CCN6 suppresses metaplastic breast carcinoma by antagonizing WNT/ß-catenin signaling to inhibit EZH2-driven EMT.

Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation. Inactivation of the tumor suppressor gene CCN6 (also known as WISP3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with EMT. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. Here, we showed that CCN6 interacts with the Wnt receptor FZD8 and co-receptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of ß-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a ß-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/ß-catenin/TCF signaling in Ccn6-KO mBrCa cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacological inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated ß-catenin and high EZH2 in human spindle mBrCAs compared to other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a ß-catenin/TCF-EZH2 axis and highlight inhibition of ß-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs.

Photoacoustic lifetime oxygen imaging of radiotherapy-induced tumor reoxygenation In Vivo.

Purpose: Early detection and diagnosis of cancer is critical for achieving positive therapeutic outcomes. Biomarkers that can provide clinicians with clues to the outcome of a given therapeutic course are highly desired. Oxygen is a small molecule that is nearly universally present in biological tissues and plays a critical role in the effectiveness of radiotherapies by reacting with DNA radicals and subsequently impairing cellular repair of double strand breaks.Techniques for measuring oxygen in biological tissues often use blood oxygen saturation to approximate the oxygen partial pressure in surrounding tissues despite the complex, nonlinear, and dynamic relationship between these two separate oxygen populations. Methods and materials: We combined a directly oxygen-sensitive, tumor-targeted, chemical contrast nanoelement with the photoacoustic lifetime-based (PALT) oxygen imaging technique to obtain image maps of oxygen in breast cancer tumors in vivo. The oxygen levels of patient-derived xenografts in a mouse model were characterized before and after a course of radiotherapy. Results: We show that, independent of tumor size, radiotherapy induced an increase in the overall oxygenation levels of the tumor. Further, this increase in the oxygenation of the tumor significantly correlated with a positive response to radiotherapy, as demonstrated by a reduction in tumor volume over the twenty-day monitoring period following therapy and histological staining. Conclusion: Our PALT imaging presented here is simple, fast, and non-invasive. Facilized by the PALT approach, imaging of tumor reoxygenation may be utilized as a simple, early indicator for evaluating cancer response to radiotherapy. Further characterization of the reoxygenation degree, temporal onset, and possible theragnostic implications are warranted.

Intracardiac echography-guided fluoroless ablation versus conventional fluoroscopy-guided ablation for cardiac arrhythmias: a systematic review and meta-analysis

BACKGROUND: Intracardiac echocardiography (ICE) has improved catheter ablation procedures, reducing reliance on fluoroscopy. Yet, the efficacy and safety of zero-fluoroscopy (ZF) procedures remain uncertain. METHODS: We conducted a systematic review and meta-analysis comparing ZF ablation procedures guided by ICE vs. conventional techniques regarding efficacy and safety outcomes. PubMed, Cochrane, and embase were searched. A random-effects model was used to calculate risk ratios (RRs), odds ratios (OR) and mean differences (MDs) with 95% confidence intervals (CI). RESULTS: We includedfourteen studies with 1,919 patients of whom 1,023 (58.72%) performed ZF ablation using ICE. We found a significant reduced ablation time (SMD -0.18; 95% CI -0.31;-0.04; p=0.009), procedure time (MD -7.54; 95% CI -14.68;-0.41; p=0.04), fluoroscopic time (MD -2.52; 95% CI -3.20;-1.84; p<0.001) in patients treated with ZF approach compared with NZF approach. However, there was no significant difference between the two groups in acute success rate (RR 1.00; 95% CI 0.99-1.01; p=0.85), long-term success rate (RR 0.99; 95% CI 0.93-1.05; p=0.77) and complications (RR 0.84, 95% CI: 0.48-1.46; p = 0.54). CONCLUSION: Our findings suggest that among patients undergoing arrhythmia ablation, fluoroscopy-free ICE-guided technique reduces procedure time and radiation exposure with comparable short and long-term success rates and complications.

Complete versus culprit-only revascularization for older adults with acute coronary syndromes: a meta-analysis and systematic review

BACKGROUND: Randomized studies support complete over culprit-only revascularization for patients with acute coronary syndrome (ACS) However,whether these findings extend to elderly patients has not been thoroughly explored. METHODS: We conducted a systematic review and meta-analysis comparing clinical outcomes of elderly individuals (defined as age > 75 years) with ACS and multivessel coronary artery disease submitted to complete vs. culprit-only percutaneous coronary intervention (PCI). PubMed, Embase, and Cochrane were searched. We computed pooled hazard ratios (HRs) with 95% confidence intervals (CI) to preserve time-to-event data RESULTS: We included 7 studies, of which 2 were randomized controlled trials (RCTs), comprising 7,409 patients, of whom 3225 (43.5%) underwent complete revascularization. As compared with culprit lesion only PCI, complete revascularization was associated with a lower risk of all-cause mortality (HR 0.76; 95% CI 0.68-0.85; p<0.001), cardiovascular mortality (HR 0.67; 95% CI 0.54-0.82; p<0.001), and recurrent myocardial infarction (MI) (HR 0.65; 95% CI 0.50-0.85; p=0.002). There was no significant difference between the groups regarding the risk of recurrent revascularizations (HR 0.79; 95% CI 0.54-1.16; p=0.23). CONCLUSION: Among elderly patients with ACS and multivessel CAD, complete revascularization is associated with a lower risk of all-cause mortality, cardiovascular mortality, and recurrent MI.

Cardioneuroablation for reflex syncope: a systematic review and single-arm meta-analysis

BACKGROUND: Reflex syncope reduces quality of life and leads to fall-related injuries, with no highly effective treatment. In this context, cardioneuroablation (CNA) presents as a promising therapy for these patients. METHODS: We searched PubMed, Embase and Cochrane Central for studies that evaluated safety and efficacy outcomes related to CNA procedures. Two reviewers independently performed study selection, data extraction and assessment of bias. Generalized linear mixed models was used. We performed a single-arm meta-analysis using R version 4.2.3. RESULTS: A total of 25 studies comprising 871 patients were included. The mean follow-up ranged from 8 to 40 months. Mean age ranged from 32.9 to 53.9 years and 541 (62.1%) were female. The ablation target was biatrial in 302 patients (34%), left atrium only in 433 (49%), and right atrium only in 136 (15%). The freedom from syncope was 94% (95% confidence interval (CI) 90.13-97.00; P<0.01). Left and right atrial CNA was associated with a significant higher freedom from syncope (96.03%; 95% CI 93.13-97.73) than left atrial ablation only (94.61%; 95% CI 82.88-98.45) and right ablation only (84.53%; 95% CI 74.30-91.18). Peri-procedural adverse event occurred on 1.4% (95% CI 0.44- 4.50). CONCLUSION: Our findings suggest that in patients with reflex syncope, CNA is a procedure associated with a significant reduction in syncope incidence and with low complication rates. Among the procedures used, both right and left ablation were more effective.

Cardiac myosin inhibitors in obstructive hypertrophic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Selective cardiac myosin inhibitors (CMI) are promising therapies for obstructive hypertrophic cardiomyopathy (HCM). Yet, the extent of their benefits remains unclear due to the limited population studied. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing CMI vs. placebo in patients with obstructive HCM. PubMed, Cochrane, and embase were searched. We calculated risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs) with 95% confidence intervals (CI). RESULTS: Four RCTs with 485 patients with obstructive HCM were included, of whom 261 (53.8%) were prescribed CMI (10.7% were aficamten and 89.3% were mavacamten). CMI significantly reduced resting left ventricular outflow tract (LVOT) gradient (SMD -1.4, 95% CI -1.6,-1.2, p<0.001), but also reduced left ventricular ejection fraction (LVEF) (MD -5.1%, 95% CI -7.6,-2.6, p<0,001). Patients receiving CMI had a higher rate of study-defined complete hemodynamic response (RR 16.8, CI 95% 5.5, 51.4, p<0,001; Figure 1A) with a number needed to treat (NNT) of 8; and improvement of at least one point in NYHA functional class (RR 2.29, CI 95% 1.8,2.9, p<0,001; Figure 1B). Conclusion: In this meta-analysis of RCTs including patients with obstructive HCM, CMI led to a significant reduction in LVOT gradient and symptomatic improvement. The NNT to achieve one complete hemodynamic response was 8. There was a significant, albeit modest, decrease in LVEF in the CMI group.

Effects of anabolic androgenic steroids in athletes on left ventricle systolic and diastolic function: a systematic review and meta-analysis

BACKGROUND: The use of anabolic androgenic steroids (AAS) among athletes has been linked to pathological structural and functional cardiac changes. However, the studies are small, and the results are inconsistent. METHODS: We conducted a systematic review and meta-analysis of echocardiographic outcomes comparing athletes with prolonged use of AAS (at least 2 years of use) versus sex and age- matched athletes who were did not use AAS. PubMed, Cochrane, and embase were searched. A random-effects model was used to calculate mean differences (MDs), with 95% confidence intervals (CI). Statistical analyses were performed using Review Manager 5.4.1. RESULTS: We included 17 studies comprising 1,023 athletes, of whom 543 (53%) were AAS users. The mean age ranged to 24.2 to 43 years. Compared with non-AAS users, athletes who used AAS exhibited a significant increase in interventricular septal wall thickness (MD 1.33 mm; 95% CI [0.8,1.89], p<0.001), a reduction in left ventricular ejection fraction (MD 2.77 %; 95% CI [-4.2,-1.34], p<0.001;Figure 1B) , and worsening of global longitudinal strain (MD 3.39%; 95% CI [2.88,3.91], p<0.001;Figure 1B). Additionally, there was a significant reduction in the E/A ratio (MD -0.21; 95% CI [-0.35,-0.07], p=0.003) and an increase in the E/e' ratio (MD 1.71; 95% CI [0.96,2.46], p<0.001). CONCLUSION: Our findings suggest that prolonged use of AAS in athletes is associated with increased left ventricular wall thickness and worsening of systolic and diastolic parameters.

Caracterización clínica y factores predictivos de desarrollo de síndrome neurológico tardío en la intoxicación por monóxido de carbono: estudio AMICO / Clinical features and predictors of delayed neurological syndrome in carbon monoxide poisoning: the AMICO study

Objetivos. Identificar factores pronósticos de desarrollo de síndrome neurológico tardío (SNT) después de un episodio inicial de intoxicación por monóxido de carbono (ICO), con el fin detectar precozmente a la población más susceptible y facilitar su acceso a un seguimiento específico. Métodos. Revisión retrospectiva de todos los casos de ICO que acudieron a los servicios de urgencias (SU) de 4 hospitales durante los últimos 10 años. Se analizaron datos demográficos y características clínicas en el momento del episodio. En la cohorte de pacientes con datos de seguimiento disponibles, se evaluó la aparición de SNT y su relación con diferentes variables en la exposición inicial al CO a través de técnicas de análisis multivariante. Resultados. Se identificaron 240 pacientes. La mediana de edad fue de 36,2 años (17,6-49,6). De ellos 108 (45,0%) eran hombres y 223 casos (92,9%) fueron accidentales. El nivel medio de COHb fue del 12,7% (6,2-18,7). En 44 (18,3%) episodios se disponía de datos de un seguimiento específico. En esta cohorte, 11 (25%) pacientes desarrollaron SNT. Una puntuación inicial más baja en la Escala Coma de Glasgow (GCS) (OR: 0,61, IC 95%: 0,41-0,92) fue predictor independiente del desarrollo del SNT, con un ABC en la curva COR de 0,876 (IC 95%: 0,761-0,990, p < 0,001). Conclusiones. Una puntuación inicial baja en la GCS parece ser un predictor clínico de desarrollo de SNT en la ICO. Dada la incidencia de SNT, consideramos fundamental establecer protocolos de seguimiento específico de estos pacientes tras su asistencia inicial en los SU. (AU)

Objectives. To identify predictors for developing delayed neurological syndrome (DNS) after an initial episode of carbon monoxide (CO) poisoning in the interest of detecting patients most likely to develop DNS so that they can be followed. Methods. Retrospective review of cases of CO poisoning treated in the past 10 years in the emergency departments of 4 hospitals in the AMICO study (Spanish acronym for the multicenter analysis of CO poisoning). We analyzed demographic characteristics of the patients and the clinical characteristics of the initial episode. The records of the cohort of patients with available follow-up information were reviewed to find cases of DNS. Data were analyzed by multivariant analysis to determine the relationship to characteristics of the initial exposure to CO. Results. A total of 240 cases were identified. The median (interquartile range) age of the patients was 36.2 years (17.6-49.6 years); 108 patients (45.0%) were men, and the poisoning was accidental in 223 cases (92.9%). The median carboxyhemoglobin concentration on presentation was 12.7% (6.2%-18.7%). Follow-up details were available for 44 patients (18.3%). Eleven of those patients (25%) developed DNS. A low initial Glasgow Coma Scale score predicted the development of DNS with an odds ratio (OR) of 0.61 (95% CI, 0.41-0.92) and an area under the receiver operating characteristic curve of 0.876 (95% CI, 0.761-0.990) (P <.001). Conclusions. The initial Glasgow Coma Scale score seems to be a clinical predictor of DNS after CO poisoning. We consider it important to establish follow-up protocols for patients with CO poisoning treated in hospital EDs. (AU)

Clinical features and predictors of delayed neurological syndrome in carbon monoxide poisoning: the AMICO study. / Caracterización clínica y factores predictivos de desarrollo de síndrome neurológico tardío en la intoxicación por monóxido de carbono: estudio AMICO.

OBJECTIVES: To identify predictors for developing delayed neurological syndrome (DNS) after an initial episode of carbon monoxide (CO) poisoning in the interest of detecting patients most likely to develop DNS so that they can be followed. MATERIAL AND METHODS: Retrospective review of cases of CO poisoning treated in the past 10 years in the emergency departments of 4 hospitals in the AMICO study (Spanish acronym for the multicenter analysis of CO poisoning). We analyzed demographic characteristics of the patients and the clinical characteristics of the initial episode. The records of the cohort of patients with available follow-up information were reviewed to find cases of DNS. Data were analyzed by multivariant analysis to determine the relationship to characteristics of the initial exposure to CO. RESULTS: A total of 240 cases were identified. The median (interquartile range) age of the patients was 36.2 years (17.6-49.6 years); 108 patients (45.0%) were men, and the poisoning was accidental in 223 cases (92.9%). The median carboxyhemoglobin concentration on presentation was 12.7% (6.2%-18.7%). Follow-up details were available for 44 patients (18.3%). Eleven of those patients (25%) developed DNS. A low initial Glasgow Coma Scale score predicted the development of DNS with an odds ratio (OR) of 0.61 (95% CI, 0.41-0.92) and an area under the receiver operating characteristic curve of 0.876 (95% CI, 0.761-0.990) (P .001). CONCLUSION: The initial Glasgow Coma Scale score seems to be a clinical predictor of DNS after CO poisoning. We consider it important to establish follow-up protocols for patients with CO poisoning treated in hospital EDs.

OBJETIVO: Identificar factores pronósticos de desarrollo de síndrome neurológico tardío (SNT) después de un episodio inicial de intoxicación por monóxido de carbono (ICO), con el fin detectar precozmente a la población más susceptible y facilitar su acceso a un seguimiento específico. METODO: Revisión retrospectiva de todos los casos de ICO que acudieron a los servicios de urgencias (SU) de 4 hospitales durante los últimos 10 años. Se analizaron datos demográficos y características clínicas en el momento del episodio. En la cohorte de pacientes con datos de seguimiento disponibles, se evaluó la aparición de SNT y su relación con diferentes variables en la exposición inicial al CO a través de técnicas de análisis multivariante. RESULTADOS: Se identificaron 240 pacientes. La mediana de edad fue de 36,2 años (17,6-49,6). De ellos 108 (45,0%) eran hombres y 223 casos (92,9%) fueron accidentales. El nivel medio de COHb fue del 12,7% (6,2-18,7). En 44 (18,3%) episodios se disponía de datos de un seguimiento específico. En esta cohorte, 11 (25%) pacientes desarrollaron SNT. Una puntuación inicial más baja en la Escala Coma de Glasgow (GCS) (OR: 0,61, IC 95%: 0,41-0,92) fue predictor independiente del desarrollo del SNT, con un ABC en la curva COR de 0,876 (IC 95%: 0,761-0,990, p 0,001). CONCLUSIONES: Una puntuación inicial baja en la GCS parece ser un predictor clínico de desarrollo de SNT en la ICO. Dada la incidencia de SNT, consideramos fundamental establecer protocolos de seguimiento específico de estos pacientes tras su asistencia inicial en los SU.

Regulation of EZH2 protein stability: new mechanisms, roles in tumorigenesis, and roads to the clinic.

The importance of EZH2 as a key methyltransferase has been well documented theoretically. Practically, the first EZH2 inhibitor Tazemetostat (EPZ6438), was approved by FDA in 2020 and is used in clinic. However, for most solid tumors it is not as effective as desired and the scope of clinical indications is limited, suggesting that targeting its enzymatic activity may not be sufficient. Recent technologies focusing on the degradation of EZH2 protein have drawn attention due to their potential robust effects. This review focuses on the molecular mechanisms that regulate EZH2 protein stability via post-translational modifications (PTMs), mainly including ubiquitination, phosphorylation, and acetylation. In addition, we discuss recent advancements of multiple proteolysis targeting chimeras (PROTACs) strategies and the latest degraders that can downregulate EZH2 protein. We aim to highlight future directions to expand the application of novel EZH2 inhibitors by targeting both EZH2 enzymatic activity and protein stability.

Full-length isoform concatenation sequencing to resolve cancer transcriptome complexity.

BACKGROUND: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB_FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms. RESULTS: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB_FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB_FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB_FLIC-Seq method, we detected several cancer-specific novel isoforms. CONCLUSION: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes.

Long-term outcomes of second-generation drug-eluting stents versus coronary artery bypass graft: a sistematic review and meta-analysis

INTRODUCTION: Long-term data is limited on the comparative outcomes of percutaneous coronary intervention (PCI) with second-generation drug-eluting stents (S-DES) versus coronary artery bypass grafting (CABG) in patients with coronary artery disease (CAD). Hypothesis: Our aim was to conduct a systematic review and meta-analysis comparing mortality and cardiovascular outcomes in patients with left main or multivessel CAD who underwent PCI with an S-DES versus CABG with a minimum mean follow-up period of 3 years. METHODS: We searched PubMed, Embase, and Cochrane for studies that examined our clinical question. Three reviewers independently performed study selection and data extraction. Statistical analysis was performed using Review Manager 5.4.1. We calculated pooled hazard ratios (HR) with 95% confidence intervals (CI) under a random effects model. The data from observational studies were extracted and pooled as multivariable-adjusted HR or propensity score matching to minimize confounding. RESULTS: We included 10 studies, 2 of which were randomized controlled trials (RCT), with a total of 25,866 patients, of whom 11,482 (44.3%) underwent PCI. The mean follow-up ranged from 3.0 to 11.8 years. S-DES had a significantly higher risk than CABG for all-cause mortality (HR 1.36; 95% CI 1.10-1.68; p=0.005) and myocardial infarction (MI) (HR 1.89; 95% CI 1.12-3.18; p=0.02). No significant difference between the groups was found for major cardiovascular events (HR 1.10; 95% CI 0.98-1.23; p=0.11) and stroke (HR 0.83; CI: 0.60-1.15; p=0.27). In a subgroup analysis of RCTs, there was no significant difference between patients who underwent S-DES or CABG. CONCLUSION: In this meta-analysis of RCTs and multivariable or propensity-matched observational studies, our findings suggest that PCI with S-DES is associated with an increased risk of mortality and MI events compared with CABG in patients with left main or multivessel CAD.

A hybrid breast cancer/mesenchymal stem cell population enhances chemoresistance and metastasis.

Patients with triple-negative breast cancer remain at risk for metastatic disease despite treatment. The acquisition of chemoresistance is a major cause of tumor relapse and death, but the mechanisms are far from understood. We have demonstrated that breast cancer cells (BCCs) can engulf mesenchymal stem/stromal cells (MSCs), leading to enhanced dissemination. Here, we show that clinical samples of primary invasive carcinoma and chemoresistant breast cancer metastasis contain a unique hybrid cancer cell population coexpressing pancytokeratin and the MSC marker fibroblast activation protein-α. We show that hybrid cells form in primary tumors and that they promote breast cancer metastasis and chemoresistance. Using single-cell microfluidics and in vivo models, we found that there are polyploid senescent cells within the hybrid cell population that contribute to metastatic dissemination. Our data reveal that Wnt Family Member 5A (WNT5A) plays a crucial role in supporting the chemoresistance properties of hybrid cells. Furthermore, we identified that WNT5A mediates hybrid cell formation through a phagocytosis-like mechanism that requires BCC-derived IL-6 and MSC-derived C-C Motif Chemokine Ligand 2. These findings reveal hybrid cell formation as a mechanism of chemoresistance and suggest that interrupting this mechanism may be a strategy in overcoming breast cancer drug resistance.

Personalized Oncology by In Vivo Chemical Imaging: Photoacoustic Mapping of Tumor Oxygen Predicts Radiotherapy Efficacy.

We hereby apply the approach of photoacoustic chemical imaging, performing an in vivo chemical analysis that is spatially resolved (200 µm) and in real time, to predict a given tumor's response to therapy. Using triple negative breast cancer as a model, we took photoacoustic images of tumors' oxygen distributions in patient-derived xenografts (PDXs) in mice using biocompatible, oxygen-sensitive tumor-targeted chemical contrast nanoelements (nanosonophores), which function as contrast agents for photoacoustic imaging. Following radiation therapy, we established a quantitatively significant correlation between the spatial distribution of the initial oxygen levels in the tumor and its spatial distribution of the therapy's efficacy: the lower the local oxygen, the lower the local radiation therapy efficacy. We thus provide a simple, noninvasive, and inexpensive method to both predict the efficacy of radiation therapy for a given tumor and identify treatment-resistant regions within the tumor's microenvironment.

Frontal aslant tract: Anatomy and tractography description in the Mexican population.

Background: The aim of the study was to describe the origin, course, and termination of frontal aslant tract (FAT) in the Mexican population of neurosurgical referral centers. Methods: From January 2018 to May 2019, we analyzed 50 magnetic resonance imaging (MRI) studies in diffusion tensor imaging sequences of patients of the National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez." Five brains were fixed by the Klingler method and dissected in the neurosurgery laboratory of the Hospital Civil de Guadalajara to identify the origin, trajectory, and ending of the FAT. Results: FAT was identified in 100% of the MRI and brain dissections. The origin of the FAT was observed in 63% from the supplementary premotor area, 24% from the supplementary motor area, and 13% in both areas. Its ending was observed in the pars opercularis in 81%, pars triangularis in 9%, and in both pars opercularis and ventral premotor area in 10% in the magnetic resonance images, with a left side predominance. In the hemispheres dissections, the origin of FAT was identified in 60% from the supplementary premotor area, 20% from the supplementary motor area, and 20% in both areas. Its ending was observed in the pars opercularis in 80% and the pars triangularis in 20%. It was not identified as an individual fascicle connected with the contralateral FAT. Conclusion: In the Mexican population, FAT has a left predominance; it is originated more frequently in the supplementary premotor area, passes dorsal to the superior longitudinal fascicle II and the superior periinsular sulcus, and ends more commonly in the pars opercularis.

EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression.

Triple-negative breast cancers (TNBCs) are frequently poorly differentiated with high propensity for metastasis. Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 that mediates transcriptional repression in normal cells and in cancer through H3K27me3. However, H3K27me3-independent non-canonical functions of EZH2 are incompletely understood. We reported that EZH2 phosphorylation at T367 by p38α induces TNBC metastasis in an H3K27me3-independent manner. Here, we show that cytosolic EZH2 methylates p38α at lysine 139 and 165 leading to enhanced p38α stability and that p38 methylation and activation require T367 phosphorylation of EZH2. Dual inhibition of EZH2 methyltransferase and p38 kinase activities downregulates pEZH2-T367, H3K27me3, and p-p38 pathways in vivo and reduces TNBC growth and metastasis. These data uncover a cooperation between EZH2 canonical and non-canonical mechanisms and suggest that inhibition of these pathways may be a potential therapeutic strategy.

The matricellular protein CCN6 differentially regulates mitochondrial metabolism in normal epithelium and in metaplastic breast carcinomas.

Metaplastic breast carcinoma (MBC) is an aggressive subtype of triple negative breast cancer with undefined precursors, limited response to chemotherapy, and frequent distant metastasis. Our laboratory has reported that CCN6/WISP3, a secreted protein that regulates growth factor signaling, is downregulated in over 85% of MBCs. Through generation of a mammary epithelial cell-specific Ccn6 knockout mouse model (MMTV-cre;Ccn6fl/fl) we have demonstrated that CCN6 is a tumor suppressor for MBC; MMTV-cre;Ccn6fl/fl mice develop tumors recapitulating the histopathology and proteogenomic landscape of human MBC, but the mechanisms need further investigation. In this study, we report that preneoplastic mammary glands of 8-week-old MMTV-Cre;Ccn6fl/fl female mice show significant downregulation of mitochondrial respiratory chain genes compared to controls, which are further downregulated in MBCs of MMTV-Cre;Ccn6fl/fl mice and humans. We found that CCN6 downregulation in non-tumorigenic breast cells reduces mitochondrial respiration and increases resistance to stress-induced apoptosis compared to controls. Intracellular ectopic CCN6 protein localizes to the mitochondria in MDA-MB-231 mesenchymal-like breast cancer cells, increases mitochondrial respiration and generation of reactive oxygen species, and reverses doxorubicin resistance of MBC cells. Our data highlight a novel function of CCN6 in the regulation of redox states in preneoplastic progression and suggest potential preventative and treatment strategies against MBC based on CCN6 upregulation.

Noncanonical Functions of the Polycomb Group Protein EZH2 in Breast Cancer.

Enhancer of Zeste Homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that is critical for determining cell identity. An epigenetic writer, EZH2 has a well-defined role in transcriptional repression by depositing trimethyl marks on lysine 27 of histone H3. However, there is mounting evidence that histone methyltransferases like EZH2 exert histone methyltransferase-independent functions. The relevance of these functions to breast cancer progression and their regulatory mechanisms are only beginning to become understood. Here, we review the current understanding of EZH2 H3K27me3-independent, noncanonical, functions and their regulation in breast cancer.