological well-being. It is concluded that older cancer patients have similar levels of psychosocial resources compared to younger patients, but that lack of hope is a vulnerability factor for older patients in particular.

Adolescent↗