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PubMed2000

Human DNA-Topoisomerases - Diagnostic and Therapeutic Implications for Cancer.

Topoisomerases constitute a family of highly conserved essential enzymes, which exist in all investigated living pro- and eukaryotic cells. They are indispensable for the control of DNA topology. Humans possess 4 types of topoisomerases, i. e. topoisomerase (topo) I, II, III and V. Topo I, a 100-kDa protein, is a member of the type-I enzyme group (type IB). Functionally, it is an ATP-independent DNA single-strand endonuclease and ligase that functions mainly during transcription but also during DNA replication. Topo II belongs to the type-II enzymes and is represented in humans by 2 highly homologous isoforms, alpha (170 kDa) and beta (180 kDa). Contrary to topo I, the 2 topo II isoforms are ATP-dependent double-strand endonucleases and ligases. Topo I and the beta-form of topo II are expressed in a proliferation-independent manner, whereas topo IIalpha is cell-cycle-regulated. Because of the crucial role of topoisomerases for the maintenance and replication of DNA during proliferation, cells become highly vulnerable when these functions are lost. Consequently, a wide range of drugs with cytostatic effects are topo inhibitors. Topo I inhibitors in clinical use belong to the camptothecin family, e. g. topotecan and irinotecan. Topo IIalpha inhibitors are constituents of most chemotherapeutic protocols and form a large heterogeneous group. It includes clinically used compounds such as the podophyllotoxin analogues etoposide and teniposide, the anthracyclines daunorubicin, doxorubicin and idarubicin, the anthracenedione mitoxantrone and amsacrine. Recently, substances with dual specificity that inhibit both topo I and topo IIalpha have been found. The clinical relevance of these new compounds remains to be established. Specific inhibitors of topo IIbeta have not been described yet. The majority of topo inhibitors interfere with the religation step in the normal action of the enzymes, which leads to a stabilisation of the so-called cleavable complex. This results in DNA single-strand breaks in the case of topo I or double-strand breaks in the case of topo II. DNA single-strand breaks due to topo I inhibition are converted into double-strand breaks in the course of DNA replication. Such topo-mediated DNA strand breaks likely induce repair or apoptosis mechanisms via p53 and/or p21(WAF1/Clip1). As a consequence, while topoisomerases are required for proliferation, proliferation is also essential for efficacious topo inhibition. The cell-cycle-dependent expression of topo IIwas also successfully used for prognostic evaluations of survival in patients with cancer. Copyright 2000 S. Karger GmbH, Freiburg

Journal Article↗
PubMed2005

Penicillin allergy in cancer patients manifesting as Kounis syndrome.

Two cases of allergic angina and allergic myocardial infarction (Kounis syndrome) following penicillin administration are described. The patients suffered from lung and mandible neoplasms and had previously received several courses of antineoplastic therapy without any sequelae. One patient had normal coronary arteries (type I variant of the syndrome) and the other had coronary artery disease with previous myocardial infarction (type II variant of the syndrome). The allergic reaction following penicillin administration seemed to have triggered the development of an acute coronary artery spasm in the first patient and an acute myocardial infarction in the second. This report shows that susceptible individuals expressing a magnified mast cell degranulation effect may be more vulnerable to coronary artery spasm and plaque erosion or rupture.

Bone Neoplasms↗
PubMedDate not supplied

Depression, Hopelessness, and suicidal ideation in the terminally ill.

This study investigated the mediational hypothesis of hopelessness in predicting suicidal ideation in a group of 196 patients with advanced terminal cancer. Each patient underwent a semistructured interview to assess hopelessness and suicidal ideation, and also completed the Beck Depression Inventory (short form). Hopelessness was correlated more highly with suicidal ideation than was the level of depression. In multiple linear-regression analyses, hopelessness contributed uniquely to the prediction of suicidal ideation when the level of depression was controlled. For health care providers attending to the needs of dying patients, hopelessness appears to be an important clinical marker of suicidal ideation in this vulnerable patient population.

Aged↗
PubMed2002

Our interest is swelling: a collaborative venture to establish the world's first free public screening for lymphoedema.

This article describes the collaborative processes involved in the implementation of a free public health screening program for people at risk of lymphoedema following the removal of lymph nodes during surgery to control breast, prostate and other cancers, or injury. The planning phase of the program is described with emphasis on the need to secure a well situated venue, the commitment of a cohort of key health professionals, service club and lay volunteers, and the need to carefully target and publicise the event widely. The implementation phase requires careful consideration of the physical layout of the event, the direction and management of the flow of human traffic, information and equipment requirements, and recognition that screening programs place people in vulnerable positions. Effective communication skills are essential, as is a knowledge of where people can be referred should the need arise. A budget is provided together with discussion regarding the success of the program and recommendations for future consideration such as the need to target men to attend screening and for long term follow up of the outcomes.

Australia↗
PubMed2001

Relationship issues of women with breast cancer.

This in-depth, qualitative pilot study explored the impact of breast cancer on specific dimensions of the relationships and roles of women. It included interaction within the partner relationship as well as with family, friends, and colleagues. Data were obtained by individual and group interviews from 10 women with a diagnosis of breast cancer and 5 male partners. Both partnered and single women participated. There were four major findings seldom discussed in the literature, which have important implications for preventive intervention. First, partner relationships troubled before the diagnosis as well as those characterized by mutual caring faced challenges and negative changes. Second, in an effort to protect each other, communication within the partner dyad became less open, and there were changes in the usual manner of conflict resolution. Third, unpartnered women appeared to be more vulnerable to problems of negative adjustment, largely because of relationship issues. Fourth, participants confirmed the need for a comprehensive intervention to facilitate coping with issues relative to relationships, intimacy, and sexuality. Although the sample was small, in-depth data were obtained that provide a basis for specific areas in which further empirical investigation is needed, and they indicate that preventive intervention may well be warranted.

Adaptation, Psychological↗
PubMed2003

Relationship between fatigue and nutritional status in patients with cancer undergoing radiotherapy.

PURPOSE: The purpose of this study was to identify the relationship between fatigue and nutritional status in patients undergoing radiotherapy. DESIGN: A correlational and crossectional study design was used. METHOD: One-hundred-fifty-one subjects with cancer receiving radiotherapy were recruited from a university hospital in Chonan, Korea. Fatigue was measured using Piper's Fatigue Scale (PFS). The parameters for nutritional status included body weight, body mass index, hemoglobin, and lymphocyte counts. Cancer stage was controlled in analyzing the differences in fatigue, body weight and body mass index. RESULTS: The patients who experienced most fatigue were in their fifties, employed, had head and neck cancer, received radiotherapy on the head and neck, and had concomitant chemotherapy. Disease-related characteristics such as cancer type, and treatment type were frequently related to poorer nutritional status. Patients who showed poorer nutritional status, such as those with lower body weight, lower body mass index and lower hemoglobin levels were more fatigued than those who did not exhibit such characteristics. Lymphocyte counts did not correlate with fatigue. CONCLUSION: The findings can be used by nurses who are taking care of patients undergoing radiotherapy. Considering the relationship between fatigue and nutritional status, nurses can identify the risk group most vulnerable to fatigue and malnourishment in order to provide appropriate interventions for them.

Journal Article↗
PubMed2026

Fatty acids and breast cancer: Epidemiology, subtype-specific metabolism, immune regulation, and clinical translation.

Fatty acids (FAs) are bioactive dietary and metabolic molecules that participate in membrane architecture, energy homeostasis, inflammatory signaling, gene regulation and immune function, all of which intersect with breast cancer (BC) risk, progression and treatment response. In this narrative review we integrate epidemiological, clinical, translational and mechanistic evidence on the role of FAs in BC. Saturated, monounsaturated, trans- and polyunsaturated FAs (PUFAs) are treated as distinct biological exposures rather than interchangeable measures of total fat intake. Similarly, evidence from dietary assessment, circulating biomarkers, erythrocyte membrane composition, adipose tissue stores and tumor lipid signatures is interpreted separately, because each captures exposure and biology at a different level. BC subtypes differ in FA synthesis, uptake, oxidation, storage and remodeling: luminal tumors are frequently linked to hormone-regulated lipogenesis, human epidermal growth factor receptor 2 (HER2)-positive tumors to growth-factor-driven lipid metabolism, and triple-negative tumors to exogenous FA uptake, inflammatory lipid mediators and ferroptosis-related vulnerabilities. FA-derived mediators also shape immune-cell polarization, cytokine signaling and the tumor microenvironment, and dietary FAs may reshape the gut microbiota; the fiber-derived short-chain FAs it produces, distinct from dietary FAs, likewise help regulate immune and inflammatory tone. Clinical data suggest possible roles for fat-quality modification and selected n-3 PUFA interventions, but findings are heterogeneous and not yet sufficient to support routine biomarker-guided precision onco-nutrition. Candidate biomarkers, such as erythrocyte n-6:n-3 composition, require prospective validation before clinical implementation. FA biology thus represents a modifiable but complex axis in BC prevention, tumor biology and supportive care.

Humans↗
PubMed2006

Incompatible land uses and the topology of cumulative risk.

The extensive literature on environmental justice has, by now, well defined the essential ingredients of cumulative risk, namely, incompatible land uses and vulnerability. Most problematic is the case when risk is produced by a large aggregation of small sources of air toxics. In this article, we test these notions in an area of Southern California, Southeast Los Angeles (SELA), which has come to be known as Asthmatown. Developing a rapid risk mapping protocol, we scan the neighborhood for small potential sources of air toxics and find, literally, hundreds of small point sources within a 2-mile radius, interspersed with residences. We also map the estimated cancer risks and noncancer hazard indices across the landscape. We find that, indeed, such large aggregations of even small, nondominant sources of air toxics can produce markedly elevated levels of risk. In this study, the risk profiles show additional cancer risks of up to 800 in a million and noncancer hazard indices of up to 200 in SELA due to the agglomeration of small point sources. This is significant (for example, estimates of the average regional point-source-related cancer risk range from 125 to 200 in a million). Most importantly, if we were to talk about the risk contour as if they were geological structures, we would observe not only a handful of distinct peaks, but a general "mountain range" running all throughout the study area, which underscores the ubiquity of risk in SELA. Just as cumulative risk has deeply embedded itself into the fabric of the place, so, too, must intervention seek to embed strategies into the institutions and practices of SELA. This has implications for advocacy, as seen in a recently initiated participatory action research project aimed at building health research capacities into the community in keeping with an ethic of care.

Air Pollutants↗
PubMed2005

Neuromuscular junction channelopathies: a brief overview.

The neuromuscular junction lacks the protection of the blood-nerve barrier and is vulnerable to antibody-mediated disorders. In myasthenia gravis (MG), 85% of patients have IgG antibodies to acetylcholine receptors (AChRs). About half the remaining patients have IgG antibodies to Muscle Specific Kinase (MuSK), an AChR-associated transmembrane post-synaptic protein concerned in AChR aggregation. Bulbar weakness is typically predominant in this form of MG, and females are more often affected. The Lambert-Eaton Myasthenic Syndrome (LEMS) can occur in a paraneoplastic form (P-LEMS) usually with small cell lung cancer, or in a non-paraneoplastic form (NP-LEMS). In both, IgG antibodies to nerve terminal voltage-gated calcium channels (VGCCs), detectable in over 90% of patients, lead to VGCC loss and impaired quantal release of transmitter and may be implicated in the occasionally associated cerebellar ataxia. Neuromyotonia (NMT) and Cramp-Fasciculation syndrome (C-FS) are manifestations of peripheral nerve hyperexcitability and share some clinical and electromyographic features. Antibodies to voltage-gated potassium channels (VGKCs) are present in about 40% of NMT patients, but less frequently in C-FS, and appear to cause loss of functional VGKCs. They may also be implicated in the Maladie de Morvan and limbic encephalitis that can associate with NMT: The antibodies described here provide valuable aids to diagnosis and management. The Congenital Myasthenic Syndromes are a group of genetically determined heterogeneous disorders, usually recessively inherited. The commonest mutation sites appear to be the acetylcholine receptor epsilon-subunit and rapsyn.

Adult↗
PubMed1990

The asbestos worker who smokes: adding insult to injury.

Evaluates whether asbestos workers who smoke cigarettes, thereby increasing their cancer risk synergistically, differ from asbestos workers who choose not to smoke. Demographic, personality, psychologic, and cognitive differences were examined. Engaging in this highly detrimental health behavior was related exclusively to cognitive factors. Although current smokers were cognitively aware of their added health risk, in comparison to past and "never" smokers, they minimized the salience of awareness by fatalistically attributing their health to chance factors such as luck and by minimizing the dangers of smoking, the benefits of smoking cessation, and their own increased vulnerability to life-threatening illnesses. Results are explained in light of the apparent denial of risk. The need for physician intervention is strongly advocated.

Asbestosis↗
PubMed2026

A novel lactylation-related gene signature deciphers the immunosuppressive microenvironment and stratifies precision therapy in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality, largely due to the heterogeneity of the tumor microenvironment (TME) and the limited efficacy of immunotherapy in microsatellite stable (MSS) tumors. Histone lactylation, a post-translational modification derived from the Warburg effect, serves as a critical bridge linking metabolic reprogramming to gene regulation and immune evasion; however, its specific prognostic value and clinical implications in CRC remain to be fully elucidated. METHODS: In this study, we systematically analyzed transcriptome profiling data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts, supplemented by single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) protein-level validation. By integrating univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox regression, we constructed a novel lactylation-related gene (LRG) risk signature. We extensively evaluated the association between this risk signature and patient prognosis, immune infiltration patterns, somatic mutations, and therapeutic sensitivity. RESULTS: A robust 9-gene prognostic signature (DHRS7, SPR, MBD2, RBM17, CSRP2, S100A4, TMSB4X, TKT, COPS4) was identified and corroborated at the protein level. Patients with high risk scores exhibited significantly worse overall survival (OS) across the training and two independent validation cohorts. Immunogenomic and scRNA-seq analyses revealed that high-risk tumors were characterized by an immunosuppressive and stromal-dense microenvironment-with stromal cells exhibiting the highest lactylation risk scores-enriched with regulatory T cells (Tregs), and frequently harbored PIK3CA mutations. Differential expression analysis indicated that this immune exclusion is structurally maintained by enriched extracellular matrix (ECM) organization and TGF-β signaling. Conversely, low-risk tumors displayed an inflamed phenotype with active antitumor immunity. Pharmacogenomic prediction identified distinct therapeutic stratifications: low-risk patients exhibited significant sensitivity to standard chemotherapeutics (fluorouracil, oxaliplatin) and EGFR/HER2 inhibitors (e.g., lapatinib, erlotinib). In contrast, high-risk patients showed specific vulnerabilities to novel targeted agents, including PI3K pathway inhibitors (TG-100-115, XL765), microenvironment-modulating agents (sildenafil, GANT-61), and epigenetic inhibitors (UNC0638). CONCLUSION: We established a novel lactylation-related risk signature that effectively stratifies CRC patients by prognosis and TME characteristics. By elucidating the crosstalk between metabolic dysregulation, stromal barriers, and immune exclusion, this study provides potential biomarkers and stratified therapeutic strategies-ranging from standard chemotherapy to targeted metabolic and stromal interventions-to optimize precision medicine for CRC patients.

Colorectal cancer↗
PubMed2005

Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis.

OBJECTIVE: To reconcile apparently conflicting evidence regarding the use of hormone therapy as a health-preserving strategy in postmenopausal women in light of that fact that findings from animal studies, human observation studies, and human clinical trials are consistent for outcomes such as fracture and breast cancer but differ for coronary heart disease (CHD). DESIGN: Literature review and generation of a unified hypothesis consistent with all of the data. SETTING: Animal trials, human observational studies, human studies of biologic intermediates, and human clinical trials. PATIENT(S): Premenopausal and postmenopausal women with or without antecedent CHD. MAIN OUTCOME MEASURE(S): Coronary heart disease events, proxies, risk factors, and related mechanisms. RESULT(S): The complex CHD responses to hormone therapy in recent human trials likely reflect a combination of [1] early erosion/rupture of "vulnerable" coronary plaque, which is made worse by hormone therapy, [2] long-term reduction in plaque formation, which is improved by hormone therapy, and [3] modulation of the vasculoprotective actions of estrogens by systemic progestogens. CONCLUSION(S): The unified hypothesis predicts that hormone therapy initiated at the time of menopause should produce a decrease in CHD over time. In contrast, hormone therapy begun years after menopause should produce an increase in CHD events shortly after therapy is begun, followed later by benefit. In women who require progestogens for endometrial protection, there should be greater CHD benefit from use of progestogens with less systemic activity. The unified hypothesis is consistent both with plausible biologic mechanisms and with evidence from animal studies, human observational studies, and human clinical trials such as the Women's Health Initiative. In the absence of evidence from human trials that specifically involve initiation of hormone therapy in perimenopausal women, practitioners and patients can use the unified hypothesis as a rational tool to guide decisions about clinical management.

Animals↗
PubMed2003

Alcohol abuse and dependence: psychopathology, medical management and dental implications.

BACKGROUND: The authors review the clinical features, epidemiology, pathophysiology, medical management, dental findings and dental treatment of patients with alcoholism. LITERATURE REVIEWED: The authors conducted a MEDLINE search for 1995 through 2001 using the key terms of alcoholism, epidemiology, pathophysiology, treatment and dentistry. Reports selected for further review included those published in English in peer-reviewed journals. The authors gave preference to articles reporting randomized, controlled trials. CONCLUSIONS: Alcoholism is a chronic and progressive psychiatric illness that afflicts more than 14 million Americans. It is characterized by a loss of control over the use of alcohol, resulting in impaired social functioning, and the consequent development of medical illnesses. The disease arises in genetically vulnerable people when they are overwhelmed by their cravings for the alcohol-associated euphoria that results from the actions of several neurotransmitter systems in the brain's pleasure center. New medications to counteract alcohol-induced neurotransmission imbalance may assist patients in reducing their craving. CLINICAL IMPLICATIONS: The prevalence of dental disease usually is extensive because of a disinterest in performing appropriate oral hygiene techniques and diminished salivary flow. Concurrent abuse of tobacco products worsens dental disease and heightens the risk of developing oral cancer. Identification of the alcohol-abusing patient, a cancer-screening examination, preventive dental education, and use of saliva substitutes and anticaries agents are indicated. Special precautions must be taken when performing surgery and when prescribing or administering analgesics, antibiotics or sedative agents that are likely to have an adverse interaction with alcohol or psychiatric medications.

Alcohol Deterrents↗
PubMed1991

Psychological morbidity associated with local recurrence of breast cancer.

Twenty-two individuals who had suffered from local recurrence of breast cancer were interviewed to determine psychosocial morbidity. Psychometric assessment using the Hamilton Anxiety Scale, the Eysenck Personality Questionnaire and the Montgomery Asberg Depression Rating Scale was conducted prior to clinical evaluation including a structured interview, the Composite International Diagnostic Interview. Lifetime and current psychiatric diagnoses were established. Ten (45%) of the recurrence group had current psychiatric illness (anxiety and depression) at the time of local recurrence, a similar prevalence to that described by others at mastectomy. Previous psychiatric illness and trait neuroticism are predictive of vulnerability to psychiatric morbidity at local recurrence. These results suggest that a significant proportion of patients with local recurrence suffer from major depressive illness.

Adult↗
PubMed2005

Health-related quality-of-life in low-income, uninsured men with prostate cancer.

The objective was to describe health-related quality-of-life (HRQOL) in low-income men with prostate cancer. Subjects were drawn from a statewide public assistance prostate cancer program. Telephone and mail surveys included the RAND 12-item Health Survey and UCLA Prostate Cancer Index Short Form and were compared with normative age-matched men without cancer from the general population reported on in the literature. Of 286 eligible men, 233 (81%) agreed to participate and completed the necessary items. The sample consisted of 51% Hispanics, 23% non-Hispanic whites, and 17% African Americans. The low-income men had worse scores in every domain of prostate-specific and general HRQOL than had the age-matched general population controls. The degree of disparity indicated substantial clinical differences in almost every domain of physical and emotional functioning between the sample group and the control group. Linear regression modeling determined that among the low-income men, Hispanic race, and income level were predictive of worse physical functioning, whereas only comorbidities predicted mental health. Low-income patients with prostate cancer appear to have quality-of-life profiles that are meaningfully worse than age-matched men from the general population without cancer reported on in the literature.

Adaptation, Psychological↗
PubMed2001

Effective strategies that enhance adherence to breast cancer screening guidelines.

Mammography has long been recognized as the most effective cancer screening modality. Nevertheless, substantial numbers of women either do not utilize mammography or do not do so in compliance with recommended screening guidelines. A substantial body of literature has been published that discusses strategies likely to be effective in increasing mammography screening. Health care provider recommendation for a mammogram is the single most effective intervention. This paper reviews the more recent literature to highlight a selection of the additional strategies that are most likely to be effective among all women, and among women of various vulnerable cultural and population subgroups. African American, Hispanic, Pacific Asian, and Native American communities are included in the discussion. The paper also addresses other communities with special needs, such as those who are lesbians, elderly, low users of health services, and those who are physically or mentally challenged.

Journal Article↗
PubMed2026

Unraveling the c-Myc-CASC19/HDAC1-NPM1 epigenetic axis: A novel regulatory circuitry and therapeutic target in gastric carcinogenesis.

Mounting evidence implicates long non-coding RNA cancer susceptibility candidate 19 (CASC19) in the pathogenesis of diverse malignancies. However, its functional role and molecular mechanisms in gastric cancer (GC) remain elusive. Herein, we identified a novel 717-bp transcript isoform of CASC19 in GC cells. This study aimed to delineate the biological functions and underlying mechanisms of this novel CASC19 transcript in GC pathogenesis. CASC19 was significantly upregulated in GC tissues and cell lines, correlating with adverse clinicopathological features and poor prognosis in GC patients. Functional investigations demonstrated that CASC19 overexpression potentiated GC cell proliferation, metastasis, and epithelial-mesenchymal transition, whereas CASC19 knockdown attenuated these malignant phenotypes and suppressed tumorigenesis in xenograft models. Mechanistically, CASC19 functioned as a molecular scaffold by recruiting histone deacetylase 1 (HDAC1) to the nucleophosmin 1 (NPM1) promoter. This recruitment sustained H3K27 deacetylation, thereby transcriptionally repressing NPM1 promoter activity and accelerating gastric carcinogenesis. Crucially, Depletion of HDAC1 or NPM1 partial rescued CASC19-mediated oncogenic effects. Intriguingly, the transcription factor c-Myc was found to transcriptionally activate CASC19 through direct binding to its promoter region. Collectively, our findings indicate that the c-Myc-CASC19/HDAC1-NPM1 axis acts as a potential prognostic biomarker candidate for GC and may represent a therapeutic vulnerability worthy of future investigation.

Humans↗
PubMedDate not supplied

Dissociation of innate and adaptive immunity by UVB irradiation.

Increasing ultraviolet-B irradiation (UVB) resulting from diminution of stratospheric ozone is becoming a serious international problem. UVB irradiation exerts not only carcinogenic effects on animals but also causes them to become vulnerable to infections by modulating their immune responses. UVB irradiation suppresses innate immune functions of cells such as macrophages, neutrophils, Langerhans cells, dendritic cells, and the serum component, complement. UVB irradiation also causes changes in cytokine profiles, represented by the induction of a paradigm switch involving Th1/Th2 phenotypes. According to earlier studies, Th1 responses are suppressed, whereas Th2 activities are augmented by UVB irradiation. These immune modulations are caused by several pathways via cytokines and neuropeptides, and eventually may lead to increasing incidences of infection, allergy, and cancer. We have reviewed reports concerning UVB-irradiation induced immune modulation from the viewpoint of risks for human diseases and, in addition, for ecosystems and immunity of lower animals.

Journal Article↗