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PubMed2003

The biology of aging.

In humans, aging is inexorable. The progressive decrease in physiological capacity and the reduced ability to respond to environmental stresses lead to increased susceptibility and vulnerability to disease. Consequently, mortality due to all causes increases exponentially with aging. Attempts at understanding the causes of aging are limited by the complexity of the problem. Aging changes are manifest from the molecular to the organismic level; environmental factors affect experimental observations; secondary effects complicate elucidation of primary mechanisms; and precisely defined, easily measurable biomarkers are lacking. No one unifying theory may exist, since the mechanisms of aging could be quite distinct in different organisms, tissues, and cells. Evolutionary pressures have selected for successful reproduction, making it likely that the post-reproductive physiology of an organism (i.e., aging) is an epigenetic and pleiotropic manifestation of the optimization for early fitness. Indeed, antagonistic pleiotropy, wherein genes that enhance early survival and function but are disadvantageous later in life, may play an overriding role in aging. Theories of aging can be divided into two general categories: stochastic and developmental-genetic. These are not mutually exclusive, particularly when considering the free radical/mitochondrial DNA theory of aging. Increasing evidence suggests that cellular senescence and organismic aging are antagonistically pleiotropic manifestations of evolutionary pressures to prevent malignant transformation. In other words, aging may be the price we pay to avoid cancer. The beneficial paradox may be that the maximum lifespan potential of humans may have been achieved, in part, due to our ability to grow old.

Adaptation, Physiological↗
PubMed2004

The Appalachia Cancer Network: cancer control research among a rural, medically underserved population.

Residents of Appalachia, especially those in rural Appalachia, are generally considered to be medically underserved. In fact, cancer mortality in Appalachia, especially in rural Appalachia, is higher than it is in the remainder of the United States. Developing from the Appalachia Leadership Initiative on Cancer, the Appalachia Cancer Network (ACN) is a network of academic and community organizations that seek to conduct surveillance, intervention, and dissemination research to reduce this excess cancer burden in Appalachia. The purpose of this report is to (1) describe the approach to cancer control research in ACN, a Special Population Network, among the medically underserved of Appalachia, and (2) to put forward observations from this experience to enhance the research of other academic and community networks among underserved populations. ACN has instituted a conceptual model, organizational structure, and other methods to foster this research and to develop junior and community-based investigators. Important issues and questions related to the effectiveness of such research networks have also been articulated.

Appalachian Region↗
PubMed1999

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors.

The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein EIB19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.

Actins↗
PubMed2006

Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies.

The main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft-versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies. After transplantation, 91% of the patients achieved full donor chimaerism. They also showed rapid recovery of CD3(+) T-cells, T-cell receptor (TCR) excision circle counts, TCRbeta repertoire diversity and natural killer (NK)-cells during the first 4 months post-transplantation, compared with those results from a group of patients treated with a myeloablative conditioning regimen. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

Adolescent↗
PubMed2003

Depression and anxiety during isolation and radionuclide therapy.

The combination of a diagnosis of malignancy and hospitalization, isolation and radioactivity of a radionuclide therapy may have an important effect on the psychological equilibrium of patients and may hamper compliance and acceptability. We performed a psychiatric evaluation in order to study psycho-pathological manifestations and underlying personality related vulnerabilities. During radioisolation, 48 patients (24 male, 24 female; mean age 57.8 years) with a malignant (n=26) or non-malignant (n=22) pathology who needed isolation for radionuclide therapy, completed a series of questionnaires in order to assess anxiety (Spielberger State and Trait Anxiety Inventory; STAI), depression (Beck Depression Inventory; BDI), hopelessness (Beck Hopelessness Scale; BHS), personality characteristics (Temperament and Character Inventory; TCI) and coping strategies (Utrecht's Coping List; UCL). Compared to patients with low state anxiety, patients who experienced a high level of state anxiety showed higher levels of depression (t=-2.10; P=0.04) and hopelessness (t=-4.20; P=<0.001). Their personality was characterized by significantly higher scores on harm avoidance (t=-2.78; P=0.008) and lower scores on self-directedness (t=3.12; P=0.003). Coping strategies were more passive (t=-2.43; P=0.02), avoiding (t=-2.15; P=0.04) and less well aimed (t=2.64; P=0.01). Surprisingly, the nature of disease (malignant versus non-malignant) did not influence these results, nor was there a difference between males and females, age, years of education, having a relationship or not, or the duration of hospitalization. Thus, contrary to what may be expected in isolation with radionuclide therapy, subgroups such as women, elderly, cancer patients or lower educated people do not, a priori, exhibit a higher state anxiety level. Our study shows these levels to be closely related to individual personality traits and coping strategies that are inadequate for the situation. Screening for trait anxiety before admission can be easily done and may guide interventions aimed at increasing patient comfort and acceptability.

Adaptation, Psychological↗
PubMed2025

Efficacy of MET-targeting CAR T cells against glioblastoma patient-derived xenograft models.

BACKGROUND: Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity. METHODS: GBM patient-derived xenografts (PDX) harboring MET amplification (METamp) or PTPRZ-MET fusion (ZM) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo. RESULTS: Although GBM are heterogeneous tumors, neuro-sphere cells isolated from METamp or ZM fusion PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both METamp and ZM fusion tumors showed MET overexpression but only the METamp cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status. CONCLUSIONS: Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially METamp and ZM fusion may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.

Glioblastoma↗
PubMed2000

Taking control: findings of a prospective study of an educational course for patients with leukaemia.

The challenge of coping with a chronic and life-threatening diagnosis such as a haematological malignancy, with the associated repeated, lengthy, and often invasive treatment interventions, can have a profound effect on all aspects of life. Patients and their families not only need information to help them understand the cancer experience, but also need support to generate coping strategies as the demands of the illness and its treatment exceed the individual's resources. Structured psycho-educational interventions, based on a strong informational component that aim to improve participants' adaptation to the disease and cancer situation, are one approach to providing such support. This article presents the findings from a recent prospective evaluation of the Leukaemia Foundation of Queensland's educational support course, Taking Control, which is designed for patients with a haematological malignancy and their families. The aim of this study was to record the participants' understanding of the positive and negative aspects and outcomes of course attendance. This is a prospective study of participants' perceptions of their experience with the 'Taking Control' course during the first half of 1999 (n =35; response rate 74.3%), using an author-designed, self-report questionnaire. The findings indicate that participants experience a high level of satisfaction, gain substantially in terms of knowledge, coping skills, and a positive framework within which to view their illness. Many obtain great value from the opportunity to meet and talk with others in similar situations. This study, which builds on previous retrospective research, affirms that this course has much to offer those who are confronted with the life-altering diagnosis of a haematological malignancy. However, the work also points to the need for special consideration to be given to a consistent minority of participants who will find socialising with their peers difficult whilst they are feeling so vulnerable and who have styles of processing information that can easily lead to 'information overload'. It is anticipated that the discussion of these findings will go some way to providing sufficient information and insight for similar courses to be duplicated, with confidence, elsewhere.

Adaptation, Psychological↗
PubMed1989

[Autologous bone marrow transplantation as a measure against myelosuppression in cancer chemotherapy].

One hundred seventy-three patients were treated 256 times with chemotherapy supported by autologous bone marrow transplantation during the past 9 years. The two most commonly used protocols were (cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 80 mg/m2 + ACNU 3 mg/kg) and (cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 100 mg/m2 + CDDP 100-150 mg/m2). Among 115 patients in the therapeutic setting in which two courses were usually given, 75 were evaluable and the overall response rate was 42.7% with 12.0% CR rate. Breast and pediatric groups responded well; the response rate in breast cancer was 67.9% with 21.4% CR rate. Two patients with breast cancer who had multiple distant metastases and 2 pediatric patients are now alive with NED after 5 years of the treatment and seem to have been cured. The results in adjuvant settings have also been quite promising, e.g., 79.4% 5-year survival probability among breast patients mainly in stage III. Although drops of blood cell counts to the nadirs (WBC counts: less than 100-300) could not be prevented, the periods of myelosuppression appeared to have been effectively shortened so that the patients could be safely managed with intensified general supportive measures. Platelet counts are usually less affected, but the recovery is slower than for WBC counts. There were 13 patients who died within 10 weeks of the initiation of the treatment. Two of them succumbed to sepsis, and progressive disease was the cause of death in 8 patients whose terminal phases were undoubtedly affected by some infectious problems. We have shown that there are inverse relationships between infused numbers of CFU-GM and marrow recovery judged by the duration of neutropenia and the time required for neutrophils to recover over 500. Our recent laboratory experiments testing CFU-E, BFU-E and CFU-Mk in addition to MNC counts and CFU-GM showed that vulnerabilities of marrow progenitors seem to differ from cell lineage to cell lineage. This must therefore be taken into careful consideration in pursuing marrow transplantation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Hypopituitarism after cranial irradiation.

Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. While the rapidity of onset of these abnormalities is primarily radiation dose-dependent, their frequency and severity also depend on the length of follow-up. The GH axis is the most vulnerable to radiation damage, and GH deficiency is usually the only neuro-endocrine abnormality following irradiation of the h-p axis with doses <30 Gy. With higher radiation doses (30-50 Gy), the frequency of GH insufficiency can be as high as 50-100% and that of TSH and ACTH around 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently, and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia has been described in both sexes and all ages, but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies, (30-60% after 10 yr) occurs after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy, to improve linear growth and prevent short stature in children cured from cancer, to preserve sexual function, prevent ill health and osteoporosis, and improve the quality of life.

Brain Neoplasms↗
PubMed2003

Sunbed use among Swedish adolescents in the 1990s: a decline with an unchanged relationship to health risk behaviors.

AIMS: Sunbed use is common among adolescents, and may give an increment to UV exposure and an overall skin cancer risk comparable to that of the sun. Sunbed use was studied among 15- to 19-year-old adolescents in Stockholm County. METHODS: Data from two questionnaire surveys (1252 respondents in 1993, and 2950 respondents in 1999, survey tool partly revised) were analysed. By stepwise binary logistic regression the occurrence of sunbed use was assessed and analysed versus sunbed erythema, skin type, outdoor tanning, sunscreen use and smoking. RESULTS: Sunbed use declined between the surveys. In 1993, 70% of females, and 44% of males used sunbeds; in 1999, these were 45% and 19% respectively. Sunbeds were used against user recommendations. Of the sunbed users in 1993, 45% and 43% reported sunbed erythema; in 1999, 29% and 19% did so. Sunbed erythema, though related to sun sensitivity, occurred in all skin types. In both surveys, sunbed use was positively related to moderately sensitive skin type (females), outdoor tanning, and smoking (females). Smoking was a strong predictor for sunbed use among females in both surveys. CONCLUSIONS: Even though different survey tools were used, and in spite of a decline in sunbed use, sunbed erythema was still common, and the relation to other health risk behaviour remained. Further research on sunbed use and its role in the aggregation of health risk behaviours in vulnerable ages is warranted, particularly its relation to outdoor tanning and smoking. A national and international harmonization of survey tools is also recommended for improved comparability.

Adolescent↗
PubMed2026

Integrative Multiomics and Drug Sensitivity Profiling Reveal Potential Biomarkers and Therapeutic Strategies in Pediatric Solid Tumors.

UNLABELLED: Cure rates for childhood malignancies using established therapy protocols have increased to an average of 80% but have reached a plateau. Moreover, survival rates are particularly low for some pediatric tumors-such as high-risk group 3 medulloblastomas, osteosarcomas, Ewing sarcomas, high-risk neuroblastomas, and high-grade gliomas-and dismal for patients with relapsed malignancies. A functional drug response profiling platform for pediatric solid and brain tumors has been established within the INFORM program to identify patient-specific vulnerabilities and biomarkers and to unravel molecular mechanisms associated with drug response profiles for clinical translation. In this study, we performed a multiomics analysis using drug sensitivity profiles, as well as genomic and transcriptomic data, of 81 pediatric solid tumor samples. The integrative analysis suggested two multiomics signatures associated with drug sensitivity. One signature distinguished neuroblastoma samples with sensitivity to navitoclax, a BCL2 family inhibitor. A second signature was specific to a subset of Wilms tumors harboring the SIX1 (Q177R) hotspot mutation that displayed high expression of MGAM, PTPN14, STAT4, and KDM2B and high sensitivity to MEK inhibitors. A patient-specific causal interaction network analysis suggested possible molecular interactions between MEK inhibitors and the SIX1 mutation in Wilms tumor samples. In conclusion, the integration of drug sensitivity profiling and multiomics data revealed potential biomarkers that may be associated with drug sensitivity in pediatric solid tumors. Patient-specific causal interaction network analysis further elucidated the interaction between inhibitors and signature biomarkers, providing insights that may inform clinical translation. SIGNIFICANCE: The combination of multiomics analysis and drug sensitivity profiling identified two signatures related to drug sensitivity in pediatric solid tumors, contributing to the advancement of functional precision medicine and personalized treatment strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .

Humans↗
PubMed2004

Health promotion interventions for disadvantaged women: overview of the WISEWOMAN projects.

BACKGROUND: The Well-Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) program aims to remove racial and ethnic disparities in health by addressing the screening and intervention needs of midlife uninsured women. This paper describes the WISEWOMAN program requirements, the design of the 12 projects funded in 2002, the use of a standardized data reporting and analysis system, risk factors among participants, effective behavioral strategies, and plans for the future. METHODS: The WISEWOMAN demonstration projects are examining the feasibility and effectiveness of adding a cardiovascular disease (CVD) prevention component to the early detection of breast and cervical cancer. Women aged 40-64 are eligible if they are enrolled in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) in selected U. S. states and are financially disadvantaged and lack health insurance. The primary outcome measures are blood pressure, lipid levels, and tobacco use. Intermediate measures include self-reported diet and physical activity, measures of readiness for change, and barriers to behavior change. RESULTS: During 2002, the 10 projects that were fully operational screened 8164 financially disadvantaged women and developed culturally and regionally appropriate nutrition and physical activity interventions for a variety of racial and ethnic backgrounds. Twenty-three percent of the women screened had high total cholesterol, with 48% of these being newly diagnosed. Thirty-eight percent of the women had high blood pressure, with 24% being newly diagnosed. Approximately, 75% of participants were either overweight or obese, and in some sites up to 42% were smokers. CONCLUSIONS: The WISEWOMAN demonstration projects have been successful at reaching financially disadvantaged and minority women who are at high risk for chronic diseases. These projects face challenges because they are generally implemented by safety net providers who have limited resources and staff to conduct research and evaluation. On the other hand, the findings from these projects will be especially informative in reducing health disparities because they are conducted in those settings where the most socially and medically vulnerable women receive care.

Breast Neoplasms↗
PubMed1998

Expression of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of the lung with observations on the expression of these adhesion molecules in non-neoplastic lung tissue.

Intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and the lymphocyte function-associated antigen (LFA-1) are cell adhesion molecules thought to play an important role in the complex process of airway inflammation and tumor cell growth. The aim of this study was to examine the distribution of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of lung and in major cellular compartments of non-neoplastic lung tissue. We examined cellular compartments in tissue from five bronchoalveolar carcinomas, three acinar adenocarcinomas, and one colon cancer metastatic to the lung. The compartments in neoplasms included the tumor cells proper, endothelial cells within the tumor vasculature, tumor stromal cells, and tumor-infiltrating lymphocytes. The compartments in non-neoplastic lung tissue included lung endothelial cells, pulmonary lymphocytes, interstitial fibroblasts, Type II alveolar pneumocytes, and bronchial epithelial cells. ICAM-1 was expressed in tumor cells from all of the nine adenocarcinomas. In contrast, VCAM-1 expression was not identified in tumor cells from any of the nine adenocarcinomas. ICAM-1 was expressed in all cellular compartments of the non-neoplastic lung tissue, whereas VCAM-1 was expressed only in pulmonary lymphocytes and interstitial fibroblastic cells. LFA-1 was uniformly expressed in tumor-infiltrating lymphocytes from each of the nine tumors and all of the lymphocytes in non-neoplastic lung tissue. This study showed major differences in the expression of ICAM-1 and VCAM-1 in tumor cells from pulmonary adenocarcinoma and also provided evidence for a wider distribution of ICAM-1, compared with VCAM-1, in non-neoplastic cellular compartments of the lung. ICAM-1 expression was particularly noticeable in bronchial and alveolar epithelial cells. Upregulation of ICAM-1 in pulmonary adenocarcinoma might foster binding by LFA-1-bearing lymphocytes, with a possible impact on the vulnerability of tumor cells to host defense mechanisms.

Adenocarcinoma↗
PubMed1995

Neuropsychological effects of cranial radiation: current knowledge and future directions.

Radiation is an invaluable therapeutic tool in the treatment of cancer, with well-established palliative and curative efficacy. As patient survival has improved, attention has focused on long-range treatment side effects. One such adverse effect, neuropsychological impairment, is incompletely understood. Much of the extant research has been directed at childhood leukemia survivors treated with low-dose whole-brain radiation. Less is known about the effects of high-dose focal or whole-brain radiation used in the treatment of brain lesions. This article reviews the scientific literature in this area, with greatest emphasis on methodologically rigorous studies. Research design considerations are discussed. Review findings suggest that low-dose whole-brain radiation (18 to 24 Gy) in children is associated with mild delayed IQ decline, with more substantial deficits occurring in children treated at a young age. A high incidence of learning disabilities and academic failure is observed in this population and may be caused by poor attention and memory rather than low intellectual level. Children who receive higher dose radiation for treatment of brain tumors experience more pronounced cognitive decline. At higher doses, whole-brain radiation, in particular, is linked to deleterious cognitive outcomes. Remarkably little is known about cognitive outcomes in irradiated adults. Preliminary findings indicate that certain cognitive functions, including memory, may be more vulnerable to decline than others. Suggestions for future research are proposed.

Adult↗
PubMed2002

B-mode ultrasound and spiral CT for the assessment of carotid atherosclerosis.

More studies on the natural history of carotid artery plaques are needed to predict more reliably which plaque types or features are the most dangerous (see Table 2). Studies on carotid and coronary endarterectomy specimens indicate a dynamic process of rupture, thrombus formation, healing, and remodeling of the plaque. A plaque from a symptomatic patient may not show any signs of plaque rupture if the plaque has healed or evolved since the debut of symptoms. Selection of high-risk symptomatic patients with carotid atherosclerosis for medical or surgical treatment requires reliable, noninvasive, and cost-effective imaging methods. B-mode ultrasonography can be used for detection of early (IMT) as well as late (plaque morphology) atherosclerotic disease. Plaque morphology evaluation on spiral CT imaging is only for research and not yet for clinical use. Asymptomatic patients with carotid atherosclerosis hardly benefit from surgical treatment, as the minimal decrease in ischemic stroke risk is almost equal to the risk of perioperative stroke or death. A high degree of carotid stenosis measured using conventional angiography is an accepted risk factor for stroke but does not identify all vulnerable plaques. Echolucency on ultrasound B-mode imaging can be included as an important parameter in this risk stratification, as it appears to predict rupture-prone, lipid-rich plaques in the mild to severely stenotic carotid artery of a symptomatic patient. The subjective evaluation of plaque morphology on B-mode ultrasound should be complemented or substituted with objective evaluation such as videodensitometric analysis. This method is commercially available and is a relatively cheap and investigator-independent solution, but more studies are required to determine the exact contribution of echolucency to stroke risk. Furthermore, the evaluation of plaque morphology using ultrasound B-mode is still subject to large variations and observer-dependence, limiting its clinical use. In contrast, carotid IMT measurements are reliable to monitor progression and regression of early carotid disease as well as the impact of interventions. This method, however, suffers when used in severely diseased vessels where the boundaries of the IMT complex are hard to distinguish in all segments of the artery. Spiral CT imaging is a preliminary test for plaque characterization, as it primarily identifies calcification but not the more relevant lipid component. Moreover, it is time and resource demanding and involves use of both contrast and radiation, increasing the risk of allergic events and cancer. Standardization and continuous quality control are important, as are consensus agreements on how to quantify lesions (especially IMT), calibrate and standardize B-mode images and outline the plaque, and analyze data. The development of imaging methods for atherosclerotic research is currently fast and promising. This progress is most necessary, considering the very high demands for surrogate endpoints and risk markers in clinical intervention studies. Whether ultrasonic plaque characterization can be implemented in broad general clinical practice, for example, in screening of individuals at high risk of developing atherosclerosis and ischemic events, has to be based upon data from large prospective studies with long-term follow-up. IMT is already used in population screening, as in the ARIC study [9,101].

Arteriosclerosis↗
PubMed2026

Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5 destabilization in prostate cancer.

Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.

Male↗
PubMed2005

Poor knowledge regarding the Pap test among low-income women undergoing routine screening.

CONTEXT: Many women undergoing cervical cancer screening lack appropriate understanding of the Pap test. It is important to evaluate knowledge and informational needs about Pap testing among groups who may have difficulty accessing care or a relatively low likelihood of obtaining follow-up for an abnormal result, such as minority and low-income women. METHODS: A sample of 338 women undergoing cervical screening at two clinics in Texas completed a questionnaire measuring their knowledge of Pap testing and asking what specific information they would like to know about the test. Group comparisons and qualitative analyses were conducted. RESULTS: Women correctly answered an average of 8.7 out of 20 questions; the range was 0-17. Mean scores were higher among white women (10.2) than among blacks (8.4) and Hispanics (7.4), among women with more than a high school education than among their less educated counterparts (10.0 vs. 7.9) and among women with an annual household income of at least $10,000 than among those with a lower income (9.3 vs. 8.4). Knowledge scores did not differ according to Pap history. Open-ended questioning identified a need for information on the purpose of the test, exam procedures, abnormal test results and prognosis. CONCLUSIONS: Minority women and those of low socioeconomic status had poor understanding of Pap testing. Identifying misunderstandings in this vulnerable population and improving patient education on the most basic aspects of Pap testing may increase adherence to follow-up when abnormalities are detected.

Adolescent↗
PubMed2002

The role of biomedical and psychosocial factors for the prediction of pain and distress in patients undergoing high-dose therapy and BMT/PBSCT.

Recent research has shown that cancer patients undergoing bone marrow transplantation (BMT) experience moderate to severe mouth pain due to treatment-related mucositis in spite of morphine therapy. Treatment-related emotional distress in BMT patients is also described widely. This study examined several biomedical, psychological and social variables as possible predictors for the intensity of treatment-related mouth pain and anxious mood in 63 cancer patients undergoing BMT or stem cell transplantation (SCT) within a prospective longitudinal design. Biomedical predictors included biomedical risk, mucositis, the mode of transplantation, total body irradiation, age and gender. Psychological predictors were depression (BDI), BMT-related distress, chronic stress and resources in everyday life (KISS), pain-related coping behaviour (KPI-17) and social support (ISSS). Among the social variables we evaluated education, being married and the living situation. Criteria variables were the intensity of mouth pain and anxious mood which were assessed daily by numeric self-rating scales for 24 days after transplantation. Results of stepwise multiple regressions indicated that psychological and social variables were important predictors of mouth pain, besides biomedical variables. Whereas the biomedical variables revealed the most predictive power during the second week after BMT, psychological predictors were more important during the early and late phases of the treatment. Daily anxious mood was best predicted by psychological and social variables. Among the biomedical variables mucositis was most strongly related to mouth pain besides mode of transplantation, risk, TBI and age. Among the psychological variables BMT-related distress was the most important predictor, with resources in private life or at work and pain-related coping modes as further significant predictors. These results imply that relevant predictors should be assessed as high risk factors for an increased vulnerability for treatment-related side-effects before treatment starts indicating an additional offer of psychological treatment in high risk patients.

Adult↗