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PubMed2026

Alternative End Joining Dependency Imposed by miR-21-5p Defines Radiation Resistance and a Targetable Vulnerability in Oral Squamous Cell Carcinoma.

PURPOSE: Clinical control of oral squamous cell carcinoma (OSCC) is constrained by heterogeneous radiosensitivity driven by divergent DNA damage response programs. The architecture and functional contribution of alternative end joining (Alt-EJ), an error-prone DNA double-strand break (DSB) repair pathway frequently upregulated in cancer, to radiation resistance remains poorly defined. METHODS AND MATERIALS: We profiled microRNAs in radioresistant OSCC clones and performed multiomic integration across an institutional OSCC cohort, an external OSCC cohort from the Gene Expression Omnibus, The Cancer Genome Atlas pan-cancer tumors, and cell lines characterized by Sanger Genomics of Drug Sensitivity in Cancer to infer DNA damage response characteristics, genomic scar features, drug sensitivity, and radiation therapy outcomes. DSB repair capacity and pathway usage were validated using functional assays, including Alt-EJ reporters and droplet digital PCR quantification of microhomology-mediated repair events. Core Alt-EJ effectors such as PARP1 and POLQ were perturbed genetically and pharmacologically. Therapeutic efficacy of PARP or POLQ inhibition with or without irradiation was tested in a syngeneic OSCC model, followed by bulk tumor transcriptomics to assess pathway engagement. RESULTS: Upregulation of miR-21-5p was not only selectively detected in radioresistant OSCC, but also modulated radiosensitivity in vitro and in vivo, and was associated with inferior postradiation therapy survival. A calibrated miR-21-5p target-gene signature tracked Alt-EJ activity across patient and mouse tumors and cancer cell lines, correlated with microhomology-mediated indels and broader genomic scarring, and predicted sensitivity to clinically available PARP inhibitors. Functionally, enforced miR-21-5p expression increased Alt-EJ usage and accelerated DSB repair, whereas inhibition or depletion of key Alt-EJ effectors reduced repair efficiency and restored radiosensitivity. In vivo, Alt-EJ targeting with PARP or POLQ inhibitor abrogated miR-21-5p-driven radiation resistance; transcriptomic profiling supported suppression of Alt-EJ programs as the operative mechanism. CONCLUSIONS: These findings establish a mechanistic link between miR-21-5p activity and Alt-EJ dependence, provide a clinically deployable signature to identify Alt-EJ-dependent OSCC, and support rational combinations of Alt-EJ targeting agents with radiation therapy to overcome treatment failure and advance precision radiation oncology.

MicroRNAs↗
PubMed2026

CARS1 as a Prognostic Biomarker and Candidate Therapeutic Vulnerability in Hepatocellular Carcinoma: Insights Into Tumor Progression and the Immune Microenvironment.

BACKGROUND: Cysteinyl-tRNA synthetase 1 (CARS1) has been included in ferroptosis-related prognostic signatures, but its clinicopathological relevance, cellular functions, and relationship with the immune microenvironment in hepatocellular carcinoma (HCC) remain incompletely characterized. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset were integrated with corresponding data from an institutional HCC tissue cohort of 60 patients. CARS1 expression was evaluated by immunohistochemistry, and immune infiltration was examined using single-sample gene-set enrichment analysis (ssGSEA) and multiplex immunofluorescence, as well as by analyzing public single-cell datasets. The effects of CARS1 depletion were evaluated in MHCC97H and Hep3B cells using Cell Counting Kit-8 (CCK-8) assays, cell-cycle profiling, wound-healing assays, Transwell migration assays, western blotting, and erlotinib-sensitivity assays. RESULTS: CARS1 expression was elevated in HCC and was associated with adverse clinicopathological features and poor overall survival. Quantitative immunohistochemistry confirmed elevated CARS1 protein expression in tumor tissues. CARS1 depletion inhibited cell proliferation, altered cell-cycle distribution, impaired migration, and enhanced in vitro sensitivity to erlotinib. High CARS1 expression was also associated with increased infiltration of Th2-like immune cells. CONCLUSIONS: Elevated CARS1 expression is associated with an adverse biological and immune phenotype in HCC. These clinical, histopathological, and loss-of-function findings support further investigation of CARS1 as a prognostic marker and candidate therapeutic target in HCC, although additional mechanistic and in vivo validation is required.

Humans↗
PubMed2003

Environmental hazards to children's health in the modern world.

Patterns of illness in children have changed dramatically in the last century, and will continue to change in this century. The major diseases confronting children are now chronic and disabling conditions termed the "new pediatric morbidity"-asthma, leukemia and brain cancer, neurodevelopmental dysfunction and neurobehavioral abnormality, reproductive and systemic developmental problems. Chemical toxicants in the environment, poverty, and little or no access to health care are all factors contributing to life-threatening pediatric diseases; children are uniquely vulnerable to chemical toxicants because of their disproportionately heavy exposures and their inherent biological growth and development. Genetic susceptibility and environmental exposures during vulnerable periods of development are also important contributors to the etiologies of many diseases of childhood. It is vital that we develop a better understanding of the mechanisms and interactions between nutrition, infectious disease, environmental exposures, and genetic predisposition in order to develop better prevention methods. This paper briefly examines modern contributors to children's environmental health problems, efforts to date on both the regional and international level to address these challenges, and reflects upon major research needs that must be addressed in order to close the gaps that exist in our understanding of the relationship between environmental exposures and children's health.

Child↗
PubMed2001

Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect.

Cellular genomes are vulnerable to an array of DNA-damaging agents, of both endogenous and environmental origin. Such damage occurs at a frequency too high to be compatible with life. As a result cell death and tissue degeneration, aging and cancer are caused. To avoid this and in order for the genome to be reproduced, these damages must be corrected efficiently by DNA repair mechanisms. Eukaryotic cells have multiple mechanisms for the repair of damaged DNA. These repair systems in humans protect the genome by repairing modified bases, DNA adducts, crosslinks and double-strand breaks. The lesions in DNA are eliminated by mechanisms such as direct reversal, base excision and nucleotide excision. The base excision repair eliminates single damaged-base residues by the action of specialized DNA glycosylases and AP endonucleases. Nucleotide excision repair excises damage within oligomers that are 25 to 32 nucleotides long. This repair utilizes many proteins to remove the major UV-induced photoproducts from DNA, as well as other types of modified nucleotides. Different DNA polymerases and ligases are utilized to complete the separate pathways. The double-strand breaks in DNA are repaired by mechanisms that involve DNA protein kinase and recombination proteins. The defect in one of the repair protein results in three rare recessive syndromes: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. This review describes the biochemistry of various repair processes and summarizes the clinical features and molecular mechanisms underlying these disorders.

Alkylation↗
PubMed2005

p53 codon 72 and MDM2 SNP309 polymorphisms and age of colorectal cancer onset in Lynch syndrome.

PURPOSE: The Arg/Pro polymorphism in codon 72 of p53 was recently associated with age of onset of colorectal cancer in Lynch syndrome. A novel polymorphism in the promoter region of MDM2 was associated with age of cancer onset in Li-Fraumeni syndrome. We studied the influence of both polymorphisms on age of onset in Lynch syndrome and of the p53 polymorphism also in sporadic colorectal cancer. EXPERIMENTAL DESIGN: We genotyped p53 codon 72 in 193 individuals with Lynch syndrome mutations, 93 patients with sporadic microsatellite unstable colorectal cancer, and 93 patients with sporadic microsatellite stable colorectal cancer from Finland and 323 Finnish controls. We genotyped 30 colorectal cancer patients with Lynch syndrome mutations from Ohio and 118 U.S. controls. We genotyped SNP309 of MDM2 in the Lynch syndrome groups. We used chi2 test, Kaplan-Meier statistics, and Cox regression model to analyze the data. RESULTS: Allele frequencies of both polymorphisms were similar in subjects and controls from both populations and showed Hardy-Weinberg equilibrium. Neither polymorphism was associated with age of colorectal cancer onset in any of the subject groups. CONCLUSIONS: This study failed to show any role of the p53 polymorphism on age of colorectal cancer onset in Lynch syndrome and sporadic colorectal cancer. The polymorphism in the MDM2 promoter had no affect on age of onset in Lynch syndrome. Accurate information about age of onset is important in clinical practice, especially in high-risk conditions. As association studies are vulnerable to biologically insignificant variation, both positive and negative findings need to be reported to enable unbiased assessment of the significance of putative risk variants.

Adult↗
PubMed2003

Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management.

Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma. In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents. The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality. Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described.

Antineoplastic Agents↗
PubMed1984

Carcinoma of the urinary bladder treated by interstitial radiotherapy.

Bladder cancers are usually only poorly radiosensitive and require a very high dose of radiation in order to become completely eradicated. Radioactive material inserted interstitially, however, can deliver an extremely high dose to the bladder malignancy and still spare vulnerable adjacent tissues and organs. Indications for implantation, treatment results, and prognosis are presented.

Brachytherapy↗
PubMed1994

Alcohol and cancers of the upper aerodigestive tract in men and women.

In order to explore the potential differences in the effect of alcohol in men and women we took advantage of a case-control study of upper aerodigestive tract tumors conducted between 1986 and 1991 in Northern Italy Five hundred forty-six incidence cases of cancer of the oral cavity and pharynx (of whom 81 were women), 410 of cancer of the esophagus (of whom 67 were women), and 388 with cancer of the larynx, (of whom 19 were women) were interviewed. The control group included 2263 inpatients (of whom 557 were women) with acute conditions unrelated to alcohol and tobacco consumption. Among alcohol drinkers, similar odds ratios were detected in men and women. In the highest, well comparable intake category (i.e., > or = 42 drinks/week in women and 42-55 drinks/week in men), odds ratios were 4.5 and 3.8 for cancer of the oral cavity and pharynx, 3.0 and 4.7 for cancer of the esophagus, and 2.6 and 2.0 for cancer of the larynx in women and men, respectively, as compared to light drinkers. However, for all cancer sites a reduced risk was found among abstaining women but not in abstaining men, when compared with light-to-moderate drinkers. The present study, therefore, does not support the hypothesis that women may be substantially more vulnerable than men to alcohol carcinogenesis, at least at the level of the upper aerodigestive tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Octreotide in the management of treatment-related diarrhoea.

Octreotide appears to have a major therapeutic effect in the management of diarrhoea related to cancer therapy. This effect is seen in the acute diarrhoea following radiation therapy and chemotherapy, and also in late radiation enteritis. As well as providing improved symptom control, early treatment can prevent potentially important morbidity in patients who are vulnerable to infection and fluid loss. Patients who suffer diarrhoea as a complication of AIDS, graft-versus-host disease and tumour-related diarrhoea can also obtain major benefit from treatment with octreotide. It should be considered as a first-line treatment in patients for whom diarrhoea may be a serious complication.

Animals↗
PubMed2005

Prostate cancer among African-American males: understanding the current issues.

Prostate cancer affects African-American males within the United States in a disproportionate number compared to White males. African-American males are 1.7 times more likely to develop and 2-3 times more likely to die from prostate cancer than White males. Numerous reasons for this disparity exist, including low socioeconomic status, distrust, conflicting cultural beliefs, and past health-care experiences. Controversies surrounding this topic and perhaps contributing to the disparity include cancer-screening recommendations, cancer-related myths, and potential prevention modalities. Nursing research must focus on cancer-related issues among African-Americans to increase the awareness and knowledge of health-care professionals and the public to help decrease morbidity and mortality within African-Americans and other minority populations, and particularly among more vulnerable sections of at-risk minority populations. This article focuses on current issues related to African-American men and prostate health.

Black or African American↗
PubMed1983

Emotional effects of cancer and cancer therapy.

Prevention of adverse psychological sequelae of cancer begins at the time of diagnosis (D'Angio 1975). By proper management, in which accurate information is given in a positive way, misinformation is corrected and a supportive continuous relationship to a physician and staff is established. Information should similarly be given about when termination of therapy is anticipated and re-entry to normal life can be expected. Attachment to the hospital, staff and fellow patients is expected and can be used as a positive force by development of "veteran" and "fellow" patient groups. When symptoms of psychological distress do occur in a long-term survivor, they warrant immediate attention and a workup that takes into account the vulnerability to endocrine and neurologic delayed effects, as well as psychological. Interventions should be based on diagnostic findings and include consideration of maladaptive patterns of interaction within the family and the patient's social setting. More clinical studies of long-survivors are needed to clarify the interaction of medical and psychological variables which contribute to quality of life of the cured cancer patient.

Adolescent↗
PubMed1990

Environment and the skin.

The skin is an important organ of defense adaptation and a portal of entry for xenobiotics. It is vulnerable to physical, chemical, and biologic agents and capable of expressing responses to these agents in a variety of pathologic patterns. These patterns are characterized by morphologic and functional features which are elicited by careful examination and test procedures. Cutaneous cancer may result from exposure to nonionizing as well as ionizing radiation, to specific identifiable chemical hazards, and may be enhanced by trauma. Cutaneous hazards of chemical sources are largely found in the workplace and among consumer products, including drugs and toilet goods. Environmental skin diseases and injuries are preventable. Prior to use assessment for safety and for possible risks from exposure to an agent, product, or process is of primary importance in the prevention and control of environmental skin disease and injury.

Dermatitis, Occupational↗
PubMed1977

Lumbo-sacral radiculopathy induced by radiation.

Two patients had lumbo-sacral radiculopathy following radiation treatment of cancer. Twenty previously reported cases were similar. The clinical picture is one of progressive motor and sensory loss in the legs, usually appearing within a year after radiation, but sometimes delayed up to several years. Experimental studies quoted indicate greater vulnerability of peripheral nerves to ionizing radiation than has been previously recognized. Lumbo-sacral radiculopathy is readily produced in the experimental animal (rat) and affords an experimental model closely resembling the human cases reported.

Carcinoma, Squamous Cell↗
PubMed2000

Bidi smoking and health.

Bidi, made of low-grade tobacco, is popular among rural folk and the urban poor, in the South Asian region. The objectives of this study were: (1) to assess the extent of bidi smoking in different countries; (2) to compare its smoke and health hazards with conventional cigarettes and; (3) to recommend preventive measures. English language articles were identified through a MEDLINE computerised search (1966-1998) using the term 'bidi', 'beedi', 'beedie', 'biri' and manually in order to collate all the available information and to present a descriptive epidemiological profile. The prevalence of bidi smoking was found to be 21-56% among men in South Asian countries with very little information available about women. Concentrations of nicotine, tar and other toxic agents in the smoke are higher for bidi than for other cigarettes. Bidi smoking is also considered to cause about 2-3 times greater nicotine and tar inhalation than do conventional cigarettes, due to the poor combustibility of the bidi wrapper and greater puff frequency needed to keep the bidi alight. It has also been shown to have greater odds ratios, although not statistically significant, for various cancerous and chronic conditions in comparison with other cigarettes. Since bidi is hand-rolled, workers employed in bidi factories are at risk of developing cancerous conditions due to exposure to tobacco dust and flakes. We suggest that anti-smoking campaigns should be directed to the bidi smokers of all South Asian countries. Most bidi smokers are illiterate and malnourished which makes them more vulnerable to smoking-related morbidity and mortality. At the same time, measures should be taken to make bidi less harmful and to produce bidi by machine to reduce exposure-related toxicity among bidi production workers.

Adolescent↗
PubMed1987

Cellular, biochemical, and molecular basis of T-cell senescence.

The elucidation of age-related changes in immune functions is of great importance in light of the rising susceptibility of elderly individuals to infections, the likelihood that immunosenescence might also contribute to the age-related rise in cancer, and the role autoantibodies and immune complexes might play in general physical deterioration of aging individuals through their participation in subclinical chronic tissue damage. An attempt has been made to summarize our present knowledge on immune functions that are vulnerable to aging. It revealed that at the cellular level, all four antigen-responsive immune cells (T cells, B cells, monocytes, and killer cells) are vulnerable to aging, but T cells are perhaps the most vulnerable. Therefore, this article specifically examines the cellular and biochemical T cell-dependent concomitants of age-altered immune functions. One picture that is emerging suggests that at the molecular level, several control points exist along the path of gene expression that could be vulnerable to aging.

Aging↗
PubMed2026

NSCLC in Vulnerable and Special Populations: Toward Personalized Care.

NSCLC encompasses a heterogeneous patient population whose clinical needs, biological features, and treatment outcomes differ substantially from those represented in pivotal studies. Adolescents and young adults, women, pregnant patients, individuals with actionable genomic alterations or constitutional pathogenic variants, immunocompromised patients, including those with chronic viral infections, older adults, patients with brain metastases, and survivors with second primary lung cancers remain consistently underrepresented in research programs. This limits the generalizability of current evidence and challenges the delivery of equitable precision oncology. Across these populations, distinct disease biology, differential genomic landscapes, sex- and age-related variations in pharmacology, and complex psychosocial or ethical considerations shape clinical decision-making. Advances in molecular testing and targeted therapies have improved outcomes for some subgroups; however, persistent disparities in diagnostic access, trial eligibility, and supportive care remain major barriers. In parallel, modern systemic agents including brain-penetrant targeted therapies, immunotherapy combinations, and antibody-drug conjugates have broadened therapeutic options, although their safety, effectiveness, and long-term consequences require dedicated evaluation in underrepresented populations. This review synthesizes contemporary evidence from these special NSCLC populations, highlighting shared challenges and unique considerations. We discuss implications for clinical practice, supportive care, survivorship, and research design and outline opportunities to strengthen inclusivity in precision oncology. Addressing longstanding gaps in representation, trial methodology, and structural inequities is essential to ensure that recent therapeutic advances translate into improved outcomes for the full spectrum of patients living with NSCLC.

Humans↗