Anti-Müllerian hormone does not predict cumulative pregnancy rate in non-infertile women following four IUI cycles with donor sperm.

PURPOSE: To evaluate the predictive value of serum AMH for clinical pregnancy in non-infertile population undergoing intrauterine insemination with donor sperm (ds-IUI). METHODS: This multicenter prospective study (ClinicalTrials.gov ID: NCT06263192) recruited all non-infertile women undergoing ds-IUI from June 2020 to December 2022 in three different fertility clinics in Spain and Chile. Indications for ds-IUI included severe oligoasthenoteratozoospermia, female partner, or single status. Clinical pregnancy rates were compared between women with AMH ≥ 1.1 and < 1.1 ng/mL. The main outcome measure was the cumulative clinical pregnancy rate after up to 4 ds-IUI cycles. RESULTS: A total of 458 ds-IUI cycles were performed among 245 patients, of whom 108 (44.08%) achieved clinical pregnancy within 4 cycles, 60.2% of these occurring in the first attempt and 84.2% after two attempts. We found no significant differences in AMH levels or other parameters (such as age, BMI, FSH, AFC) between women who became pregnant and those who did not. Cumulative pregnancy rates and logistic regression analysis revealed that AMH ≥ 1.1 ng/mL was not predictive of ds-IUI success. While a high positive correlation was observed between AFC and AMH (r = 0.67, p < 0.001), ROC curve analyses indicated that neither of these ovarian reserve markers accurately forecasts cumulative ds-IUI outcomes in non-infertile women. CONCLUSIONS: The findings of this multicenter study suggest that AMH is not a reliable predictor of pregnancy in non-infertile women undergoing ds-IUI. Even women with low AMH levels can achieve successful pregnancy outcomes, supporting the notion that diminished ovarian reserve should not restrict access to ds-IUI treatments in eligible non-infertile women.

Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Non-smokers and Tobacco Smokers.

PURPOSE: Non-smokers account for 10-13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose computed tomography (LDCT). EXPERIMENTAL DESIGN: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA) were analyzed and quantified using liquid chromatography-mass spectrometry to determine if non-smoker cases can be distinguished from sex and age-matched controls in comparison to tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening. RESULTS: Urinary levels of CR and NANA were significantly higher and comparable in non-smokers and tobacco smoker cases as compared to population controls in both cohorts. Receiver Operating Characteristics (ROC) analysis for combined CR and NANA levels in non-smokers of the exploratory cohort resulted in better predictive performance with the area under the curve (AUC) of 0.94, whereas the validation cohort non-smokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in non-smokers as well as tobacco smoker cases in both cohorts. CONCLUSIONS: Measuring CR and NANA in urine liquid biopsies could identify non-smokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

Obstructive Sleep Apnea and Oxygenation in Very Old Adults: A Propensity-Score Match Study.

OBJECTIVES: The prevalence of obstructive sleep apnea (OSA) escalates with advancing age. Although the apnea-hypopnea index (AHI) is the standard measure for assessing OSA severity, it does not account for additional oximetric parameters that may influence disease progression in older adults. This study aimed to evaluate disparities in respiratory polygraphy/polysomnography parameters among patients with OSA, stratified by age and sex. DESIGN: Retrospective propensity score-matched study. SETTING AND PARTICIPANTS: Sleep unit of a university hospital; 11,747 participants, 210 aged 80 years or older. METHODS: Propensity score matching was used to establish 4 age cohorts, with the 210 oldest adults serving as the reference group. Primary outcome variables included the total sleep time with oxygen saturation (SaO2) below 90% (T90), average SaO2, minimum SaO2, and AHI. The association between T90 and AHI, as well as the severity of OSA, was assessed across the 4 age categories. RESULTS: Despite comparable AHI scores, the oldest patients with OSA exhibited the highest T90 and the lowest SaO2 levels compared to younger counterparts. The proportion of patients with severe OSA and T90 in the highest quartile increased with age: 12.5% in young adults, 14.8% in adults, 21.7% in the old, and 34% in the very old participants (P < .001). old and very old patients had a greater likelihood of being in the most severe OSA category compared to the younger ones, with odds ratios (OR) 2.57 (95% CI 1.42-4.65) and 5.52 (95% CI 3.06-9.97), respectively. These patterns were more pronounced in women of advanced age, indicating a sex-specific variation in disease severity with increasing age. CONCLUSIONS AND IMPLICATIONS: Old patients with OSA, particularly women, demonstrate elevated T90 and reduced SaO2 levels, irrespective of AHI, indicating a hypoxemia increased risk. The diagnostic criteria, management, and outcomes for OSA may require adaptations to address the unique needs of very old populations.

Comprehensive proteogenomic characterization of rare kidney tumors.

Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.

Acidovorax temperans skews neutrophil maturation and polarizes Th17 cells to promote lung adenocarcinoma development.

Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Here, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1ß signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells, polarizing them to an IL-17A+ phenotype detectable in CD4+ and γδ populations (T17). These T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate bacterial exposure promotes tumor growth by modulating inflammation.

Monitoring data on the effect of domestic livestock and rabbits on Androcymbiumeuropaeum (Lange) K. Richt. and its xerophytiques pastures for thirteen years.

Background: Dataset of annual monitoring of herbivory effects on the conservation status of the endangered species Androcymbiumeuropaeum (Lange) K. Richt and its associated plant communities is presented in this manuscript. This dataset encompasses the annual monitoring of herbivory effects on the conservation status of the endangered species Androcymbiumeuropaeum. Since 2010, the SERPAM Department (Service of Evaluation, Restoration and Protection of Mediterranean Agrosystems) at the Zaidin Experimental Station, belonging to the Spanish National Research Council (CSIC-EEZ), has conducted annual sampling to assess the impact of both domestic and wild livestock, specifically rabbits, on the pastures where A.europaeum lives. The study consisted of a randomised block design, implementing three distinct treatments to evaluate different management strategies: (1) rabbit and domestic herbivory, (2) exclusion of domestic livestock and (3) exclusion of rabbits and domestic livestock. Within each treatment, two types of monitoring were conducted. Firstly, the abundance of A.europaeum was estimated by counting individuals within 50 cm x 50 cm quadrats. Secondly, plant species diversity was assessed along 2-m long transects using the modified Point-Quadrat method. The research was conducted within the Cabo de Gata-Níjar Natural Park in southern Spain, specifically in the Amoladeras Nature Reserve in Almería. New information: The dataset contains information spanning from 2010 to 2023, providing valuable insights into the annual monitoring of herbivory effects on the conservation status of A.europaeum, contributing to our understanding of the species' interaction with domestic and wild animal in the studied area.

Pan-cancer proteogenomics characterization of tumor immunity.

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies.

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice.

Beneficial effect of temporary methotrexate interruption on B and T cell responses upon SARS-CoV-2 vaccination in patients with rheumatoid arthritis or psoriatic arthritis.

B and T cell responses were evaluated in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) after 1 or 2 weeks of methotrexate (MTX) withdrawal following each COVID-19 vaccine dose and compared with those who maintained MTX. Adult RA and PsA patients treated with MTX were recruited and randomly assigned to 3 groups: MTX-maintenance (n = 72), MTX-withdrawal for 1 week (n = 71) or MTX-withdrawal for 2 weeks (n = 73). Specific antibodies to several SARS-CoV-2 antigens and interferon (IFN)-γ and interleukin (IL)-21 responses were assessed. MTX withdrawal in patients without previous COVID-19 was associated with higher levels of anti-RBD IgG and neutralising antibodies, especially in the 2-week withdrawal group and with higher IFN-γ secretion upon stimulation with pools of SARS-CoV-2 S peptides. No increment of RA/PsA relapses was detected across groups. Our data indicate that two-week MTX interruption following COVID-19 vaccination in patients with RA or PsA improves humoral and cellular immune responses.

Frozen tissue coring and layered histological analysis improves cell type-specific proteogenomic characterization of pancreatic adenocarcinoma.

BACKGROUND: Omics characterization of pancreatic adenocarcinoma tissue is complicated by the highly heterogeneous and mixed populations of cells. We evaluate the feasibility and potential benefit of using a coring method to enrich specific regions from bulk tissue and then perform proteogenomic analyses. METHODS: We used the Biopsy Trifecta Extraction (BioTExt) technique to isolate cores of epithelial-enriched and stroma-enriched tissue from pancreatic tumor and adjacent tissue blocks. Histology was assessed at multiple depths throughout each core. DNA sequencing, RNA sequencing, and proteomics were performed on the cored and bulk tissue samples. Supervised and unsupervised analyses were performed based on integrated molecular and histology data. RESULTS: Tissue cores had mixed cell composition at varying depths throughout. Average cell type percentages assessed by histology throughout the core were better associated with KRAS variant allele frequencies than standard histology assessment of the cut surface. Clustering based on serial histology data separated the cores into three groups with enrichment of neoplastic epithelium, stroma, and acinar cells, respectively. Using this classification, tumor overexpressed proteins identified in bulk tissue analysis were assigned into epithelial- or stroma-specific categories, which revealed novel epithelial-specific tumor overexpressed proteins. CONCLUSIONS: Our study demonstrates the feasibility of multi-omics data generation from tissue cores, the necessity of interval H&E stains in serial histology sections, and the utility of coring to improve analysis over bulk tissue data.

Estudio multicéntrico de conciliación de la medicación en onco-hematología pediátrica / Multicentre study of medication reconciliation in paediatric onco-hematology

Objetivo determinar la prevalencia de errores de conciliación (EC) al ingreso hospitalario en la población pediátrica onco-hematológica para comprobar si ésta presenta una susceptibilidad similar a la de los adultos para ser afectados por estos EC y describir las características de los pacientes en los que se producen.Métodoestudio prospectivo y multicéntrico de 12 meses de duración, de conciliación de medicación al ingreso en la población pediátrica onco-hematológica para evaluar la incidencia de EC y describir las características de los pacientes en los que se producen.Resultadosse concilió la medicación de 157 pacientes. En 96 pacientes se detectó al menos una discrepancia de la medicación. De las discrepancias detectadas, el 52,1% fueron justificadas por la nueva situación clínica del paciente o por el médico responsable mientras que el 48,9% se consideraron EC. El tipo de EC más frecuente fue la «omisión de algún medicamento», seguido por «una dosis, frecuencia o vía de administración diferente». Se efectuaron un total de 77 intervenciones farmacéuticas, de las que se aceptaron el 94,2%. En el grupo de pacientes con un número igual o mayor a 4 fármacos en tratamiento domiciliario se observó un incremento de 2,1 veces la probabilidad de experimentar un EC.Conclusionespara evitar o reducir los errores en uno de los puntos críticos de seguridad como son las transiciones asistenciales, existen medidas, como la conciliación de la medicación. En el caso de los pacientes pediátricos crónicos complejos, como los pacientes onco-hematológicos, el número de fármacos como parte del tratamiento domiciliario es la variable que se ha asociado a la presencia de EC al ingreso hospitalario, siendo la omisión de algún medicamento la causa principal de estos errores. (AU)

Objective To determine the prevalence of reconciliation errors (RE) on admission to hospital in the paediatric onco-haematological population in order to check whether they are similarly susceptible to these RE as adults and to describe the characteristics of the patients who suffer them.MethodsA 12-month prospective, multicentre study of medication reconciliation on admission in the paediatric onco-haematological population to assess the incidence of RE and describe the characteristics of the patients in whom they occur.ResultsMedication reconciliation was performed in 157 patients. At least 1 medication discrepancy was detected in 96 patients. Of the discrepancies detected, 52.1% were justified by the patient's new clinical situation or by the physician, while 48.9% were determined to be RE. The most frequent type of RE was the "omission of a medication", followed by "a different dose, frequency or route of administration". A total of 77 pharmaceutical interventions were carried out, 94.2% of which were accepted. In the group of patients with a number equal to or greater than 4 drugs in home treatment, there was a 2.1-fold increase in the probability of suffering a RE.ConclusionsIn order to avoid or reduce errors in one of the critical safety points such as transitions of care, there are measures such as medication reconciliation. In the case of complex chronic paediatric patients, such as onco-haematological patients, the number of drugs as part of home treatment is the variable that has been associated with the presence of medication RE on admission to hospital, with the omission of some medication being the main cause of these errors. (AU)

Conciliación de la medicación al ingreso en paciente crónico pediátrico: estudio multicéntrico / Medication reconciliation at admission in paediatric patients with chronic illness: A multicentre study

Introducción: La conciliación de la medicación (CM) es una de las principales estrategias para disminuir los errores de medicación en las transiciones asistenciales. En España existen publicadas diferentes guías con recomendaciones para la implantación y el desarrollo de la CM orientadas a la población adulta, sin estar los pacientes pediátricos incluidos. En el año 2018 se llevó a cabo un estudio que permitió la posterior publicación de un documento con criterios de selección de pacientes pediátricos en los que priorizar la CM. Objetivos: Describir las características de los pacientes pediátricos con mayor probabilidad de sufrir errores de conciliación (EC), para confirmar si los resultados de un estudio previo son extrapolables. Metodología: Estudio prospectivo y multicéntrico con pacientes pediátricos ingresados. Se analizaron los EC detectados durante la realización de la CM al ingreso. La mejor historia farmacoterapéutica posible del paciente fue obtenida utilizando diferentes fuentes de información y confirmándose con una entrevista con el paciente/cuidador. Resultados: Se detectaron 1.043 discrepancias, determinándose como EC 544, afectando a 317 pacientes (43%). La omisión de algún medicamento fue el error más común (51%). La mayoría de los EC se asociaron con los medicamentos de los grupos A (31%), N (23%) y R (11%) de la clasificación ATC. La polimedicación y la enfermedad de base onco-hematológica fueron los factores de riesgo asociados a la presencia de EC con significación estadística. Conclusiones: Los hallazgos de este estudio permiten priorizar la CM en un grupo concreto de pacientes pediátricos, favoreciendo la eficiencia del proceso. Los pacientes onco-hematológicos y la polimedicación se confirman como los principales factores de riesgo para la aparición de EC en la población pediátrica.(AU)

Introduction: Medication reconciliation (MR) is one of the main strategies used to reduce medication errors in care transitions. In Spain, several guidelines have been published with recommendations for the implementation and development of MR processes aimed at the adult population, and not applicable to paediatric patients. In 2018, a study was carried out that allowed the subsequent publication of a document establishing criteria for the selection of paediatric patients in whom CM should be prioritised. Objectives: To describe the characteristics of the paediatric patients most likely to be subject to reconciliation errors (REs) to confirm whether the results of a previous study could be extrapolated. Methodology: Prospective, multicentre study in paediatric inpatients. We analysed the REs detected in the MR at the time of admission. We obtained the best possible medication history of the patient using different sources of information, subsequently confirmed through an interview with the patient/caregiver. Results: 1043 discrepancies were detected, of which 544 were categorised as REs, affecting 317 patients (43%). Omission of a drug was the most common error (51%). Most REs involved drugs in groups A (31%), N (23%) and R (11%) of the ATC classification. Polypharmacy and oncological/haematological disease were the risk factors that exhibited a statistically significant association with the occurrence of REs. Conclusions: The findings of this study allow the prioritisation of MR in a specific group of paediatric patients, contributing to improve the efficiency of the process. Oncological/haematological disease and polypharmacy were confirmed as the main risk factors for the occurrence of REs in the paediatric population.(AU)

Medication reconciliation on admission in paediatric chronic patients: A multicentre study.

INTRODUCTION: Medication reconciliation (MC) is one of the main strategies to reduce medication errors in care transitions. In Spain, several guidelines have been published with recommendations for the implementation and development of MC aimed at the adult population, although paediatric patients are not included. In 2018, a study was carried out that led to the subsequent publication of a document with criteria for selecting paediatric patients in whom CM should be prioritised. OBJECTIVES: To describe the characteristics of paediatric patients most likely to suffer from errors of reconciliation (EC), to confirm whether the results of a previous study can be extrapolated. METHODOLOGY: Prospective, multicentre study of paediatric inpatients. We analysed the CE detected during the performance of the CM on admission. The best possible pharmacotherapeutic history of the patient was obtained using different sources of information and confirmed by an interview with the patient/caregiver. RESULTS: 1043 discrepancies were detected, 544 were identified as CD, affecting 317 patients (43%). Omission of a drug was the most common error (51%). The majority of CD were associated with drugs in groups A (31%), N (23%) and R (11%) of the ATC classification. Polymedication and onco-haematological based disease were the risk factors associated with the presence of CD with statistical significance. CONCLUSIONS: The findings of this study allow prioritisation of CM in a specific group of paediatric patients, favouring the efficiency of the process. Onco-haematological patients and polymedication are confirmed as the main risk factors for the appearance of CD in the paediatric population.

The Thing (1982): un primer modelo de prediagnóstico para las infecciones y alteraciones de la fisiología / The Thing (1982): A First Prediagnostic Model for Infections and Alterations of Physiology

The Thing / La cosa (El enigma de otro mundo) (1982) de John Carpenter, supone un reto audiovisual para pensar en el descubrimiento de claves para la detección temprana de infecciones hostiles. La búsqueda de técnicas rápidas y sencillas para la resolución de casos supone la diferencia entre la supervivencia y mantenerse en la desconfianza para un grupo que trata de descubrir quienes de ellos están infectados, y no terminar transformados en «otra cosa». Este trabajo permitirá al estudiantado conocer los cambios en el equilibrio homeostático que supondría la relación con los microorganismos de distinta naturaleza presentes en la sangre. (AU)

The Thing (1982) by John Carpenter represents an audiovisual challenge to think about the discovery of keys for the early detection of hostile infections. The search for quick and easy techniques for solving cases means the difference between survival and remaining suspicious for a group that tries to discover which of them are infected, and not end up transformed into «something else». This work will allow the student body to know the changes in the homeostatic balance that the relationship with microorganisms of different nature present in the blood would imply. (AU)

Identification of a specific exporter that enables high production of aconitic acid in Aspergillus pseudoterreus.

Aconitic acid is an unsaturated tricarboxylic acid that is attractive for its potential use in manufacturing biodegradable and biocompatible polymers, plasticizers, and surfactants. Previously Aspergillus pseudoterreus was engineered as a platform to produce aconitic acid by deleting the cadA (cis-aconitic acid decarboxylase) gene in the itaconic acid biosynthetic pathway. In this study, the aconitic acid transporter gene (aexA) was identified using comparative global discovery proteomics analysis between the wild-type and cadA deletion strains. The protein AexA belongs to the Major Facilitator Superfamily (MFS). Deletion of aexA almost abolished aconitic acid secretion, while its overexpression led to a significant increase in aconitic acid production. Transportation of aconitic acid across the plasma membrane is a key limiting step in its production. In vitro, proteoliposome transport assay further validated AexA's function and substrate specificity. This research provides new approaches to efficiently pinpoint and characterize exporters of fungal organic acids and accelerate metabolic engineering to improve secretion capability and lower the cost of bioproduction.

[Translated article] Medication reconciliation in pediatric hemato-oncologic patients: A multicenter study.

OBJECTIVE: To determine the prevalence of reconciliation errors on admission to hospital in the pediatric onco-hematological population in order to check whether they are similarly susceptible to these reconciliation errors as adults and to describe the characteristics of the patients who suffer them. METHODS: A 12-month prospective, multicentre study of medication reconciliation on admission in the pediatric onco-hematological population to assess the incidence of reconciliation errors and to describe the characteristics of the patients. RESULTS: Medication reconciliation was performed in 157 patients. At least a medication discrepancy was detected in 96 patients. Of the discrepancies detected, 52.1% were related to patient's new clinical situation or by the physician, while 48.9% were determined to be reconciliation errors. The most frequent type of reconciliation error was the "omission of a medication", followed by "a different dose, frequency or route of administration". A total of 77 pharmaceutical interventions were carried out, 94.2% of which were accepted. In the group of patients with a number equal to or greater than 4 drugs in home treatment, there was a 2.1-fold increase in the probability of suffering a reconciliation error. CONCLUSIONS: In order to avoid or reduce errors in one of the critical safety points such as transitions of care, there are measures such as medication reconciliation. In the case of complex chronic pediatric patients, such as onco-hematological patients, the number of drugs as part of home treatment is the variable that has been associated with the presence of medication reconciliation errors on admission to hospital, and the omission of some medication was the main cause of these errors.

Pan-cancer proteogenomics connects oncogenic drivers to functional states.

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.

Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin.

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.

Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation.

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.