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PubMed2026

Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.

Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system-the major pathway for MGO detoxification-restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC.

Humans↗
PubMed2006

Family impact of neurodevelopmental late effects in survivors of pediatric cancer: review of research, clinical evidence, and future directions.

Children and adolescents who have survived childhood cancer are vulnerable to late effects of their disease and treatment experience, including both physical and psychological sequelae. The neurodevelopmental (ND) sequelae (e.g., difficulties with attention, memory, information processing, and other executive functions) faced by children surviving central nervous system (CNS) cancers or CNS treatments can have a range of effects on their psychological adjustment and quality of life as they reintegrate into school and social settings. Survivors facing such difficulties may be influenced by their family environment, and these struggles may in turn impact the perceived burden of their parents and family system, suggesting a bidirectional framework for understanding the impact of ND late effects within the family. The current study summarizes the following: Findings of family outcomes in children with ND late effects of cancer treatment; evaluation of methodological and measurement issues; the importance of examining bidirectional family-child influences; and implications for future survivorship research and clinical care addressing the role of ND late effects from a systems perspective.

Child↗
PubMedDate not supplied

[Knowledge, attitudes and behaviours of women towards breast cancer screening].

The objective of this study was to describe knowledge, attitudes and behaviour of women towards breast cancer screening methods in two regions of north Tunisia. Thus 936 women from Ariana (urban region) and 993 women from Zaghouan (rural region) were selected and answered a questionnaire on their perception of the gravity of breast cancer, the vulnerability of women, the efficacy of screening and their use of screening. The use of screening was significantly more frequent in Ariana for both clinical breast examination and mammography, but screening use was modest. This low use of breast cancer screening contrasts with a positive attitude to breast cancer screening methods. The factors positively associated with use of screening were urban residence, age between 35 and 49 years, educational level and the perception that cancer treatment had advanced in Tunisia.

Adult↗
PubMedDate not supplied

Father-to-father support: fathers of children with cancer share their experience.

Fathers are important to the stability of the family and to the coping of mothers and their children when there is a child in treatment with cancer. The vulnerability they experience is stupefying and causes self-doubt, general worry, and frustration with the medical care they receive. Fathers' experiences are relatively unreported in the literature, and even less so, the experiences of fathers with children who have cancer. This research is based on two focus groups of five men each who spoke unabashedly for more than 2 hours about their grief, their struggle to come to terms with the diagnosis and the role strain, and role confusion they experienced as fathers and husbands. The findings could be described as reflecting the following themes: (1) impact on the provider role, (2) the emotional impact: I cry privately, (3) it's the fight of our lives, (4) tag-team parenting, (5) hypervigilance, (6) that place is scary!, and (7) what happens next--coping and moving on. The group format was powerful in terms of what these men were willing to share of themselves and their experience. These groups could be characterized as the coming together of strangers, bound by the common experience of "cancer," who actively supported each other and each other's process. Implications for holistic nursing practice are provided.

Adaptation, Psychological↗
PubMed2024

Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors.

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.

Humans↗
PubMed2026

Impact of oxidative stress on malignant tumor progression and emerging therapeutic strategies.

Oxidative stress, driven by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a pivotal role in cancer biology. While persistent, moderately elevated ROS levels can promote genomic instability, tumor progression, and immune evasion, excessive ROS accumulation can overwhelm antioxidant defenses and trigger cancer cell death. Despite promising preclinical findings, clinical translation remains a challenge because of the context-dependent effects of ROS. A deeper understanding of oxidative stress regulation may lead to the development of novel precision medicine strategies, optimizing cancer therapies while minimizing adverse effects. This review highlights the concentration-dependent effects of oxidative stress in tumorigenesis, focusing on its impact on DNA damage, metabolic reprogramming, and immune modulation. We discuss recent advancements in ROS-targeting strategies, including pro-oxidant therapies that exploit redox vulnerabilities in cancer cells and antioxidant-based approaches aimed at mitigating oxidative stress-driven resistance to treatment. Moreover, we examine the interplay between oxidative stress and the tumor microen-vironment, emphasizing its influence on immune surveillance and therapeutic responses. This re-view provides insights into ROS-targeting interventions and their potential in oncologic treatment paradigms.

malignant tumors↗
PubMed2005

Rationale for the treatment of cancer with sodium selenite.

Epidemiological studies conducted during several decades of the last century have demonstrated the importance of sufficient nutritional supply of selenium (Se) for human health. More importantly, low blood Se levels were found to be associated with an increased incidence and mortality from various types of cancers. Recently, attention of researchers was drawn to the relationship between free radical generation, known otherwise as oxidative stress, and carcinogenesis. It was therefore thought that antioxidants should be beneficial for prevention and inhibition of different malignancies. However, there appeared to be a paradox, because tumor growth is associated with tissue hypoxia that is accompanied by the formation of reductive rather than oxidative free radicals. Various organic and inorganic Se compounds, generally considered to be antioxidants, produced mixed results when tested in animal models and human subjects. Amongst them, sodium selenite has been shown to be the most effective in an in vitro and in vivo carcinogenesis studies. As recently demonstrated, selenite is not an antioxidant, but possesses oxidizing properties in the presence of specific substrates. Thus selenite is capable of oxidizing polythiols to corresponding disulfides, but does not react with monothiols. Such polythiols associated with cancer membrane-bound proteins appear under the reducing conditions of hypoxic tumor tissue. These thiol groups can, in turn, initiate a disulfide exchange reaction with plasma proteins, predominantly with fibrinogen, to form an insoluble and protease-resistant fibrin-like polymer. As the result, tumor cells become surrounded by a coat which masks specific tumor antigens thus allowing cancer cells to escape immune recognition and elimination by natural killer (NK) cells. Selenite by virtue of oxidizing cell membrane thiols, can prevent the formation of the coat and consequently makes cancer cells vulnerable to the immune surveillance and destruction. In addition, selenite may directly activate NK cells, as well as inhibit angiogenesis without undesirable decrease in the oxidative potential of cellular environment. It is, therefore, postulated that sodium selenite, in view of its relative low toxicity, might become a drug of choice for many types of cancer including leukemia.

Humans↗
PubMed1996

We've Got a Treatment, but What's the Disease? Or A Brief History of Hypofractionation and Its Relationship to Stereotactic Radiosurgery.

Hypofractionation has been a recurring issue during the near century-long history of radiation oncology. Coutard first introduced protracted dose-fraction regimens that uniquely allowed for the control of "deep" tumors. Subsequent studies have consistently shown that hypofractionation leads to an increase in complication rates and a paradoxical decrease in cure rates. There have, nonetheless, been several resurgences of interest in hypofractionation, based on titration of treatment for acute isoeffects and for the accommodation of an adjuvant treatment relating to presumed hypoxia-induced resistance, and more recently, stereotactic radiosurgery. In final analysis of the earlier studies, the same effects on cure and complication were noted and there was a return to multi-fractionation. Stereotactic radiosurgery is now being evaluated. Stereotactic radiosurgery takes hypofractionation to an extreme by use of a single, large fraction of radiation therapy. In doing so, the late effects radiation oncologists ordinarily strive to avoid are brought about intentionally, minimizing or even eliminating any therapeutic index within the treatment volume. Stereotactic radiosurgery has been used successfully for treatment of benign lesions such as arteriovenous malformations in which total volume necrosis of small dimensions appears to be efficacious therapy. Stereotactic radiosurgery has also recently been extrapolated to malignant tumors in the brain which require larger treatment volumes, but the data on outcome following such treatment remain sparse. Therapeutic index must be preserved to obviate an intolerable volume of necrosis and other late effects. The single fraction approach to stereotactic radiosurgery for cancer is vulnerable to the same radiobiological criticisms that have been a recurrent theme with hypofractionation. Fractionated stereotactic radiosurgery is far more consistent with the principles of conventional radiobiology and oncology and represents the quintessential application of three-dimensional treatment planning. Stereotactic radiosurgery is really stereotactic radiotherapy, and when applied in single fraction to the treatment of cancer, it is suboptimal radiation oncology. Its utilization is virtually predicated on the ability to perform another craniotomy to remove focal necrosis.

Journal Article↗
PubMed2026

Translational control by RPL22L1-specific ribosomes enhances DNA repair and chemoresistance.

Ribosome heterogeneity has emerged as a regulatory layer in gene expression, yet its biological roles in cancers remain poorly characterized. Here, we identify RPL22L1, a paralog of the ribosomal protein RPL22, as a key modulator of DNA damage response (DDR) in colorectal cancer cells. DNA damage induces RPL22L1 upregulation and ribosomal incorporation, forming RPL22L1-specific ribosomes. Ribosome profiling reveals that RPL22L1-containing ribosomes preferentially translate mRNAs with highly structured 5' untranslated region (5'UTR). In particular, RPL22L1 enhances the translation of ATRX through a cap-independent mechanism. ATRX subsequently recruits DNA-PKcs to DNA damage sites, thereby enhancing the DNA repair capacity. RPL22L1 loss creates exploitable DDR vulnerabilities, sensitizing cancer cells to cisplatin and PARP inhibitors in vitro and in vivo. Collectively, these findings uncover a specialized ribosome-mediated translational program in DDR and highlight RPL22L1 as a potential therapeutic target in DDR-based cancer therapy.

DNA Repair↗
PubMed1999

Ethical issues in the development of new agents.

In the early drug development process for cancer therapy, several ethical dilemmas result from the use of cancer patients with advanced disease as the subjects of research in clinical trials studying agents of unknown toxicity and/or efficacy. Although several accepted ethical principles guide the behavior of involved physicians and investigators, many of these principles are allowed to be violated in order to achieve the overall goal of clinical research in improving medical care for future patients. Informed consent has been a process viewed by many as a mechanism which protects potentially vulnerable patients from harm in the clinical trial process. However, the ability of the traditionally regulated process of obtaining informed consent for clinical research may be inadequate to ensure appropriate understanding of the purposes and the goals of early clinical trial research by potentially vulnerable advanced cancer patients. This creates further dilemmas with regard to physician-investigator and patient-subject communications. In the setting of phase I trials, where the specific goal of the research is to obtain toxicity information regarding a new potential anticancer agent, many heightened ethical conflicts are present. The fact that patients do not participate in these studies as a result of altruism, and that their main goals of participation are intensely therapeutic, create issues that may be in direct conflict with the research purpose of phase I trials. As well, the presence of therapeutic intentions on the part of involved physician-investigators creates challenging issues when one realizes the very low likelihood of benefit for individual patients participating in these studies. Within the phase II setting, the statistical constraints placed on new drug trials and, again, the low likelihood of benefit for participating-subjects, also creates challenging dilemmas. These statistical requirements may be in direct conflict with involved clinicians' attitudes and beliefs regarding potential efficacy of an agent in this setting. As well, these issues become problematic when thinking about the desired structure and outcome for informed consent in phase II anticancer trials. The ability to conduct clinical research on advanced cancer patients using agents of unknown efficacy and toxicity is a daunting privilege granted to physicians and accompanying institutions. The weight of this privilege should not be underestimated, and involved physician-investigators should be aware of the significant ethical challenges involved in appropriately and successfully conducting this form of research.

Antineoplastic Agents↗
PubMed1999

[Therapeutic strategy for the recurrence of pancreatic cancer following pancreatectomy].

It is well-known that the patients with pancreatic cancer are vulnerable for recurrence such as local relapse and liver metastasis after surgical resection. We revealed that a patient with local relapse without liver metastasis showed better prognosis as compared with a patient having liver metastasis. We usually adapt further therapeutic intervention for local recurrence using external radiation therapy accompanied with 5FU infusion as a radiosensitizer, if the patient is not revealed with liver metastasis. On the other hand, there is no effective intervention for liver metastasis accompanying pancreatic cancer, as small lesions of multiple liver metastases progress rapidly. We insert the tip of catheter in proper hepatic artery in order to infuse MMC once a week at outpatient clinic. However, we were not yet able to evaluate the effect of arterial infusion therapy.

Infusions, Intra-Arterial↗
PubMed2026

Functional genomic screens uncover FERMT2 as a critical regulator of YAP/TAZ-driven tumorigenicity.

YAP and TAZ are transcriptional regulators essential for mechanotransduction, development, and tissue homeostasis, whose dysregulation is implicated in multiple diseases, including cancer. To identify key regulators of YAP/TAZ signaling required for breast cancer cell fitness, we performed CRISPR/Cas9-based loss-of-function genetic screens both in vitro and in vivo. A custom sgRNA library targeting 216 candidate YAP/TAZ modulators was screened across three breast cancer cell lines. Among these, FERMT2, a component of the integrin signaling pathway, consistently emerged as a strong drop-out hit, highlighting its essential role in sustaining YAP/TAZ-dependent fitness. Bioinformatic analysis of large-scale cancer datasets further revealed genetic co-dependency between FERMT2, YAP, and TAZ, particularly in tumors with high YAP/TAZ expression. Functional validation through FERMT2 knockout and silencing demonstrated its requirement for proliferation, anchorage-independent growth, and tumorigenicity in triple-negative breast cancer cells. FERMT2 loss impaired YAP/TAZ nuclear accumulation, reduced the expression of YAP/TAZ target genes, and decreased phosphorylation at key tyrosine residues. Mechanistically, FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK. Consistent with this, glucocorticoid-driven FAK activation restored YAP/TAZ signaling in FERMT2-depleted cells. Partial epistasis analyses also indicate that FERMT2 modulates actin-dependent regulation of YAP/TAZ. Together, these findings identify FERMT2 as a pivotal upstream regulator of YAP/TAZ via FAK signaling, demonstrate that YAP/TAZ are principal effectors of integrin activity, and suggest that FERMT2 may represent a selective vulnerability in cancers with elevated YAP/TAZ signaling.

Humans↗
PubMedDate not supplied

Quality of life of elderly persons with cancer: a 3-month follow-up.

We investigated the quality of life (QoL) of newly diagnosed persons with cancer aged 65 years at baseline and 3 months after, in relation to age, contact with the healthcare system, activities of daily living, hope, social network and support using the European Organization for Research and Treatment of Cancer QLQ-C30, Katz ADL, Nowotny's Hope Scale, and the Interview Schedule for Social Interaction. Participation at baseline was 101 (74 women, 27 men), and after 3 months was 85(66 women, 19 men). Fatigue was the most reported symptom both at baseline and 3 months after. No significant changes were found in QoL from baseline to 3 months after, whereas perceived social network and 2 subscales ("confidence" and "comes from within") in Nowotny's Hope Scale deteriorated significantly. Dependency, reduced economic ability, and low level of hope were significantly associated with low QoL at the 3-month follow-up. From the perspective of QoL, nurses need to address more specifically the most vulnerable elderly cancer patients: those who are dependent in instrumental activities of daily living, those who perceive reduced economic ability, and those who need assistance to discover new strategies to strengthen hope.

Activities of Daily Living↗
PubMed2007

Macrophage-mediated bystander effect triggered by tumor cell apoptosis.

Restoration of apoptosis is an important therapeutic strategy for cancer, but bystander effects may be crucial to treatment success. We examined the involvement of bystander effects in the outcome of pro-apoptotic treatments and investigated the role of macrophages. Using a murine N202 breast cancer chamber model and intravital microscopy, we observed bystander apoptosis in vivo in mixed spheroids consisting of bystander N202 cells plus modified N202 cells overexpressing the p14ARF N-terminal region, which promotes p53-mediated apoptosis. The effect was not observed in cocultures in vitro, and could not be transferred through conditioned medium from modified N202 cells. However, if macrophages were also included in the N202 co-cultures, bystander apoptosis was restored, and correlated with elevated surface expression of phosphatidyl serine, a macrophage recognition molecule, on the modified N202 cells. Bystander killing was not observed in cocultures of N202 cells plus macrophages plus cisplatin-treated or 5-fluorouracil-treated N202 cells, where apoptosis induction in the target cell population was inefficient, suggesting that specific activation of macrophages by apoptotic tumor cells was required. The results suggest that pro-apoptotic therapies benefit both from the intrinsic vulnerability of cancer cells to apoptosis and from an innate immune response that amplifies the therapeutic effect.

Animals↗
PubMed2006

The role of child abuse and age in vulnerability to emotional problems after surgery for breast cancer.

Emotional problems are common after breast cancer, but patients differ in their vulnerability. Childhood abuse is a risk factor for emotional problems in adult women, and we tested whether it explains some of the variability in emotional problems after breast cancer. Women with primary breast cancer (N=355) 2-4 d after surgery (mastectomy or wide local excision) self-reported current emotional distress, post-traumatic stress, self-blame, bodily shame and recollections of childhood sexual, physical and emotional abuse. Multiple logistic regression analyses tested the relationship of each emotional problem to abuse, distinguishing three age-groups, divided at 50 and 65 years. Emotional distress, post-traumatic stress, self-blame and shame were present in 49%, 8%, 22% and 13% of women, respectively. Each problem was more common in women who recalled one or other form of abuse. Apart from emotional distress, emotional problems were less common in older women. Older women were also less likely to recall abuse, and recall of abuse contributed statistically to explaining the relationship of youth to emotional problems. Childhood abuse is a risk factor for emotional problems after surgical treatment for breast cancer, and the challenge of identifying and helping those patients in whom emotional problems reflect pre-morbid vulnerabilities needs careful consideration. Because both emotional problems and abuse are strongly age-linked, future research should avoid generalisations across the age spectrum.

Affective Symptoms↗
PubMed1988

Do health beliefs predict health behaviour? A follow-up analysis of breast self-examination.

In a previous paper, we suggested that women who attended classes on breast self-examination showed significant improvements in behaviour, and that part of the reason was a change in their beliefs. Further analysis of our data confirms the original conclusion, and indicates that the perceived value of doing the behaviour is a more important predictor than perceived vulnerability to cancer.

Breast↗
PubMed2005

The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia.

The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia. We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naïve patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (TDT chi(2)=4.23, P<0.05; 4.15, P<0.05; 8.49 P<0.01, respectively; HHRRchi(2)=5.54, P<0.05; 4.40, P<0.05; 9.79, P<0.01, respectively). We found a significant association between the APC haplotypes from rs2229992-rs42427-rs465899 and schizophrenia (Global chi(2)=44.376,df=7, P<0.001). The C-A-T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (chi(2)=15.04, P<0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia.

Adenomatous Polyposis Coli Protein↗
PubMed2005

In my end is my beginning: control of end resection and DSBR pathway 'choice' by cyclin-dependent kinases.

The genome is constantly subjected to chemical alterations that have the potential to cause genetic mutation, chromosomal rearrangements and, in the case of multicellular organisms, cancer. Particular vulnerability exists during DNA replication, when the two DNA strands of a chromosome separate to form templates for the synthesis of sister chromatids. Attempted replication across a damaged or nicked DNA template can result in the formation of a double-strand break (DSB), arguably the most dangerous of DNA lesions. DSBs can also arise directly at any cell cycle stage following exposure to ionizing radiation or radiomimetic agents. To combat these recurrent threats of genomic instability, numerous distinct enzyme systems have evolved that sense DNA damage and coordinate its repair. Part of this coordination involves the activation of signal transduction cascades that target repair proteins, trigger DNA damage-dependent cell cycle checkpoints and profoundly affect chromatin neighboring a DSB. Here, we discuss current models of how lesion processing itself helps to coordinate these signals in dividing cells. Recent evidence in yeast of a role for cyclin-dependent kinases in DNA end resection suggests a possible solution to the long-standing puzzle of how DSBR pathway 'choice' is regulated through the cell cycle.

Cyclin-Dependent Kinases↗