Multiomics-Based Feature Extraction and Selection for the Prediction of Lung Cancer Survival.

Lung cancer is a global health challenge, hindered by delayed diagnosis and the disease's complex molecular landscape. Accurate patient survival prediction is critical, motivating the exploration of various -omics datasets using machine learning methods. Leveraging multi-omics data, this study seeks to enhance the accuracy of survival prediction by proposing new feature extraction techniques combined with unbiased feature selection. Two lung adenocarcinoma multi-omics datasets, originating from the TCGA and CPTAC-3 projects, were employed for this purpose, emphasizing gene expression, methylation, and mutations as the most relevant data sources that provide features for the survival prediction models. Additionally, gene set aggregation was shown to be the most effective feature extraction method for mutation and copy number variation data. Using the TCGA dataset, we identified 32 molecular features that allowed the construction of a 2-year survival prediction model with an AUC of 0.839. The selected features were additionally tested on an independent CPTAC-3 dataset, achieving an AUC of 0.815 in nested cross-validation, which confirmed the robustness of the identified features.

CINner: modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types. We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) further uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions. Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Inferring Bladder Cancer Evolution from Mucosal field Effects by Whole-Organ Spatial Mutational, Proteomic, and Metabolomic Mapping.

Multi-platform mutational, proteomic, and metabolomic spatial mapping was used on the whole-organ scale to identify the molecular evolution of bladder cancer from mucosal field effects. We identified complex proteomic and metabolomic dysregulations in microscopically normal areas of bladder mucosa adjacent to dysplasia and carcinoma in situ. The mutational landscape developed in a background of complex defects of protein homeostasis which included dysregulated nucleocytoplasmic transport, splicesome, ribosome biogenesis, and peroxisome. These changes were combined with altered urothelial differentiation which involved lipid metabolism and protein degradations controlled by PPAR. The complex alterations of proteome were accompanied by dysregulation of gluco-lipid energy-related metabolism. The analysis of mutational landscape identified three types of mutations based on their geographic distribution and variant allele frequencies. The most common were low frequency α mutations restricted to individual mucosal samples. The two other groups of mutations were associated with clonal expansion. The first of this group referred to as ß mutations occurred at low frequencies across the mucosa. The second of this group called γ mutations increased in frequency with disease progression. Modeling of the mutations revealed that carcinogenesis may span nearly 30 years and can be divided into dormant and progressive phases. The α mutations developed gradually in the dormant phase. The progressive phase lasted approximately five years and was signified by the advent of ß mutations, but it was driven by γ mutations which developed during the last 2-3 years of disease progression to invasive cancer. Our study indicates that the understanding of complex alterations involving mucosal microenvironment initiating bladder carcinogenesis can be inferred from the multi-platform whole-organ mapping.

Erratum: The origin of bladder cancer from mucosal field effects.

[This corrects the article DOI: 10.1016/j.isci.2022.104551.].

The origin of bladder cancer from mucosal field effects.

Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multiple HOX genes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of mucosa. The α mutations occurred at low frequencies while the ß mutations increased in frequency with disease progression. Modeling revealed that bladder carcinogenesis spans 10-15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was driven by ß mutations.

Predicting Time to Relapse in Acute Myeloid Leukemia through Stochastic Modeling of Minimal Residual Disease Based on Clonality Data.

Event-free and overall survival remain poor for patients with acute myeloid leukemia. Chemoresistant clones contributing to relapse arise from minimal residual disease (MRD) or newly-acquired mutations. However, the dynamics of clones comprising MRD is poorly understood. We developed a predictive stochastic model, based on a multitype age-dependent Markov branching process, to describe how random events in MRD contribute to the heterogeneity in treatment response. We employed training and validation sets of patients who underwent whole genome sequencing and for whom mutant clone frequencies at diagnosis and relapse were available. The disease evolution and treatment outcome are subject to stochastic fluctuations. Estimates of malignant clone growth rates, obtained by model fitting, are consistent with published data. Using the estimates from the training set, we developed a function linking MRD and time of relapse, with MRD inferred from the model fits to clone frequencies and other data. An independent validation set confirmed our model. In a third data set, we fitted the model to data at diagnosis and remission and predicted the time to relapse. As a conclusion, given bone marrow genome at diagnosis and MRD at or past remission, the model can predict time to relapse, and help guide treatment decisions to mitigate relapse.

Synchronous Renal Cell Carcinoma and Hepatocellular Carcinoma.

The coexistence of multiple synchronous primary malignancies is uncommon. The coexistence of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) is even rarer. We present a case of a 44-year-old male patient with a history of chronic hepatitis B and a right renal mass treated by radical nephrectomy. At the 2-month follow-up, a new lesion was detected in the left lobe of the liver. Postsurgery histologic evaluation with immunohistochemical study of both lesions confirmed the renal and hepatic lesions to be RCC and HCC, respectively.

Optimizing outcomes for patients with metastatic prostate cancer: insights from South East Asia Expert Panel.

AIMS: Clinical decision making is challenging in men with metastatic prostate cancer (mPC), as heterogeneity in treatment options and patient characteristics have resulted in multiple scenarios with little or no evidence. The South East Asia Expert Panel 2019 addressed some of these challenges. METHODS: Based on evidence in the literature and expert interviews, 19 statements were formulated for key challenges in the treatment of men with castration-sensitive and -resistant prostate cancer in clinical practice. A modified Delphi process was used to reach consensus among experts in the panel and develop clinical practice recommendations. RESULTS: The majority of the panel preferred a risk-based stratification and recommended abiraterone or enzalutamide as first-line therapy for symptomatic chemotherapy naïve patients. Abiraterone is preferred over enzalutamide as a first-line treatment in these patients. However, the panel did not support the use of abiraterone in high risk lymph-node positive only (N+M0) or in non-metastatic (N0M0) patients. In select patients, low dose abiraterone with food may be used to optimize clinical outcomes. Androgen receptor gene splice variant status may be a useful guide to therapy. In addition, generic versions of approved therapies may improve access to treatment to a broader patient population. The choice of treatment, as well as sequencing are guided by both patient and disease characteristics, preferences, drug access, cost, and compliance. CONCLUSION: Expert recommendations are key to guidance for the optimal management of mPC. Appropriate choice, timing, and sequence of treatment options can help to tailor therapy to maximize outcomes in men with mPC.

Application of the Moran Model in Estimating Selection Coefficient of Mutated CSF3R Clones in the Evolution of Severe Congenital Neutropenia to Myeloid Neoplasia.

Bone marrow failure (BMF) syndromes, such as severe congenital neutropenia (SCN) are leukemia predisposition syndromes. We focus here on the transition from SCN to pre-leukemic myelodysplastic syndrome (MDS). Stochastic mathematical models have been conceived that attempt to explain the transition of SCN to MDS, in the most parsimonious way, using extensions of standard processes of population genetics and population dynamics, such as the branching and the Moran processes. We previously presented a hypothesis of the SCN to MDS transition, which involves directional selection and recurrent mutation, to explain the distribution of ages at onset of MDS or AML. Based on experimental and clinical data and a model of human hematopoiesis, a range of probable values of the selection coefficient s and mutation rate µ have been determined. These estimates lead to predictions of the age at onset of MDS or AML, which are consistent with the clinical data. In the current paper, based on data extracted from published literature, we seek to provide an independent validation of these estimates. We proceed with two purposes in mind: (i) to determine the ballpark estimates of the selection coefficients and verify their consistency with those previously obtained and (ii) to provide possible insight into the role of recurrent mutations of the G-CSF receptor in the SCN to MDS transition.

Extragastrointestinal stromal tumor presenting as an exophytic prostatic mass.

Extragastrointestinal stromal tumors (EGISTs) are uncommon manifestation of gastrointestinal stromal tumors originating from cells outside the gastrointestinal tract. Documented sites of EGISTs include the omentum, mesentery, retroperitoneum, and prostate gland. Prostatic EGISTs are rare entities, which have been sporadically observed, yet all of them were found to be confined within enlarged prostates. We herein report a rare case of EGIST in a 66-year-old man, presenting as a large exophytic prostatic mass.

Symptom prevalence, bother, and treatment satisfaction in men with lower urinary tract symptoms in Southeast Asia: a multinational, cross-sectional survey.

PURPOSE: The overall objective of the survey was to systematically examine patients' perspectives on lower urinary tract symptoms (LUTS) and their treatment in Southeast Asia. METHODS: A multinational cross-sectional survey involving adult men seeking consultation at urology outpatient clinics because of LUTS in Southeast Asia was conducted using convenience sampling. Self-reported prevalence, bother, treatment and treatment satisfaction of selected LUTS including urgency, nocturia, slow stream, and post-micturition dribble were evaluated. RESULTS: In total, 1535 eligible patients were enrolled in the survey. A majority of respondents were aged 56-75 years, not employed, and had not undergone prostate operation before. Overall, the self-reported prevalence of nocturia was 88% (95% CI 86-90%), slow stream 61% (95% CI 59-63%), post micturition dribble 55% (95% CI 52-58%), and urgency 52% (95% CI 49-55%). There were marked differences in the country specific prevalence of LUTS complaints. Frequently, symptoms coexisted and were combined with nocturia. More than half of patients felt at least some degree of bother from their symptoms: 61% for urgency, 57% for nocturia, 58% for slow stream, and 60% for post-micturition dribble. Before seeing the present urologists, nearly half of patients have received some form of prescribed treatment and more than 80% of patients indicated they would like to receive treatment. CONCLUSION: Men who sought urologist care for LUTS often presented with multiple symptoms. Nocturia emerged as the most common symptom amongst the four core symptoms studied.

An application of the Krylov-FSP-SSA method to parameter fitting with maximum likelihood.

Monte Carlo methods such as the stochastic simulation algorithm (SSA) have traditionally been employed in gene regulation problems. However, there has been increasing interest to directly obtain the probability distribution of the molecules involved by solving the chemical master equation (CME). This requires addressing the curse of dimensionality that is inherent in most gene regulation problems. The finite state projection (FSP) seeks to address the challenge and there have been variants that further reduce the size of the projection or that accelerate the resulting matrix exponential. The Krylov-FSP-SSA variant has proved numerically efficient by combining, on one hand, the SSA to adaptively drive the FSP, and on the other hand, adaptive Krylov techniques to evaluate the matrix exponential. Here we apply this Krylov-FSP-SSA to a mutual inhibitory gene network synthetically engineered in Saccharomyces cerevisiae, in which bimodality arises. We show numerically that the approach can efficiently approximate the transient probability distribution, and this has important implications for parameter fitting, where the CME has to be solved for many different parameter sets. The fitting scheme amounts to an optimization problem of finding the parameter set so that the transient probability distributions fit the observations with maximum likelihood. We compare five optimization schemes for this difficult problem, thereby providing further insights into this approach of parameter estimation that is often applied to models in systems biology where there is a need to calibrate free parameters.

Intimate partner violence and physical health outcomes among Southeast Asian American women.

Although intimate partner violence is prevalent among Southeast Asian American women, little is known about the associations between the experience of intimate partner violence and negative health outcomes in this population. Resnick et al. proposed a model explaining the development of health problems following violent assault. This article assesses the applicability of Resnick et al.'s model to Southeast Asian American women who have experienced intimate partner violence by reviewing cultural, historical, and social factors in this population. Our review indicates that the applicability of Resnick et al.'s model to Southeast Asian American women is mixed, with some components of the model fitting well with this population and others requiring a more nuanced and complex perspective. Future studies should take into consideration cultural, historical, and social factors.

Understanding the finite state projection and related methods for solving the chemical master equation.

The finite state projection (FSP) method has enabled us to solve the chemical master equation of some biological models that were considered out of reach not long ago. Since the original FSP method, much effort has gone into transforming it into an adaptive time-stepping algorithm as well as studying its accuracy. Some of the improvements include the multiple time interval FSP, the sliding windows, and most notably the Krylov-FSP approach. Our goal in this tutorial is to give the reader an overview of the current methods that build on the FSP.

The relationship of prejudicial attitudes to psychological, social, and physical well-being within a sample of college students in the United States.

This study examined the relationship of prejudicial attitudes to psychological, social, and physical well-being among 495 college students in the Northeast region of the United States. Prejudicial attitudes included racism, sexism, homophobia, physical disability bias, weight/body-size bias, and anti-immigrant sentiment. As a secondary objective, we examined the associations among the various forms of prejudice and their relationship to key demographic and personal characteristics. We also examined the associations between psychological, social, and physical well-being. The results indicated that specific forms of prejudice, especially racism and sexism, were negative correlates of psychological, social, and/or physical well-being. The results also indicated that there may exist a prejudicial syndrome, linking diverse forms of prejudice. Furthermore, poor functioning in one area of well-being (e.g., psychological health) is related to poor functioning in other areas of well-being (social and physical health). Overall, this study provides important implications for future research and prevention programs in the area of prejudice and well-being.

Cervical cancer screening among Southeast Asian American women.

The incidence of cervical cancer is high among Southeast Asian American women, but their participation in preventive cervical cancer screening is alarmingly low. This paper reviews the literature on factors associated with participation in cervical cancer screening among women of Vietnamese, Cambodian and Hmong descent in the United States. These factors include acculturation, age, marital status, knowledge about cervical cancer, apprehension about cervical cancer screening, financial concerns, access to health care, and physician characteristics and recommendation. Suggestions for future research include the need to investigate the role of physicians treating Southeast Asian American women, the need for more extensive up-to-date studies on the current generation of young Southeast Asian American women, and the use of more advanced assessments of acculturation. Overall, much more work is needed in order to deepen our understanding of the various ways to improve the rate of cervical cancer screening among Southeast Asian American women.

A qualitative analysis of Vietnamese adolescent identity exploration within and outside an ethnic enclave.

Focusing on identity development explorations enables a greater understanding of contexts that affect immigrant adolescents. Utilizing thematic and grounded narrative analysis of 46 journal writings, during a one-month period, from first and second generation Vietnamese adolescents ranging in age from 15 to 18 (26 residents of a culturally and politically active ethnic enclave in Southern California; 20 adolescents living outside the enclave), this study establishes ways in which a focus on social context and exploration processes illuminates the complexity of immigrant adolescents' identity formation. The two groups shared many similarities, including precipitants to exploration and steps undertaken to explore identity. However, two factors-social and cultural influences and emotional reactions-revealed interesting contrasts distinguishing enclave from non-enclave dwelling Vietnamese adolescents. Data also suggested that immigrant adolescents strive to integrate different domains of identity (ethnicity, gender, career) both with one another and with the historical, social, and cultural contexts they occupy.

The influence of maternal acculturation, neighborhood disadvantage, and parenting on Chinese American adolescents' conduct problems: testing the segmented assimilation hypothesis.

Associations among neighborhood disadvantage, maternal acculturation, parenting and conduct problems were investigated in a sample of 444 Chinese American adolescents. Adolescents (54% female, 46% male) ranged from 12 to 15 years of age (mean age = 13.0 years). Multilevel modeling was employed to test the hypothesis that the association between maternal acculturation and adolescents' conduct problems could be explained by differences in mothers' reliance on monitoring and harsh discipline. In addition, guided by segmented assimilation theory, measures of neighborhood disadvantage were expected not only to be related to differences in parenting, but also to moderate the effects of maternal acculturation on parenting. Results indicated that increased maternal acculturation was related to higher levels of maternal monitoring and lower levels of harsh discipline, which, in turn, were related to lower levels of adolescents' conduct problems. Hierarchical linear modeling results revealed that neighborhood disadvantage was related to lower levels of maternal monitoring. However, neighborhood disadvantage did not moderate the link between maternal acculturation and parenting practices.

Cultural predictors of physical and mental health status among Mexican American women: a mediation model.

This study, using secondary data analysis, examined a mediation model of acculturation and ethnic pride as predictors of physical and mental health outcomes in a sample of 561 Mexican American women. Factors postulated as mediators were family support and religiosity. Systematic across-group comparison analyses were conducted to examine sources of differences in the mediation model between immigrant and non-immigrant women. The results partially supported the hypothesized mediation model, indicating that family support, but not religiosity, was a significant mediator in the relationship between ethnic pride and mental health problems. In addition, as differences between immigrant and non-immigrant women were observed only in the variables means, but not in the factor loadings or regression paths, the model tested may capture a common psychosocial process that affects these women and their health outcomes. Overall, this study offers important implications for future research and the design of intervention programs for Mexican American women.

The effects of contact with Asians and Asian Americans on White American college students: attitudes, awareness of racial discrimination, and psychological adjustment.

On the basis of acculturation theory, explicating mutual influences between different cultural or ethnic groups coming into contact, this study focused "on the other side of acculturation" theory by examining the effects of intercultural contact with Asians and Asian Americans on the psychosocial experiences of White American college students. Participants (N = 315), undergraduates attending a public university located within the state of Massachusetts, completed a survey that assessed demographic and personal characteristics, acculturation (extent of intercultural contact with Asian people and Asian cultures), attitudes towards Asians and Asian Americans, awareness of institutional discrimination and blatant racial issues, and psychological distress. Results indicated that White American students' intercultural contact with Asians and Asian Americans contributed significant variance to the prediction of their attitudes towards this ethnic group and awareness of discrimination and racial issues, but not to psychological distress. This study provides implications for understanding mutual acculturative influences between different ethnic groups in the United States.