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[Significance of prenatal exposure for long-term health effects].

A rapidly accumulating body of evidence indicates that many diseases must be understood in a life-long perspective, as trajectories that start at conception and surface upon clinical detection decades later. We know that some toxic intrauterine exposures may have life-long consequences, such as alcohol and some environmental pollutants, but it was not expected that chronic diseases such as cardiovascular disease or some cancers may have a fetal origin. Several research findings indicate that this expectation should be revised. Some studies indicate that sperm counts are declining conceiving the desired number of children. The so-called "estrogen hypothesis" states that this may be due to exposures in the intrauterine environment. About 10 years ago it was suggested that breast cancer originates in utero, which may be true also for cancer of the prostate or ovary. So far the evidence for this hypothesis is only circumstantial, but results have supported the idea. A large number of studies clearly indicate that impaired fetal growth is associated with a number of diseases. It is well known that all organs have time periods of rapid growth which may render them vulnerable to an insufficient supply of nutrition; impaired growth could alter organ structure and functioning, and the fetus could e.g. develop insulin resistance to protect itself from these "hunger" periods. "Organ programming" may be a fact we should consider when studying the etiology of e.g. cardiovascular diseases. These hypotheses--if they should hold true--are promising for new approaches to prevention. Much more work is needed however, before we can visualize these avenues of prevention, and we should make sure we develop the opportunities for doing this work now. It is high time.

Cardiovascular Diseases↗

Design and current status of the NSABP breast cancer prevention trial.

From its inception the BCPT has been the focus of bitter sustained controversy. In spite of reassessments by numerous advisory groups that have deemed the trial to be scientifically, clinically and ethically sound, its opponents have continued their assaults. That the trial has survived is a tribute to Dr. Fisher's leadership and the dedication of many clinical investigators, who, in spite of the injustice that they have endured, continue to believe in the goals of the NSABP clinical trials. Even greater credit and recognition should be given to the women randomized who have continued their commitment to the study. Their altruism and courage are to be acknowledged. These women undoubtedly understand that the trial affords potential risks, as well as benefits, and that even if the drug is eventually found effective in preventing breast cancer, half of them will have received a placebo in the trial. The ultimate tragedy will be if the study fails to answer definitively the study hypotheses because of what has occurred this past year. We are hopeful that, despite this disruption, the trial will continue to a successful completion. While larger multicenter randomized clinical trials clearly have vulnerabilities and imperfections, we should not lose sight that they are clearly the best mechanism for rigorously testing new therapies in a manner that will provide reliable, generalizable findings.

Breast Neoplasms↗

Exploring the course of psychological distress around two successive control visits in women at hereditary risk of breast cancer.

In this article we determined the course of psychological distress during a breast cancer surveillance program in women at increased risk of developing hereditary breast cancer (BC). The sample comprised of 357 unaffected women (mean age 40.5 years) adhering to a surveillance programme (MRISC-study). Before and after two successive biannual surveillance appointments, the Impact of Event Scale (BC-specific distress) and the Hospital Anxiety and Depression Scale (general distress) were administered, totalling four measurement moments. In general, psychological distress remained within normal limits and decreased significantly after a surveillance appointment, except for breast cancer specific distress after the second appointment. Scheduled imaging examinations were not significantly related to distress. The course of BC specific distress differed significantly for risk over-estimators and for young (<40 years) excessive breast self examiners. The course of general distress differed significantly for women closely involved in a sister's BC-process. These more vulnerable subgroups may be in need of extra counselling and care.

Adult↗

Lay understanding of familial risk of common chronic diseases: a systematic review and synthesis of qualitative research.

PURPOSE: Although the family history is increasingly used for genetic risk assessment of common chronic diseases in primary care, evidence suggests that lay understanding about inheritance may conflict with medical models. This study systematically reviewed and synthesized the qualitative literature exploring understanding about familial risk held by persons with a family history of cancer, coronary artery disease, and diabetes mellitus. METHODS: Twenty-two qualitative articles were found after a comprehensive literature search and were critically appraised; 11 were included. A meta-ethnographic approach was used to translate the studies across each other, synthesize the translation, and express the synthesis. RESULTS: A dynamic process emerged by which a personal sense of vulnerability included some features that mirror the medical factors used to assess risk, such as the number of affected relatives. Other features are more personal, such as experience of a relative's disease, sudden or premature death, perceived patterns of illness relating to gender or age at death, and comparisons between a person and an affected relative. The developing vulnerability is interpreted using personal mental models, including models of disease causation, inheritance, and fatalism. A person's sense of vulnerability affects how that person copes with, and attempts to control, any perceived familial risk. CONCLUSIONS: Persons with a family history of a common chronic disease develop a personal sense of vulnerability that is informed by the salience of their family history and interpreted within their personal models of disease causation and inheritance. Features that give meaning to familial risk may be perceived differently by patients and professionals. This review identifies key areas for health professionals to explore with patients that may improve the effectiveness of communication about disease risk and management.

Chronic Disease↗

Tahoe-100M: Mapping drug-induced molecular phenotypes at single-cell resolution.

We present Tahoe-100M, a giga-scale single-cell perturbation atlas comprising 100 million transcriptomes from 50 diverse cancer cell lines treated with 1,100 drug-dose conditions. This parallel profiling of thousands of perturbations at single-cell resolution with minimal batch effects is enabled by the Mosaic platform, which multiplexes genetically distinct cell models into balanced "cell villages." Beyond cataloging transcriptomic shifts, Tahoe-100M systematically quantifies cellular phenotypes, including proliferation, cytotoxicity, lineage-specific vulnerabilities, and cell-cycle changes. It captures population-level transcriptomic heterogeneity, characterizing whether drug responses drive cells toward divergent fates or convergent states. Pathway-based signatures define drug-induced expression programs, classify mechanisms of action, reveal off-target activities, and expose adaptive stress responses associated with resistance. By unifying cellular and molecular readouts, this broadly applicable perturbation atlas advances our ability to model gene regulation, drug response, and network dynamics. Its public release enables the training of AI frameworks to advance predictive models of cell behavior.

Humans↗

RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS Activation in Non-Small Cell Lung Cancer.

UNLABELLED: Small-molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C-mutant tumors, yet responses tend to be transient because of emergence of on-treatment resistance. Recently, RAS(ON) G12C-selective inhibitors, which bind to the active GTP-bound state of RAS, were described, and elironrasib is undergoing evaluation in multiple clinical trials. In this study, we generated resistant cell lines and patient-derived xenograft models to KRASG12C(OFF) and RAS(ON) G12C-selective inhibitors and interrogated resistance mechanisms using a multiomics strategy consisting of phosphoproteomics, whole-exome sequencing, and RNA sequencing combined with functional testing using small-molecule and CRISPR screens and RAS(ON) inhibitors being evaluated in clinical trials. Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multiselective inhibitors, RMC-4998 and RMC-7977. Two models, which lacked any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity and were sensitive to RAS-GTP inhibition by RMC-7977. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS dependence, and acquired reliance on cell-cycle kinases and proteins associated with DNA damage response. This work highlights KRASG12C-selective inhibitor resistant states that parallel and complement clinical findings and demonstrate that a large subset could be overcome with a RAS(ON) multi-selective inhibitor as a stand-alone agent or in combination with other therapies. SIGNIFICANCE: Multi-omic characterization of resistance mechanisms to KRASG12C-selective inhibitors in non-small cell lung cancer provides insights that could inform precision medicine-based therapeutic approaches for improving the treatment of KRASG12C mutant tumors. See related article by Stern et al., p. 485.

Humans↗

Pro-apoptotic action of PAR-4 involves inhibition of NF-kappaB activity and suppression of BCL-2 expression.

Par-4(1) (prostate apoptosis response 4) is known to function at an early stage in apoptosis in several different cell types, including neurons. On the other hand, activation of the transcription factor NF-kappaB can prevent apoptosis in various cancer cells and neurons. We now report that overexpression of full-length Par-4 in cultured PC12 cells results in a suppression of basal NF-kappaB DNA-binding activity and NF-kappaB activation following trophic factor withdrawal (TFW). The decreased NF-kappaB activity is correlated with enhanced apoptosis. Conversely, NF-kappaB activity is increased and vulnerability to apoptosis reduced in cells overexpressing a dominant-negative form of Par-4. Par-4 overexpression or functional blockade had no effect on AP-1 DNA-binding activity. Expression of the antiapoptotic protein Bcl-2 was dramatically reduced in PC12 cells overexpressing Par-4. Our data suggest that suppression of NF-kappaB activation plays a major role in the proapoptotic function of Par-4.

Animals↗

Smoking habits in survivors of childhood and adolescent cancer.

Because of their increased risk for second cancers, childhood cancer survivors are people who really should not smoke, but available evidence suggests that they do. We studied the smoking habits of long-term childhood cancer survivors in data collected from 1289 adult survivors of childhood cancer and 1930 of their sibling controls. Survivors were diagnosed with cancer between 1945 and 1974 when they were less than 20 years old. Using matched analyses that controlled for the influence of family, survivors were 8% less likely than controls to be current smokers, 13% less likely to be ever-smokers, but 12% less likely to have quit smoking; these differences were not statistically significant. In a logistic regression analysis there was a significant difference by year of diagnosis for current smoking rate ratios (RR); survivors were less likely to be current smokers if diagnosed in recent years (RR = 0.76; 95% confidence intervals = 0.58-0.98, between 1965-74) and quite similar to controls if diagnosed in earlier years (RR = 1.05 between 1945 and 1954). In our group of long-term cancer survivors, the reduction in current smoking came about because survivors were more inclined never to start smoking than controls. Once addicted to tobacco, they were less likely to quit. While the fact that survivors are less likely to start smoking is encouraging, the persistence of smoking habits strongly suggests the need for continuing efforts to prevent smoking in this most vulnerable group.

Adolescent↗

The catalytic subunit of telomerase protects neurons against amyloid beta-peptide-induced apoptosis.

The catalytic subunit of telomerase (TERT) is a specialized reverse transcriptase that has been associated with cell immortalization and cancer. It was reported recently that TERT is expressed in neurons throughout the brain in embryonic and early postnatal development, but is absent from neurons in the adult brain. We now report that suppression of TERT levels and function in embryonic mouse hippocampal neurons in culture using antisense technology and the telomerase inhibitor 3' -azido-2' 3' -dideoxythymidine significantly increases their vulnerability to cell death induced by amyloid beta-peptide, a neurotoxic protein believed to promote neuronal degeneration in Alzheimer's disease. Neurons in which TERT levels were reduced exhibited increased levels of oxidative stress and mitochondrial dysfunction following exposure to amyloid beta-peptide. Overexpression of TERT in pheochromocytoma cells resulted in decreased vulnerability to amyloid beta-peptide-induced apoptosis. Our findings demonstrate a neuroprotective function of TERT in an experimental model relevant to Alzheimer's disease, and suggest the possibility that restoration of TERT expression in neurons in the adult brain may protect against age-related neurodegeneration.

Alzheimer Disease↗

Mortality and morbidity of heart diseases in Hong Kong, 1971-1994.

This the second of two feature articles at the end of this issue. "In Hong Kong, heart diseases have been the second leading cause of death, after cancer, since the 1960s.... The purpose of this article is to examine the trends of mortality and morbidity of heart diseases in Hong Kong from 1971 to 1994. Age and sex differentials of deaths due to heart diseases are also analysed.... In general, the number of deaths due to heart diseases increased with age for either sex and males were more vulnerable to heart diseases than females. The age-specific death rates of either sex were quite stable over time and no increasing trend was observed. Compared with the crude death rate due to heart diseases, the standardized death rate showed a marked downward trend. These suggest that the increase in deaths due to heart diseases was mainly due to the ageing population."

Age Factors↗

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Lamin Type A↗

Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice.

The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. Ruptured and intact plaques differed in terms of plaque cross-sectional area (intact, 0.109+/-0.016 mm2; ruptured, 0.192+/-0.009 mm2; P=0.0005), luminal occlusion (intact, 35.3+/-3.3%; ruptured, 57.7+/-1.9%; P<0.0001), the number of buried caps within the lesion (intact, 1.06+/-0.12; ruptured, 2.66+/-0.16; P<0.0001), fibrous cap thickness (intact, 4.7+/-0.6 microm; ruptured, 2.0+/-0.3 microm; P=0.0004), and lipid fractional volume (intact, 35.9+/-3.0%; ruptured, 50.7+/-2.2%; P=0.0019). This study confirms that plaque rupture is a frequent occurrence in the brachiocephalic arteries of apolipoprotein E knockout mice on a high-fat diet. The data also show that ruptured plaques in these mice show many of the characteristics of vulnerable plaques in humans. This supports the use of this model in studies of the mechanisms and therapy of plaque rupture.

Animals↗

Race and ethnic disparities in cervical cancer screening in a safety-net system.

OBJECTIVES: The three objectives of this research were: 1) to examine the use of Pap smear tests among low-income women, including minority and immigrant women who were patients in a safety-net healthcare system; 2) to identify policy relevant variables that could lead to changes in use of Pap smear screening services for these women; and 3) to contribute to the literature on use of Pap smear screening, especially among minorities and immigrants. The Behavioral Model for Vulnerable Populations was used as the theoretical framework. METHODS: Pap smear screening predictors were examined using telephone interviews with a random sample of women aged 18-60, including 465 Non-Hispanic Whites, 285 African Americans, 164 Hispanic Americans, and 256 Hispanic immigrants, enrolled in a safety-net healthcare system in Texas in Fall 2000. Binary logistic regression analysis was used. RESULTS: The research revealed that Non-Hispanic Whites were most likely to have been screened ever and in the past 3 years, followed by African Americans, Hispanic immigrants, and Hispanic Americans. Among Hispanics, immigrants were most likely to have had Pap smear screening, supporting the "healthy immigrant hypothesis." Older women were most likely to have ever been screened, with younger women, most likely in the past year. Having a usual source of healthcare and a checkup for current pregnancy increased screening, while competing needs (food, clothing, housing) affected screening negatively. CONCLUSIONS: Culturally competent, community-based care for women is needed to increase Pap smear screening among minority groups, especially Hispanic immigrant and Hispanic American women.

Adolescent↗

Impact of childhood cancer on siblings and family: family strategies for primary health care.

The article reviews the impact of a chronic illness with a potentially life-threatening outcome on siblings and suggests strategies to enhance sibling support by an advanced practice nurse. The well siblings in the family system have the potential to perceive threatened or actual losses as a result of their brother's or sister's illness. The importance of considering total family structure, including the sibling's emotional needs, in an ongoing assessment to determine strengths, vulnerabilities, and coping abilities is presented. The advanced practice nurse in an ambulatory care setting, community setting, or hospital is in a unique position to provide comprehensive guidance and coordination of mechanisms of support in concert with the family in an effort to reduce vulnerability and to maintain the emotional well-being of the siblings.

Adaptation, Psychological↗

Cutaneous nasal malignancies: is primary reconstruction safe?

BACKGROUND: The nose is particularly vulnerable to cutaneous malignancies, making it the most common location for presentation. Recurrence of these cutaneous lesions is not uncommon, often compromising the timing of nasal restoration. It is the purpose of this report to reexamine the safety of primary nasal reconstruction in selected patients. METHODS: Seventy-one patients who underwent nasal reconstruction at The University of Texas M. D. Anderson Cancer Center between 1987 and 1995 were retrospectively reviewed. There were 35 men and 36 women with an average age of 60 years. All nasal reconstructions were performed for defects secondary to malignancies. Basal cell carcinoma was the most common lesion (n = 49), followed by squamous cell carcinoma (n = 10) and melanoma (n = 7), with five additional variable malignancies. The most common location of the cutaneous lesions was the nasal dorsum, and the forehead flap was the most common adjacent tissue used for reconstruction. Immediate reconstruction was performed for 42 of the basal cell carcinomas, 6 of the squamous cell carcinomas, 6 melanomas, and 3 other lesions. Delayed restoration was performed for 7 basal cell carcinomas, 4 squamous cell carcinomas, 1 melanoma, and 2 additional lesions. The average time between surgical extirpation and the start of nasal reconstruction was 8.2 months for basal cell carcinoma, 29 months for squamous cell carcinoma, and 10 months for melanoma. RESULTS: Twenty-six recurrent lesions were identified at an average of 36 months after extirpation. Despite these numbers, only three recurred after nasal reconstruction at our institution. Follow-up averaged 41 months, with none less than 1 year. Seventy patients are still alive with no evidence of disease. CONCLUSION: Primary reconstruction is safe in selected patients. Surgical delay in reconstruction should be considered if margins are questionable, the pathology is determined to be aggressive, if there is perineural or deep bony invasion, or if postoperative radiotherapy is to be initiated. Nasal reconstruction ultimately is based upon a complex series of issues but can be performed with few complications in an effort to restore self-image.

Adolescent↗

Emotional distress in men with life-threatening illness.

This descriptive survey explored the relationship of health status, functional status, stressful life events, stress resistance resources and emotional distress in 60 men with life-threatening illness (N = 30 with cancer and N = 30 with AIDS). Sixty-two percent met CES-D criteria for clinical depression. This study's results supported the hypotheses that poorer functional status and greater negative stressors are associated with both higher levels of hopelessness and depression. Twenty-four patients constituted a group with severe emotional distress. This group was significantly different from the less vulnerable group with poorer functional status (KPS), a greater number and severity of negative stressors, less satisfaction with social support, and less hopefulness.

Acquired Immunodeficiency Syndrome↗

KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.

AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context. MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms. KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Kr&#xfc;ppel-like factor 5 (KLF5) directly activates G6PD transcription. SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.

Ferroptosis↗

Stability and inoculation of risk comparisons' effects under conflict: replicating and extending the "asbestos jury" study by Slovic et al.

Promotion or criticism of risk comparisons in risk communication has far exceeded empirical tests of their effects. Slovic et al. (1990) experimented with a hypothetical jury trial in which an asbestos-installing firm was accused of subjecting school occupants to unreasonable risk. A risk comparison sharply reduced subjects' estimates of risk and judgments that the firm was guilty, but a critique of the risk comparison had risk estimates and guilt judgments rebounding to the original (without risk comparison) level. Slovic et al. concluded that risk comparisons' effects were highly unstable, at least in conflict-ridden situations such as a jury trial. The present study replicates and extends this important study, using the same stimuli and questions. The respective effects of the risk comparison and the critique recurred, although much less sharply than in Slovic et al. Moreover, judgments of guilt, risk, and other aspects of the case seemed shaped more by demographics and beliefs about risk generically (e.g., about the likelihood of cancer after exposure to a carcinogen) than by either risk comparison or critique. A variant design, in which the defense's expert witness dismissed potential criticisms of the risk comparison, appeared to "inoculate" people against shifting their views after seeing the critique. Overall, these results show that risk comparisons might change some beliefs about risks in conflict and that "inoculation" can reduce vulnerability to criticism. However, the results also show strong limits on effects of both comparisons and their critiques: they shifted only a minority of judgments and had small effects relative to people's social locations and prior risk beliefs.

Adult↗