K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.

K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein.

Association Between Influenza Vaccine Uptake and Health Awareness: A Cross-Sectional Questionnaire-Based Study Among Medical Students and Healthcare Workers in Northern Vietnam.

BACKGROUND Seasonal influenza poses a significant global health concern. Despite the proven effectiveness of the influenza vaccine, its uptake remains low in Vietnam. This study aimed to assess the knowledge, attitudes, and practices of medical students and healthcare workers on influenza vaccine uptake in northern Vietnam. MATERIAL AND METHODS A cross-sectional survey was conducted among 585 participants from northern Vietnam institutions through an anonymous online survey via Google form from June to August 2022. The cut-off for a high level of knowledge and a positive attitude was set at 70% for each variable. Bivariate analysis was conducted to establish associations. Multiple binary logistic regression models were used to identify factors associated with knowledge, attitude, and practice. RESULTS Among the participants, 463 (79.15%) were women, 354 (60.51%) were below 25 years old, 426 (72.82%) were of "Kinh" ethnicity, and 454 (77.61%) were single. Only 237 (40.51%) were vaccinated. Good knowledge and attitude were reported by 36.58% and 42.39% of the participants, respectively. Having a high level of knowledge was found positively associated with having a positive attitude (odds ratio 2.11 [1.48-3.01]). Kinh ethnicity was positively associated with knowledge (1.67 [1.12-2.49]) and attitude (1.97 [1.32-2.94]). Female participants displayed a more positive attitude (2.08 [1.33-3.25]). Several factors influenced the uptake, such as being single (2.07 [1.19-3.59]), being a medical doctor (2.34 [1.09-5.06]), and being advised by a healthcare provider (2.96 [2.00-4.37]). CONCLUSIONS A noticeable gap in knowledge and attitude related to influenza vaccine uptake was found among the target population. Tailored interventions are necessary to improve vaccination coverage.

Pre-stroke anticoagulation for atrial fibrillation in primary English speakers and non-primary English speakers: a multicentre retrospective cohort study.

BACKGROUND: Anticoagulation can prevent most strokes in individuals with atrial fibrillation (AF); however, many people presenting with stroke and known AF are not anticoagulated. Language barriers and poor health literacy have previously been associated with decreased patient medication adherence. The association between language barriers and initiation of anticoagulation therapy for AF is uncertain. AIMS: The aims of this study were to determine whether demographic factors, including non-English primary language, were (1) associated with not being initiated on anticoagulation for known AF prior to admission with stroke, and (2) associated with non-adherence to anticoagulation in the setting of known AF prior to admission with stroke. METHODS: A multicentre retrospective cohort study was conducted for consecutive individuals admitted to the three South Australian tertiary hospitals with stroke units over a 5-year period. RESULTS: There were 6829 individuals admitted with stroke. These cases included 5835 ischaemic stroke patients, 1333 of whom had pre-existing AF. Only 40.0% presenting with ischaemic stroke in the setting of known pre-existing AF were anticoagulated. When controlling for demographics, socioeconomic status and past medical history (including the components of the CHADS2VASC score and anticoagulation contraindications), having a primary language other than English was associated with a lower likelihood of having been commenced on anticoagulant for known pre-stroke AF (odds ratio: 0.52, 95% confidence interval: 0.36-0.77, P = 0.001), but was not associated with a differing likelihood of anticoagulation adherence. CONCLUSIONS: A significant proportion of patients with stroke have pre-existing unanticoagulated AF; these rates are substantially higher if the primary language is other than English. Targeted research and interventions to minimise evidence-treatment gaps in this cohort may significantly reduce stroke burden.

Resuscitation orders demonstrate differences by gender, stroke type and intervention.

BACKGROUND AND PURPOSE: Resuscitation orders describe individual preferences and types of intervention, such as suitability for cardiopulmonary resuscitation (CPR), that may provide benefit in the event of critical deterioration. The purpose of this study was to examine stroke inpatient resuscitation order completion and content. METHODS: This retrospective cohort study examined resuscitation orders in consecutive individuals admitted to a tertiary stroke centre over a 21-month period. Multivariable logistic regression was used to identify factors associated with resuscitation order completion and content. RESULTS: 1924 individuals were included in the study. The proportion of individuals who had resuscitation orders completed was 37.4%. Several factors were associated with an increased likelihood of resuscitation order completion including having received endovascular thrombectomy (p=0.013) and having intracerebral haemorrhage (p=0.001). Females were more likely to have a resuscitation order that is not for CPR (p=0.021, OR 95%CI 1.080-2.542). Patients with intracerebral haemorrhage were also more likely to be not for CPR (p=0.037, OR 95%CI 1.039-3.353). CONCLUSIONS: Disparities exist in resuscitation order completion and content based on demographic and stroke characteristics. Further research is required to identify the reasons for these differences and to optimise resuscitation order completion.

Clinical and Laboratory Characteristics of Kawasaki Disease and COVID-19-Related Multisystem Inflammatory Syndrome in Children.

Geographical and racial factors constitute important distinctions between Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C), but no study has been conducted in Vietnam. Forty-one children with KD from January 2018 to July 2020 and 42 with KD/MIS-C from August 2020 to December 2022 were included in this study. Of the patients, 52.3% were aged between 12 and 35 months. Only two were aged over 5 years, and both were belong to the KD/MIS-C group. A 59.5% of the patients were male. Apart from fever, all symptoms tended to be more frequent in patients with KD/MIS-C. The prevalence of diffuse skin rash, hand and foot edema or erythema and gastrointestinal signs was significantly higher in patients hospitalized with KD/MIS-C. There was no significant difference in laboratory findings between the two groups. Coronary artery dilation was more frequently observed in patients with KD/MIS-C compared to those with KD (40.5% vs. 14.6%, P = 0.009).

Factors associated with delay to carotid endarterectomy for acute ischaemic stroke in South Australia: A multicentre retrospective cohort study.

BACKGROUND: The greatest benefits of carotid endarterectomy (CEA) accrue when performed within two weeks of acute ischaemic stroke (AIS) due to symptomatic carotid stenosis. Previous studies have identified multiple factors contributing to CEA delay. AIMS: To determine factors associated with delayed CEA in patients admitted to tertiary stroke centres within a major metropolitan region with AIS METHODS: In a retrospective cohort study, consecutive patients admitted to the tertiary hospitals with stroke units within South Australia (Lyell McEwin Hospital, Royal Adelaide Hospital and Flinders Medical Centre) between 2016 to 2020 were included. Univariable and multivariable logistic regression were used to identify individual factors associated with time from symptom onset to CEA of over two weeks. RESULTS: A total of 174 patients were included. The median time to CEA was 5 days (IQR 3-9.75). Delayed CEA beyond 14 days occurred in 28/174 (16%). Factors most associated with delayed CEA included presentation to a tertiary hospital without onsite Vascular Surgical Unit (OR 3.71, 95%CI 1.31-10.58), history of previous stroke (OR 3.38, 95% CI 1.11-9.84) and presenting NIHSS above 6 (OR 5.16, 95% CI 1.60-16.39). CONCLUSION: This study identified that presentation to a tertiary hospital without a Vascular Surgery Unit, history of previous stroke and presenting NIHSS above 6 were associated with delay to CEA in AIS patients in South Australia. Interventional studies aiming to improve the proportion of patients that receive CEA within 14 days are required.

Visualising and quantifying microvascular structure and function in patients with heart failure using optical coherence tomography.

Heart failure (HF) is characterised by abnormal conduit and resistance artery function in humans. Microvascular function in HF is less well characterised, due in part to the lack of tools to image these vessels in vivo. The skin microvasculature is a surrogate for systemic microvascular function and health and plays a key role in thermoregulation, which is dysfunctional in HF. We deployed a novel optical coherence tomography (OCT) technique to visualise and quantify microvascular structure and function in 10 subjects with HF and 10 age- and sex-matched controls. OCT images were obtained from the ventral aspect of the forearm, at baseline (33°C) and after 30 min of localised skin heating. At rest, OCT-derived microvascular density (20.3 ± 8.7%, P = 0.004), diameter (35.1 ± 6.0 µm, P = 0.006) and blood flow (82.9 ± 41.1 pl/s, P = 0.021) were significantly lower in HF than CON (27.2 ± 8.0%, 40.4 ± 5.8 µm, 110.8 ± 41.9 pl/s), whilst blood speed was not significantly lower (74.3 ± 11.0 µm/s vs. 81.3 ± 9.9 µm/s, P = 0.069). After local heating, the OCT-based density, diameter, blood speed and blood flow of HF patients were similar (all P > 0.05) to CON. Although abnormalities exist at rest which may reflect microvascular disease status, patients with HF retain the capacity to dilate cutaneous microvessels in response to localised heat stress. This is a novel in vivo human observation of microvascular dysfunction in HF, illustrating the feasibility of OCT to directly visualise and quantify microvascular responses to physiological stimuli in vivo. KEY POINTS: Microvessels in the skin are critical to human thermoregulation, which is compromised in participants with heart failure (HF). We have developed a powerful new non-invasive optical coherence tomography (OCT)-based approach for the study of microvascular structure and function in vivo. Our approach enabled us to observe and quantify abnormal resting microvascular function in participants with HF. Patients with HF were able to dilate skin microvessels in response to local heat stress, arguing against an underlying structural abnormality. This suggests that microvascular functional regulation is the primary abnormality in HF. OCT can be used to directly visualise and quantify microvascular responses to physiological stimuli in vivo.

Routine Esophagograms After Hiatus Hernia Repair Minimizes Reoperative Morbidity: A Multicenter Comparative Cohort Study.

OBJECTIVE: Determine the utility of routine esophagograms after hiatus hernia repair and its impact on patient outcomes. BACKGROUND: Hiatus hernia repairs are common. Early complications such asre-herniation, esophageal obstruction and perforation, although infrequent, incur significant morbidity. Whether routine postoperative esophagograms enable early recognition of these complications, expedite surgical management, reduce reoperative morbidity, and improve functional outcomes are unclear. METHODS: Analysis of a prospectively-maintained database of hiatus hernia repairs in 14 hospitals, and review of esophagograms in this cohort. Results: A total of 1829 hiatus hernias were repaired. Of these, 1571 (85.9%) patients underwent a postoperative esophagogram. Overall, 1 in 48 esophagograms resulted in an early (<14 days) reoperation, which was undertaken in 44 (2.4%) patients. Compared to those without an esophagogram, patients who received this test before reoperation (n = 37) had a shorter time to diagnosis (2.4 vs 3.9 days, P = 0.041) and treatment (2.4 vs 4.3 days, P = 0.037) of their complications. This was associated with lower rates of open surgery (10.8% vs 42.9%, P = 0.034), gastric resection (0.0% vs 28.6%, P = 0.022), postoperative morbidity (13.5% vs 85.7%, P < 0.001), unplanned intensive care admission (16.2% vs 85.7%, P < 0.001), and decreased length-of-stay (7.3 vs 18.3 days, P = 0.009). Furthermore, we identified less intraoperative and postoperative complications, and superior functional outcomes at 1-year follow-up in patients who underwent early reoperations for an esophagogram-detected asymptomatic re-herniation than those who needed surgery for late symptomatic recurrences. CONCLUSIONS: Postoperative esophagograms decrease the morbidity associated with early and late reoperations, and should be considered for routine use after hiatus hernia surgery.

Biparametric MR signal characteristics can predict histopathological measures of prostate cancer.

OBJECTIVES: The aim of this study was to establish a new data-driven metric from MRI signal intensity that can quantify histopathological characteristics of prostate cancer. METHODS: This retrospective study was conducted on 488 patients who underwent biparametric MRI (bp-MRI), including T2-weighted imaging (T2W) and apparent diffusion coefficient (ADC) of diffusion-weighted imaging, and having biopsy-proven prostate cancer between August 2011 and July 2015. Forty-two of the patients who underwent radical prostatectomy and the rest of 446 patients constitute the labeled and unlabeled datasets, respectively. A deep learning model was built to predict the density of epithelium, epithelial nuclei, stroma, and lumen from bp-MRI, called MR-driven tissue density. On both the labeled validation set and the whole unlabeled dataset, the quality of MR-driven tissue density and its relation to bp-MRI signal intensity were examined with respect to different histopathologic and radiologic conditions using different statistical analyses. RESULTS: MR-driven tissue density and bp-MRI of 446 patients were evaluated. MR-driven tissue density was significantly related to bp-MRI (p < 0.05). The relationship was generally stronger in cancer regions than in benign regions. Regarding cancer grades, significant differences were found in the intensity of bp-MRI and MR-driven tissue density of epithelium, epithelial nuclei, and stroma (p < 0.05). Comparing MR true-negative to MR false-positive regions, MR-driven lumen density was significantly different, similar to the intensity of bp-MRI (p < 0.001). CONCLUSIONS: MR-driven tissue density could serve as a reliable histopathological measure of the prostate on bp-MRI, leading to an improved understanding of prostate cancer and cancer progression. KEY POINTS: • Semi-supervised deep learning enables non-invasive and quantitative histopathology in the prostate from biparametric MRI. • Tissue density derived from biparametric MRI demonstrates similar characteristics to the direct estimation of tissue density from histopathology images. • The analysis of MR-driven tissue density reveals significantly different tissue compositions among different cancer grades as well as between MR-positive and MR-negative benign.

Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.

Aberrant activation of Wnt/ß-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.

Simulated Microgravity Induces the Proliferative Inhibition and Morphological Changes in Porcine Granulosa Cells.

Astronauts are always faced with serious health problems during prolonged spaceflights. Previous studies have shown that weightlessness significantly affects the physiological function of female astronauts, including a change in reproductive hormones and ovarian cells, such as granulosa and theca cells. However, the effects of microgravity on these cells have not been well characterized, especially in granulosa cells. This study aimed to investigate the effects of simulated microgravity (SMG) on the proliferation and morphology of porcine granulosa cells (pGCs). pGC proliferation from the SMG group was inhibited, demonstrated by the reduced O.D. value and cell density in the WST-1 assay and cell number counting. SMG-induced pGCs exhibited an increased ratio of cells in the G0/G1 phase and a decreased ratio of cells in the S and G2/M phase. Western blot analysis indicated a down-regulation of cyclin D1, cyclin-dependent kinase 4 (cdk4), and cyclin-dependent kinase 6 (cdk6), leading to the prevention of the G1-S transition and inducing the arrest phase. pGCs under the SMG condition showed an increase in nuclear area. This caused a reduction in nuclear shape value in pGCs under the SMG condition. SMG-induced pGCs exhibited different morphologies, including fibroblast-like shape, rhomboid shape, and pebble-like shape. These results revealed that SMG inhibited proliferation and induced morphological changes in pGCs.

The mutational landscapes of genetic and chemical models of Kras-driven lung cancer.

Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility.

PURPOSE: MTHFR, one of the major enzymes in the folate cycle, is known to acquire single-nucleotide polymorphisms that significantly reduce its activity, resulting in an increase in circulating homocysteine. Methylation processes are of crucial importance in gametogenesis, involved in the regulation of imprinting and epigenetic tags on DNA and histones. We have retrospectively assessed the prevalence of MTHFR SNPs in a population consulting for infertility according to gender and studied the impact of the mutations on circulating homocysteine levels. METHODS: More than 2900 patients having suffered at least two miscarriages (2 to 9) or two failed IVF/ICSI (2 to 10) attempts were included for analysis of MTHFR SNPs C677T and A1298C. Serum homocysteine levels were measured simultaneously. RESULTS: We observed no difference in the prevalence of different genetic backgrounds between men and women; only 15% of the patients were found to be wild type. More than 40% of the patients are either homozygous for one SNP or compound heterozygous carriers. As expected, the C677T SNP shows the greatest adverse effect on homocysteine accumulation. The impact of MTHFR SNPs on circulating homocysteine is different in men than in women. CONCLUSIONS: Determination of MTHFR SNPs in both men and women must be seriously advocated in the presence of long-standing infertility; male gametes, from MTHFR SNPs carriers, are not exempted from exerting a hazardous impact on fertility. Patients should be informed of the pleiotropic medical implications of these SNPs for their own health, as well as for the health of future children.

Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression.

Epithelial-mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%-30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduced levels of Hras and Egfr signaling, and frequent Ink4/Arf deletions. Deletion of Hras from the mouse germline also leads to a strong reduction in squamous tumor development, but tumors now acquire activating Kras mutations and exhibit more aggressive metastatic properties. We propose that invasive carcinomas can arise by different genetic and biological routes dependent on exposure to chronic inflammation and possibly from different target cell populations within the skin. Our data have implications for the use of inhibitors of inflammation or of Ras/Egfr pathway signaling for prevention or treatment of invasive cancers.

Mechanisms underlying a thalamocortical transformation during active tactile sensation.

During active somatosensation, neural signals expected from movement of the sensors are suppressed in the cortex, whereas information related to touch is enhanced. This tactile suppression underlies low-noise encoding of relevant tactile features and the brain's ability to make fine tactile discriminations. Layer (L) 4 excitatory neurons in the barrel cortex, the major target of the somatosensory thalamus (VPM), respond to touch, but have low spike rates and low sensitivity to the movement of whiskers. Most neurons in VPM respond to touch and also show an increase in spike rate with whisker movement. Therefore, signals related to self-movement are suppressed in L4. Fast-spiking (FS) interneurons in L4 show similar dynamics to VPM neurons. Stimulation of halorhodopsin in FS interneurons causes a reduction in FS neuron activity and an increase in L4 excitatory neuron activity. This decrease of activity of L4 FS neurons contradicts the "paradoxical effect" predicted in networks stabilized by inhibition and in strongly-coupled networks. To explain these observations, we constructed a model of the L4 circuit, with connectivity constrained by in vitro measurements. The model explores the various synaptic conductance strengths for which L4 FS neurons actively suppress baseline and movement-related activity in layer 4 excitatory neurons. Feedforward inhibition, in concert with recurrent intracortical circuitry, produces tactile suppression. Synaptic delays in feedforward inhibition allow transmission of temporally brief volleys of activity associated with touch. Our model provides a mechanistic explanation of a behavior-related computation implemented by the thalamocortical circuit.

Genetic architecture of mouse skin inflammation and tumour susceptibility.

Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer. Mice of the Mus spretus species are resistant to tumour development, and crosses between M. spretus and susceptible Mus musculus strains have been used to map locations of genetic variants that contribute to skin cancer susceptibility. We have integrated germline polymorphisms with gene expression in normal skin from a M. musculus x M. spretus backcross to generate a network view of the gene expression architecture of mouse skin. Here we demonstrate how this approach identifies expression motifs that contribute to tissue organization and biological functions related to inflammation, haematopoiesis, cell cycle control and tumour susceptibility. Motifs associated with inflammation, epidermal barrier function and proliferation are differentially regulated in backcross mice susceptible or resistant to tumour development. The intestinal stem cell marker Lgr5 is identified as a candidate master regulator of the hair follicle, and the vitamin D receptor (Vdr) is linked to coordinated control of epidermal barrier function, inflammation and tumour susceptibility.

A review of methods for identifying stochastic resonance in simulations of single neuron models.

Stochastic resonance (SR) is said to be observed when the presence of noise in a nonlinear system enables an output signal from the system to better represent some feature of an input signal than it does in the absence of noise. The effect has been observed in models of individual neurons, and in experiments performed on real neural systems. Despite the ubiquity of biophysical sources of stochastic noise in the nervous system, however, it has not yet been established whether neuronal computation mechanisms involved in performance of specific functions such as perception or learning might exploit such noise as an integral component, such that removal of the noise would diminish performance of these functions. In this paper we revisit the methods used to demonstrate stochastic resonance in models of single neurons. This includes a previously unreported observation in a multicompartmental model of a CA1-pyramidal cell. We also discuss, as a contrast to these classical studies, a form of 'stochastic facilitation', known as inverse stochastic resonance. We draw on the reviewed examples to argue why new approaches to studying 'stochastic facilitation' in neural systems need to be developed.

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice.

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events and could have major implications for the design of human association studies to identify cancer susceptibility genes.