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The role of CHAMP1 in chromatin-mediated DNA damage repair.

Defects in the replication stress response are major drivers of cancer development and present key targetable vulnerabilities that can be exploited for anti-cancer therapy. Recent studies have identified CHAMP1 as a novel DNA damage repair factor with roles in double-strand break repair and the replication stress response. Mutations in CHAMP1 are associated with the neurodevelopmental disorder CHAMP1 Syndrome. More recently, children with CHAMP1 Syndrome have developed leukemia, suggesting that CHAMP1 mutations are a potential cancer risk factor. CHAMP1 is part of two DNA damage repair complexes: CHAMP1-POGZ-REV7 (Complex I) and CHAMP1-POGZ-HP1α (Complex II). Complex I promotes homologous recombination by removing the Shieldin complex from the ends of double strand breaks and allowing DSB end resection to occur. Complex II enriches heterochromatin content through the recruitment of the methyltransferase SETDB1 to DNA damage sites. Increased heterochromatin at stalled forks is associated with proper fork stability and restart, demonstrating the importance of CHAMP1 in maintaining genomic integrity. Loss of CHAMP1 leads to increased sensitivity to DNA damaging agents and increased dependence on other DNA damage repair pathways, such as the DNA damage checkpoint and the Fanconi Anemia pathway. CHAMP1 is overexpressed in breast and ovarian cancer cells with high levels of replication stress, providing a molecular mechanism for the tolerance of replication stress. These new findings on the relationship of CHAMP1 with well-established DNA damage repair pathways, suggest that targeting CHAMP1 could present a new synthetic lethality opportunity for cancer cells with high levels of replication stress.

CHAMP1↗

Geriatric neutrophils: implications for older adults.

OBJECTIVES: To review the intersection of immunosenescence and neutropenia, focusing on innate immunity, and implications for research and practice for neutropenic older adults with cancer. DATA SOURCES: Research studies, journal articles, and web sites. CONCLUSION: Immunosenescence, age-related changes within the immune system renders older adults more vulnerable to infection. This vulnerability is magnified by cancer and its treatment. Unfortunately, there has been little consideration of immunosenescence as it relates to supportive care for this population. IMPLICATIONS FOR NURSING PRACTICE: Studies detailing the impact of immunosenescence on neutropenia and outcomes for neutropenic older adults are necessary to advance clinical research and practice.

Age Distribution↗

[Suicide and cancer].

Epidemiological studies demonstrate that cancer patients are at increased risk of suicide. While affective illness and alcoholism are the most important determinants of suicide in the physically healthy population, vulnerability to suicide in cancer patients is influenced by a number of other factors including psychosocial and psychosomatic effects of advanced illness, pain, organic mental syndromes and preexisting psychopathology. Ways of influencing these risk factors are discussed, together with their use in preventive care and management of suicidal cancer patients.

Humans↗

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.

UNLABELLED: Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. SIGNIFICANCE: DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells ("pre-DTPs") that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities. This article is highlighted in the In This Issue feature, p. 873.

Breast Neoplasms↗

Environmental risk factors for breast cancer among African-American women.

There are few unequivocably established environmental carcinogens for breast cancer in women. Nevertheless, environmental factors are believed to explain much of the international variation in breast cancer risk and possibly differences among racial/ethnic groups. Along with lifestyle, some adverse exposures may be higher in minority racial/ethnic groups and in underserved populations that experience higher ambient contamination. Associations have been found between environmental agents and breast cancer in subgroups of women who can be identified by common susceptibility traits as well as by timing of exposures at certain milestones of reproductive life. Susceptibility can be defined by social, environmental, and genetic modalities-factors that may predominate in certain racial/ethnic groups but that also transcend racial/ethnic boundaries. For example, genes involved in transcription and estrogen metabolism have rapid variants that are more prevalent among African-Americans, yet risk accompanying metabolic changes from these genes will prevail in all racial/ethnic groups. Lack of reliable exposure assessment remains a principal obstacle to elucidating the role of environmental exposures in breast cancer. Resources must be identified and consolidated that will enable scientists to improve exposure assessment and to assemble studies of sufficient size to address questions regarding exposure, susceptibility, and vulnerability factors in breast cancer. Breast cancer studies should be expanded to examine combinations of chemicals as well as competing or complementary exposures such as endogenous hormones, dietary intake, and behavioral factors.

Black or African American↗

Potential prognostic benefit of lateral pelvic node dissection for rectal cancer located below the peritoneal reflection.

OBJECTIVE: To identify the parameters related to the effective selection of patients who could receive prognostic benefit from lateral pelvic node dissection. BACKGROUND: Accurate preoperative diagnosis of lateral nodal involvement (LNI) remains difficult, and the indications for lateral lymph node dissection have been controversial. PATIENTS AND METHODS: A total of 244 consecutive patients who underwent potentially curative surgery with lateral dissection for advanced lower rectal cancer (1985-2000) were reviewed. Patients were stratified into groups based on various parameters, and the therapeutic value index for survival benefit was compared among groups. The therapeutic index of lateral dissection was calculated by multiplying the frequency of metastasis to the lateral area and the cancer-related 5-year survival rate of patients with metastasis to the lateral area, irrespective of metastasis to other areas (mesorectal, superior rectal artery [SRA], and inferior mesenteric artery [IMA] areas). RESULTS: LNI was observed in 41 patients (17%); and 88% of them had nodal involvement in the region along the internal iliac/pudendal artery or in the obturator region ("vulnerable field"). The cancer-related 5-year survival rate among the patients with LNI was 42%; the therapeutic index for lateral dissection was calculated as 7.0 patients, which was much higher than that of lymphadenectomy of the SRA area (1.6 patients) and the IMA area (0.4 patients), and almost comparable to that of lymphadenectomy of the upward mesorectal area (6.9 patients). Although it was possible to select groups at high and low risk for LNI based on several parameters related to tumor aggressiveness, such as tumor differentiation in biopsy specimens, the therapeutic value index was not significantly different between these groups. Unlike these parameters, the diameter of the largest lymph node in the "vulnerable field," which was positively correlated with the rate of LNI but irrelevant to the prognosis, was able to successfully stratify patients by therapeutic index. CONCLUSIONS: Advanced lower rectal cancer patients having LNI in the lateral pelvic area are likely to receive prognostic benefit from lymphadenectomy. The most efficient means of determining the effectiveness of lateral dissection preoperatively is to estimate the nodal diameter in the "vulnerable" lateral regions by diagnostic imaging.

Disease-Free Survival↗

Self-perception profile in children with cancer: self vs parent report.

Self-perception about competence, behaviour, and self-worth were examined in 30 children (8 to 14 years) recently diagnosed as having cancer and were compared with that of their parents' perception. The poor agreement between parents' and children's ratings on physical appearance and social acceptance is noteworthy in that these two domains are particularly vulnerable in children with cancer, given the effect of chemotherapy on physical appearance and children's tendency to view themselves as socially undesirable or a burden to others. This finding, if replicated, can have implications for therapeutic intervention since the discrepancy score could be used to challenge children's negative views in the context of cognitive therapy to improve their self-esteem.

Adolescent↗

Cytotoxicity and mutagenicity of frameshift-inducing agent ICR191 in mismatch repair-deficient colon cancer cells.

BACKGROUND: Deficiency of DNA mismatch repair is a common feature of cancers exhibiting instability of microsatellite DNA sequences. Cancers with microsatellite instability are recognizable by their high rate of spontaneous frameshift mutations within microsatellite sequences, their resistance to killing by cytotoxic agents, and their localization to specific tissues, e.g., the proximal colon and stomach. We hypothesized that the mismatch repair deficiency of these cancers would make them vulnerable to environmental or chemical frameshift-inducing agents. This study was undertaken to test whether exogenous frameshift-inducing agents selectively induce mutations in mismatch repair-deficient cells of mutagen-exposed tissues like the colon and whether cytotoxic doses of these agents would preferentially kill those cells. METHODS: Cytotoxicity of the acridine mutagen 6-chloro-9-[3-(2-chloroethylamino)propylamino]-2-methoxy-acridine (ICR191), a DNA frameshift inducer, was determined in the mismatch repair-deficient human colon carcinoma cell line HCT116 versus the repair-reconstituted derivative HCT116+C3. Vulnerability to the mutagenic effects of ICR191 was determined by transfection of HCT116 or HCT116+C3 cells with a frameshift reporter vector, followed by treatment of the cells with ICR191. Alternatively, the reporter vector was reacted ex vivo with ICR191, and the derivatized vector was then transfected into HCT116 or HCT116+C3 cells. RESULTS: ICR191 proved to be fivefold to 10-fold more potent in inducing mutations in mismatch repair-deficient HCT116 cells than in mismatch repair-proficient HCT116+C3 cells. Moreover, at cytotoxic doses of ICR191, repair-deficient HCT116 cells proved to be fivefold more vulnerable to killing than did HCT116+C3 cells. CONCLUSIONS: Frameshift-inducing mutagens can selectively induce mutations in mismatch repair-deficient cells versus mismatch repair-proficient cells. Environmental exposures may, therefore, favor development of cancers with microsatellite instability in tissues like the gut. Frameshift-inducing agents can, however, also preferentially kill mismatch repair-deficient cancer cells and, thus, may be promising as model therapeutic compounds.

Aminacrine↗

Why do women attend familial breast cancer clinics?

The increasing demand for genetic assessment for familial breast cancer has necessitated the development of cancer genetics services. However, little is known about the factors motivating the client population likely to approach these services. A cross sectional questionnaire survey of 1000 women with a family history of breast cancer was conducted to identify self-reported reasons for attending a familial breast cancer clinic and possible differences in the characteristics of women who were attending for diverse reasons. Before attendance at clinic, 833 women completed a baseline questionnaire (83% response rate). Women who gave personal risk (n=188), awareness of a family history (n=120), risk to family members (n=84), reassurance (n=69), genetic testing (n=65), breast screening (n=46), or prevention (n=39) as their main reason for attending were compared on demographic and medical variables, and on psychological variables including general anxiety, cancer worry, perceived risk, and attitudes towards prophylactic surgery and genetic testing. Important differences in the psychological characteristics of these groups were found, which were unrelated to reported family history. In particular, women who primarily wanted genetic testing felt extremely vulnerable to developing breast cancer, were more likely to be considering prophylactic surgery, and perceived fewer limitations of testing. Those who primarily wanted reassurance were highly anxious about the disease. We recommend that cancer genetics services take into consideration the informational and psychological needs and concerns of their client group.

Ambulatory Care Facilities↗

Nursing intervention and older adults who have cancer: specific science and evidence based practice.

This review of a small and heterogeneous body of literature suggests intriguing and useful approaches to nursing interventions with older adults who have cancer and areas that clearly deserve greater attention in future research. Research such as that done by McCorkle and Goodwin,while disparate in design, clearly demonstrate the ability of interventions to achieve better continuity of care and appropriate treatment for physically and socially vulnerable older adults with cancer. Comparison across settings and studies that investigate similar clinical phenomena would illuminate further how to achieve more effective intervention with elders who have cancer. In studies addressing case management, comparison of work by McCorkle et al with that completed by Goodwin et al suggests that programs that are longer than 4-week interventions are more likely to be beneficial than are shorter programs. Goodwin et al constructed a 12-month intervention that might be extended even further to improve continuity to older adults who may lack family/social support. Continuity may be especially important as older patients move from primary or geriatric care to surgical care to medical oncology care. Such a program also may offer added benefits in care of older adults who survive an initial cancer but require vigilant follow-up for recurrence or a second primary cancer and who may face ageist assumptions about screening and early detection of those cancers. The work of Coleman, Earp, and Powe and Weinrich underscores the necessity of understanding the precise needs of rural elders in relation to cancer. These studies strongly suggest that nurses can improve screening rates and symptom management. Rural health care may have particularly poor specialty resources for cancer and aging. Increasing oncology nurses' presence in rural communities and supporting those nurses with specific content in aging may be a successful mechanism to ameliorate these deficits. Coleman's study especially found that increasing opportunities to ensure that practice is grounded in current evidence is critical to improving evidence-based practice and avoiding misconceptions about the effects of age in cancer care. The weak effects associated with the use of lay educators to improve cancer screening behaviors strongly reinforce the influence of nurses over other personnel to carry out educational interventions. In rural and urban areas alike, the credibility and professionalism of nurses was clearly of benefit. McDougall's research highlights the effects of cancer treatment on older people's cognitive status. His intervention supports the further testing of group activities led by nurses as a way to improve aspects of memory. Clinical application of this low-risk, possibly high-benefit intervention strategy, which is congruent with current work in dementia care, implies that elder care facilities might benefit from having a nurse on staff to address institutional and individual concerns related to cognitive function among older residents with cancer. A single often unstated theme throughout these studies is the impact of the nurse-patient relationship on outcome variables for older adults at risk for or living with cancer. The nurse-patient relationship, a touchstone of practice, reminds each nurse to focus on the individual elder, to look past chronological age and cancer diagnosis to understand that individual as having a life that, though it may be decades long in time, is still to be lived each day in the manner and capacity that the person can command and desires. Knowledge of that elder will aid the nurse in asking critical questions, using existing research, adapting other relevant evidence, and intervening more effectively over the course of that relationship.

Aged↗

Beliefs, recommendations and intentions are important explanatory factors of mammography screening behavior among Muslim Arab women in Israel.

The rates of mammography screening by Muslim Arab women in Israel are lower compared with the general population. The current study aimed to examine factors related to screening mammography behavior among Arab women by employing components from the Health Belief Model and the Theory of Reasoned Action. Sociodemographic factors, knowledge, beliefs about breast cancer and mammography, self-efficacy, cues to action, norms and intention to perform mammography were examined as explanatory variables for mammography use. Face-to-face interviews with a random sample of 510 Muslim Arab women, aged 50-69 years, were conducted. The women had limited knowledge about breast cancer and mammography, and the rate of mammography screening behavior (at the recommended interval) was only 20%. The women who were significantly more likely to undergo mammography were those who received a recommendation from a health professional or from family/friends, perceived themselves as vulnerable to getting breast cancer, believed in the efficacy of the test, perceived it as not painful, were younger, were more educated and were only of borderline significance among those who expressed an intention to undergo mammography. The findings indicate that professional recommendation and beliefs sets are essential factors for developing effective mammography screening interventions in this unique population.

Aged↗

CARM1 in human cancer: a multifunctional epigenetic node driving tumor plasticity and therapeutic vulnerability.

Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a signal-responsive epigenetic regulator that couples oncogenic and stress signals to chromatin, transcription, RNA processing, metabolism, and genome maintenance. Its effects arise from both asymmetric arginine methylation of histone and non-histone substrates and methyltransferase-independent scaffolding activities. This review critically synthesizes the structural basis, substrate networks, methylarginine readers, and cancer-contextual functions of CARM1. We propose that its apparently opposing oncogenic and tumor-suppressive activities are determined by lineage-specific substrates, regulatory post-translational modifications, cofactor and chromatin availability, and stage- or microenvironment-dependent stress signals. We further evaluate CARM1-directed therapy using an evidence-graded framework. Catalytic inhibitors such as TP-064 and EZM2302 differ in binding mode and substrate coverage, whereas emerging degraders can remove scaffolding functions but remain constrained by delivery, E3-ligase heterogeneity, pharmacokinetics, and therapeutic-window uncertainties. Biomarker-guided synthetic-lethal and immunotherapy combinations may therefore offer the most tractable route to clinical translation. This framework positions CARM1 as a context-conditioned signal-to-chromatin translator rather than a uniformly druggable oncogene.

Humans↗

Competition and natural selection in a mathematical model of cancer.

A malignant tumor is a dynamic amalgamation of various cell phenotypes, both cancerous (parenchyma) and healthy (stroma). These diverse cells compete over resources as well as cooperate to maintain tumor viability. Therefore, tumors are both an ecological community and an integrated tissue. An understanding of how natural selection operates in this unique ecological context should expose unappreciated vulnerabilities shared by all cancers. In this study I address natural selection's role in tumor evolution by developing and exploring a mathematical model of a heterogenous primary neoplasm. The model is a system of nonlinear ordinary differential equations tracking the mass of up to two different parenchyma cell types, the mass of vascular endothelial cells from which new tumor blood vessels are built and the total length of tumor microvessels. Results predict the possibility of a hypertumor-a focus of aggressively reproducing parenchyma cells that invade and destroy part or all of the tumor, perhaps before it becomes a clinical entity. If this phenomenon occurs, then we should see examples of tumors that develop an aggressive histology but are paradoxically prone to extinction. Neuroblastoma, a common childhood cancer, may sometimes fit this pattern. In addition, this model suggests that parenchyma cell diversity can be maintained by a tissue-like integration of cells specialized to provide different services.

Humans↗

Smoking among participants in the childhood cancer survivors cohort: the Partnership for Health Study.

PURPOSE: This article describes baseline data collection and the intervention design of Partnership for Health, a smoking cessation intervention for smokers in the Childhood Cancer Survivors Study. The purpose of this article is to evaluate demographic, psychosocial, and cancer-related factors that are associated with smoking behavior and mediators of smoking cessation. PATIENTS AND METHODS: This study includes 796 smokers from the Childhood Cancer Survivors Study database who were diagnosed with cancer before the age of 21, had survived at least 5 years, and were at least 18 years of age at the time of the baseline survey. Correlates of smoking behaviors included smoking rate, number of recent quit attempts, and nicotine dependence; two key mediators of smoking cessation, readiness to quit smoking and self-efficacy, were also assessed. RESULTS: Participants smoked, on average, 14 cigarettes/day; 53.2% were nicotine dependent, and 58% had made at least one quit attempt in the past year. Smoking behaviors were primarily associated with demographic variables; mediators of cessation were primarily associated with age at cancer diagnosis and perceived vulnerability to smoking-related illnesses. Severity of psychologic symptoms was associated with increased smoking rate, high nicotine dependence, and low self-efficacy. Support for quitting was related to smoking rate, number of quit attempts, readiness to quit smoking, and self-efficacy. CONCLUSION: These findings indicate that many cancer survivors who smoke are receptive to smoking cessation interventions. Factors related to mediators of smoking cessation might be particularly good targets for intervention.

Adolescent↗

Ribosomal protein P2: a potential molecular target for antisense therapy of human malignancies.

BACKGROUND: Ribosomal protein P2 is an important component of protein translation machinery. We hypothesized that antisense-mediated depletion may disrupt the proteome of cancer cells. This study includes experiments to ascertain whether this could be a useful approach for cancer therapies. MATERIALS AND METHODS: MIA PaCa-2 and BxPC-3 cells were transfected with P2-antisense oligonucleotide or controls. Growth was assayed using MTT. Protein P2 was measured using Western blotting. Proteomes were compared using two-dimensional electrophoresis and changes were characterized by mass spectrometry. A macroarray was used to identify cancers which may be vulnerable. RESULTS: Antisense-P2 reduced P2 levels by 63% (p < 0.05) and inhibited BxPC-3 growth to 65% of control (p < 0.05). Seventeen (5.4%) proteins changed on two-dimensional electrophoresis including Rho C, translationally-controlled tumor protein, vinculin, LDH, ribosomal protein L23a, F-actin capping protein and eIF-3. Breast cancer underexpressed P2 compared to normal tissue (p < 0.001). CONCLUSION: Antisense-P2 technology has potential to slow growth of cancer cells. This effect is mediated through multiple proteomic changes.

Base Sequence↗

Reading between the lines: direct-to-consumer advertising of genetic testing in the USA.

This article critiques an advertisement in a theatre playbill by a bio-technology company for its commercial test for the BRCA1 and BRCA2 genetic mutation, which may indicate a higher risk for breast and ovarian cancer. The advertisement targets a vulnerable audience attending a play about one woman's isolated and painful death from ovarian cancer. It promotes a product with incomplete and at times incorrect information, and it misguides women by suggesting that they contact the company directly about this test, rather than encouraging them to talk to their health care providers about genetic testing and their personal risk of breast cancer. In an era in which more genetic tests will be integrated into clinical practice, we can expect an increase in direct-to-consumer marketing for such tests. This advertisement is an example of what we need to be on guard against.

Advertising↗

Stress and quality of life in African American cancer survivors.

The quality of life (QOL) of cancer survivors must be investigated as we learn about the risks and protective factors associated with cancer survival. Little research has included African American cancer survivors, and this group could be more or less vulnerable to the added stress of cancer. By virtue of the greater stress burden imposed by minority status, lower socioeconomic status, and other social/ cultural factors, African Americans may be at increased risk for poor QOL and poor health outcomes. Alternatively, they may be protected from some of these negative outcomes. We propose a model to better understand the unique sociocultural features that influence QOL for certain cancer sites where racial disparities are well established. A comprehensive knowledge of QOL among these survivors will guide future research and facilitate the development of interventions to improve QOL, possibly reducing observed health disparities.

Adaptation, Psychological↗