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PubMed1995

The etiology and management of acute and late sequelae of radiation therapy in persons with head and neck cancers.

Radiation therapy is an important primary modality in the treatment of cancers of the head and neck. Persons with advanced cancers often receive combined-modality treatment with concomitant radiation and chemotherapy. The sequelae of radiation alone and that of combined therapies create an extremely vulnerable individual. The nurse caring for the person receiving cancer treatment must understand the effect of radiation on normal tissues of the head and neck region and the methods designed to ameliorate the sequelae of therapy.

Acute Disease↗

PubMed2005

Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

BACKGROUND: Barrett's metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett's mucosa for the development of esophageal adenocarcinoma. METHODS: The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. RESULTS: Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). CONCLUSIONS: The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett's mucosa seems to be the most vulnerable location for the development of invasive cancer.

Adenocarcinoma↗

PubMed2006

Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients--a preliminary PET study.

OBJECTIVES: To explore neurobiological risk factors for major depressive disorder (MDD) and adjustment disorder in cancer patients by examining regional brain metabolism before psychiatric manifestation using positron emission tomography and by prospectively observing depressive and anxiety symptoms. METHOD: Cancer patients who showed no psychiatric symptoms when they underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) were followed up for one year using the Hospital Anxiety and Depression Scale (HADS). Fourteen patients who showed high HADS scores and 14 patients who showed low HADS scores were assessed by a psychiatrist 2 years after the PET scan and grouped into the deterioration group (n=10) and the no-change group (n=9). 18F-FDG PET images were analyzed to examine the difference in local brain glucose metabolism between the two groups. RESULTS: The deterioration group showed a decreased glucose metabolism in the right medial frontal gyrus (BA6) and an increased glucose metabolism in the right posterior cingulate (BA29), right anterior cingulate (BA25), left subcallosal gyrus (BA25), and left caudate compared with the no-change group. CONCLUSION: Cancer patients who later developed MDD or adjustment disorder showed regional brain metabolic changes. These regions may be associated with vulnerability to the onset of MDD or adjustment disorder in cancer patients.

Adjustment Disorders↗

PubMed2026

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

DDT↗

PubMed2025

In vivo CRISPR screening links NFKB1 to endocrine resistance in ER⁺ breast cancer.

Resistance to endocrine therapy (ET) remains a major clinical challenge in the treatment of estrogen receptor-positive (ER⁺) breast cancer, underscoring the need for novel therapeutic targets. To identify genetic drivers of ET resistance, we conducted an in vivo genome-wide CRISPR-Cas9 screen in MCF7 cells implanted into ovariectomized nude mice under estrogen-deprived conditions. NFKB1 emerged as a top candidate whose loss promoted estrogen-independent tumor growth and recurrence. Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro and in vivo. Mechanistically, transcriptomic and biochemical analyses revealed that NFKB1 loss activated canonical NF-κB signaling, leading to inflammatory gene induction and hyperactivation of ER signaling. Importantly, pharmacologic inhibition of NF-κB signaling restored ET sensitivity in NFKB1-deficient cells. Clinically, NFKB1 downregulation was enriched in ER⁺ breast tumors and associated with poor patient outcomes. Collectively, these findings establish NFKB1 as a key suppressor of ET resistance, uncover a mechanistic link between inflammation and ER reactivation, and highlight NF-κB signaling as a therapeutic vulnerability in NFKB1-deficient ER⁺ breast cancer.

Journal Article↗

PubMed2026

Ascites reprograms innate lymphoid immune cells in ovarian cancer by promoting ILC2 enrichment and dysfunctional NK-cell states.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is commonly accompanied by malignant ascites, a clinically relevant tumor niche that promotes immune evasion, metastasis, and treatment resistance. Although natural killer (NK)-cell dysfunction has been described in ovarian cancer, the broader innate lymphoid landscape of ascites and the mechanisms linking ascites-derived signals to innate immune suppression remain insufficiently resolved. METHODS: We performed single-cell RNA sequencing of NK/innate lymphoid cells from ovarian cancer ascites to define cellular heterogeneity and differentiation states. Functional assays assessed NK-cell cytotoxicity, degranulation, and receptor expression following exposure to patient-derived ascites, with or without transforming growth factor-β (TGF-β) receptor inhibition. Proteomic profiling was used to characterize the soluble ascites milieu, and clinical associations were examined for innate lymphoid subsets. RESULTS: Single-cell analysis identified eight transcriptionally distinct NK/innate lymphoid states, including cytotoxic, precursor, early-like, tolerant/immunoregulatory, regulatory, proinflammatory, and innate lymphoid populations. Ovarian cancer ascites was characterized by depletion of cytotoxic and precursor NK-cell states together with enrichment of early-like, tolerant, regulatory, pro-inflammatory, and innate lymphoid cell (ILC) populations. Trajectory analysis indicated impaired maturation toward terminally differentiated cytotoxic NK cells. Notably, ascites contained an expanded population of programmed cell death protein 1 (PD-1)+ ILC2s, which were more abundant in patients with shorter progression-free survival. In functional assays, short-term exposure of healthy donor NK cells to ascites suppressed degranulation and tumor-cell killing, reduced expression of activating receptors including NKp30 and DNAM-1, increased inhibitory receptor expression, and shifted NK cells toward a CD56highCD16low phenotype. Proteomic profiling supported a soluble milieu consistent with type 2 immune skewing and NK-cell suppression. Importantly, TGF-β receptor inhibition partially restored NK-cell activation and function in the presence of ascites. CONCLUSIONS: HGSOC ascites establishes a type 2-skewed immunoregulatory niche that coordinately drives NK cell dysfunction and PD-1+ ILC2 accumulation. The findings identify TGF-β-linked suppression and ascites-associated immune regulators as candidate immunotherapeutic vulnerabilities for restoring antitumor immunity in ovarian cancer.

Humans↗

PubMed1989

Morphologic characteristics of pancreatic carcinoma with diabetes mellitus.

For 81 cases of resectable pancreatic carcinoma, the site of cancer origin, cancer histologic features, and hyperplasia in the noninvolved duct were studied in relation to diabetes. They were classified into the following three groups: (1) fasting blood sugar (FBS) of less than 120 mg/dl (Group A, 26 cases); (2) FBS of more than 120 mg/dl with less than 2-year history of diabetes (Group B, 38 cases); and (3) FBS of more than 120 mg/dl with more than a 2-year history of diabetes (Group C, 17 cases). Although neither tumor size nor tumor location differed between the three groups, both the highest resectability (47%) and the lowest rate (71%) of extrapancreatic invasion were seen in Group C. A pancreatic ductogram showed that the pattern of the main pancreatic duct was intact in 0% in Group C versus 35% in Group A (P less than 0.05). Histologically, papillary/well-differentiated adenocarcinoma was present in 35% of Group A patients versus 61% of Group B and 71% of Group C patients (P less than 0.05). Papillary hyperplasia was present in the ducts of 27% of the patients in Group A; this was significantly lower than the other two groups. Atypical duct hyperplasia was present in 47% of Group C patients; this was significantly higher than in the other two groups. It appears that cells in the main pancreatic duct are vulnerable to hyperplastic and well-differentiated cancerous changes in patients with a history of diabetes of more than 2 years duration.

Adenocarcinoma↗

PubMed2026

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma.

BACKGROUND: Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored. METHODS: Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers. RESULTS: Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions. CONCLUSIONS: This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

Humans↗

PubMed2003

Telomerase as a novel and potentially selective target for cancer chemotherapy.

Telomeres are the structures that protect eukaryotic chromosomes from recognition by DNA damage surveillance mechanisms and are maintained in the germ line of multicellular animals by telomerase. In most human somatic cells telomerase is silenced during development and after extensive cell division telomeres shorten to trigger growth arrest. Around 80% of human cancers escape from this growth arrest by re-activating telomerase but at diagnosis many cancers still have very short telomeres making them very vulnerable to the inhibition of telomerase. As normal cells have a considerable telomere reserve, even in elderly humans, this makes telomerase an attractive and potentially selective anti-cancer drug target. Proof-of-principle experiments are reviewed which show that this optimism may be justified at least for the subset of human cancers with short telomeres. I also address many of the commonly raised concerns that surround telomerase as a target for anti-cancer drug design.

Animals↗

PubMedDate not supplied

Melatonin suppression by static and extremely low frequency electromagnetic fields: relationship to the reported increased incidence of cancer.

An increased cancer incidence has been reported in individuals living and/or working in an environment in which they are exposed to higher than normal artificial electromagnetic fields. One of the most uniform changes associated with the exposure of animals to either pulsed static geomagnetic fields or to sinusoidal extremely low frequency magnetic fields has been a reduction in high night-time levels of melatonin. Melatonin is a hormone produced especially at night in the pineal gland, a pea-sized organ near the center of the human brain. The high nocturnal production of melatonin leads to elevated blood melatonin levels at night as well. The exposure of humans or animals to light (visible electromagnetic radiation) at night rapidly depresses pineal melatonin production and blood melatonin levels. Likewise, the exposure of animals to various pulsed static and extremely low frequency magnetic fields also reduces melatonin levels. Melatonin is a potent oncostatic agent and it prevents both the initiation and promotion of cancer. Reduction of melatonin, at night, by any means, increases cells' vulnerability to alteration by carcinogenic agents. Thus, if in fact artificial electromagnetic field exposure increases the incidence of cancer in humans, a plausible mechanism could involve a reduction in melatonin which is the consequence of such exposures.

Animals↗

PubMedDate not supplied

Attention and symptom distress in women with and without breast cancer.

BACKGROUND: The cognitive capacity to direct attention (CDA) is essential for self-care and independent functioning. Older women may be more vulnerable to fatigue-related losses in CDA following surgery for breast cancer. Normal functional variations in CDA associated with aging might affect attentional responses in older women newly diagnosed with breast cancer, and factors such as extent of surgery or symptom distress might influence CDA over time. OBJECTIVES: To examine (a) differences in CDA and symptom distress in older women newly diagnosed with breast cancer as compared to a control group of older women without breast cancer; (b) the pattern of change in CDA and symptom distress from the pretreatment period to 3 months after surgery; and (c) to examine the relationship of CDA with symptom distress and extent of surgery over time. METHODS: Women, 55 to 79 years of age, newly diagnosed with breast cancer (N = 47), were assessed with measures of CDA and symptom distress: (a) before surgery, (b) at 2 weeks postsurgery, and (c) 3 months postsurgery. To account for normal variations associated with aging, 48 women of similar age without breast cancer were assessed following a routine screening mammogram and 3 months later. RESULTS: Before treatment, the breast cancer group scored significantly lower than the control group (p < .05) on measures of CDA and higher on symptom distress. Repeated measures ANOVA showed significant main effects of group, but not time, for the measures of CDA and symptom distress with the breast cancer group having worse status than the control group. For CDA only, there was a significant group by time interaction effect (p = .005) so that the breast cancer group showed a gradual gain in CDA over time. CONCLUSIONS: Reduced performance in a cognitive function was observed before treatment and found to persist over an extended interval in older women newly diagnosed with breast cancer.

Aged↗

PubMed2004

Gel-based application of siRNA to human epithelial cancer cells induces RNAi-dependent apoptosis.

Gene silencing by RNA interference (RNAi) operates at the level of mRNA that is targeted for destruction with exquisite sequence specificity. In principle, any disease-related mRNA sequence is a putative target for RNAi-based therapeutics. To develop this therapeutic potential, it is necessary to develop ways of inducing RNAi by clinically acceptable delivery procedures. Here, we ask if inducers of RNAi can be delivered to human cells via a gel-based medium. RNAi was induced using synthetic small interfering RNAs (siRNAs), which bypass the need for expression vectors and carry the added bonus of high potency and immediate efficacy. Established cultures of human cells of normal and tumor origin were overlaid with an agarose/liposome/siRNA gel formulation without adverse effects on cell viability or proliferation. Epithelial cancer cells (but not normal human fibroblasts) proved vulnerable to specific siRNAs delivered via the agarose/liposome/siRNA formulation. Moreover, proapoptotic siRNAs induced apoptosis of cervical carcinoma cells (treated with human papillomavirus [HPV] E7 siRNA) and of colorectal carcinoma cells (treated with Bcl-2 siRNA). Thus, we demonstrate successful topical gel-based delivery of inducers of RNAi to human epithelial cancer cells. Topical induction of RNAi opens an important new therapeutic approach for treatment of human diseases, including cervical cancer and other accessible disorders.

Administration, Topical↗

PubMed2003

Cervical cancer.

Behavioral and psychosocial factors affect all aspects of cervical cancer control, from prevention to posttreatment rehabilitation. Behavioral scientists gathered at the Second International Conference on Cervical Cancer (Houston, TX, April 11-14, 2002) reviewed selected studies of behavioral factors related to cervical cancer, including women's receptivity to emerging cervical cancer screening and diagnostic technologies, factors that influence adherence to follow-up colposcopy recommendations, and cervical cancer survivors' quality of life. Researchers reported that reduced distress during examinations with new technology may improve adherence to cervical cancer screening recommendations. Until new technology becomes mainstream, research shows that distress is reduced and adherence improves when health care providers match interventions to patients' informational processing styles. Investigations of survivors' quality of life report conflicting findings, but studies indicate that survivors experience anger over reproductive loss, loss of interest in sex, and perhaps a greater vulnerability to sexual dysfunction compared with survivors of other cancers. Survivors also report a need for posttherapy support programs. Primary prevention of cervical cancer should remain a priority as research in behavioral interventions and barriers to screening, especially among vulnerable populations, moves forward.

Behavior↗

PubMed2003

Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway.

Annonaceous acetogenins are a group of potential anti-neoplastic agents isolated from Annonaceae plants. In this study, we purified annonacin, a cytotoxic mono-tetrahydrofuran acetogenin, from the seeds of Annona reticulata and analyzed its biological effects. Herein, we have shown that annonacin caused significant cell death in various cancer cell lines. T24 bladder cancer cells at the S phase were more vulnerable to the cytotoxicity of annonacin. Furthermore, annonacin activated p21 in a p53-independent manner and arrested T24 cells at the G1 phase. It also induced Bax expression, enhanced caspase-3 activity, and caused apoptotic cell death in T24 cells. In summary, these results suggest that annonacin is potentially a promising anti-cancer compound.

Antimetabolites, Antineoplastic↗

PubMed1994

Secretory IgA in cervical mucus.

PURPOSE: Sexually active adolescent girls are uniquely vulnerable to sexually transmitted disease, including cervical cancer and AIDS. Little is known about the development of genital immunity in adolescents. Secretory IgA (sIgA) in cervical mucus is an important component of genital immunity. We studied sIgA levels in cervical mucus samples for both adolescent and adult females. METHODS: Samples were collected in a university-based adolescent medicine clinic and a university student health center. Participants consisted of 13 sexually active adolescent girls and fourteen adult controls. Samples were collected in the course of routine pelvic exams. All subjects were at least two years post menarche. Mucus was aspirated directly from the cervical os. Diluted samples were liquefied with a proteolytic enzyme (bromelain). Secretory IgA levels were measured by radial immunodiffusion using IgA2 from pooled human plasma as a standard. RESULTS: Secretory IgA levels for the adolescent group (mean 0.157 g/L SD 0.080) were slightly lower than for the adult group mean (0.199 g/L SD 0.130) although not statistically significant. CONCLUSIONS: Cervical sIgA levels were comparable between sexually active adolescents and adults.

Adolescent↗

PubMed2006

Perceptions of family history across common diseases: a qualitative study in primary care.

BACKGROUND: Having an affected relative is a strong predictor of an individual's lifetime risk of developing many diseases. In primary care this is of importance in preventive healthcare. AIM: To compare and contrast perceptions of family history across common diseases among primary care patients using the theoretical framework of Leventhal's Common Sense Model (CSM). METHODS: Thirty semi-structured interviews were conducted with patients identified in general practice, who had a family history of either cancer, heart disease or diabetes. We performed qualitative constant comparative analysis of transcript data. RESULTS: People with a family history of cancer had a greater sense of personal vulnerability than people with a family history of heart disease: family history of diabetes was generally viewed as the least threatening. Using the CSM constructs we identified factors which determine individual perceptions of family history. Beliefs about consequences and timeline were influenced by witnessing painful, lingering or sudden familial death; people who felt their risk was determined by inheritance were more likely to feel vulnerable and have less control, while those who felt able to change lifestyle or behaviour felt more able to control their perceived risk. CONCLUSION: Factors influencing perceptions of family history may vary between individuals and between diseases. To use the family history as a tool in preventive healthcare we will need to consider the individual's personal understanding of disease risk and their ideas about cause and controllability of the familial illness. Perceived risk may then be used to motivate preventive health behaviours.

Adult↗

PubMed1996

Family history and perceived vulnerability to some common diseases: a study of young people and their parents.

During the last two decades, health promotion has concentrated on lifestyle factors. However, recent research in genetics has shown that inherited susceptibility may be important in many common conditions. This raises questions about how these two different messages are integrated into people's beliefs about their own susceptibility. We report a study based on interviews with 58 young people, who had all recently completed the National Curriculum science course including basic human genetics, and 54 of their parents. We aimed to examine the extent to which people take account of family history when considering their susceptibility to health risks, with comparisons being made between generations, gender, and between different diseases. Family health histories were compared between generations and the relationship between reported family history and perceived vulnerability was examined. Family health history was seen as more relevant for a perceived vulnerability to heart disease and diabetes than cancer, while actions and behaviour were seen as important in determining the chance of developing heart disease and cancer but less so for diabetes. Chance was seen as an important factor in the risk of cancer and diabetes, but was barely mentioned in connection with heart disease. Nearly half of those who reported affected family members with heart disease or cancer did not perceive this to have any effect on their own susceptibility. Notably, women were much more likely than men to see the presence or absence of affected relatives as being relevant to the chances of developing cancer. Differences were found between generations in the reporting of the family tree and in knowledge of health of family members. Although words such as genes, chromosomes, and DNA were used by both generations there was no evidence of any understanding of the process of inheritance in scientific terms.

Adolescent↗

PubMed1998

Cardiovascular reactivity and adolescent boys' physical health.

OBJECTIVE: Minor illnesses and major diseases are affected by individual, environmental, and social factors. The purpose of the study was to determine if cardiovascular reactivity, an individual characteristic, was related to adolescent boys' health status and behaviors. METHODS: A total of 89 low socioeconomic status 16-year-old boys who had been classified using teacher ratings during childhood as anxious, disruptive, anxious-disruptive, or normal participated in a laboratory stress experiment. Systolic blood pressure (SBP) and diastolic blood pressure were measured during the Social Competence Interview. Using the upper and lower quartiles of SBP change scores, 21 boys were classified as reactors and 20 boys were classified as nonreactors. Subjects were interviewed to assess health behaviors and outcomes, as well as stressful life events. RESULTS: No significant group differences were found for minor or major physical health problems. A logistic regression analysis indicated that risky health behaviors were associated with SBP reactivity, personality characteristics, and negative life events. Specifically, nonreactors, who were disruptive, had more negative life events and engaged in more health-compromising behaviors (eg, smoking cigarettes, unprotected sex), which may contribute to future health problems (eg, cancer, AIDS). Anxious individuals may be more vulnerable to cardiovascular diseases in part because of exaggerated cardiovascular reactivity to stress. CONCLUSION: Low socioeconomic status boys may be at risk for different health problems caused by differing personality characteristics associated with divergent health-related behaviors.

Adolescent↗