Targeted multiparametric magnetic resonance imaging/transrectal ultrasound-guided (mpMRI/TRUS) fusion prostate biopsy versus systematic random prostate biopsy: A comparative real-life study.

BACKGROUND: Patients with suspected prostate cancer usually undergo transrectal ultrasound-guided (TRUS) systematic biopsy, which can miss relevant prostate cancers and lead to overtreatment. AIMS: The aim of this study was to evaluate the detection rate for prostate cancer in MR-guided targeted biopsy (TB) and systematic biopsy (SB) in comparison with mpMRI of the prostate. METHODS AND RESULTS: Three hundred and eight men who underwent mpMRI due to elevated PSA values between 2015 and 2020 were studied at university hospital Aachen, Germany. MRI-images were divided into cohorts with suspicious findings (PI-RADS ≥ 3) and negative findings (PI-RADS < 3). In patients with PI-RADS ≥ 3 TB combined with SB was performed. A part of this group underwent RP subsequently. In patients with PI-RADS < 3 and clinical suspicion SB was performed. In the PI-RADS ≥ 3 group (n = 197), TB combined with SB was performed in 194 cases. Three cases were lost to follow-up. Biopsy yielded 143 positive biopsies and 51 cases without carcinoma. TB detected 71% (102/143) and SB 98% (140/143) of the overall 143 carcinoma. Overall, 102 carcinomas were detected by TB, hereof 66% (67/102) clinically significant (Gleason ≥ 3+4) and 34% (35/102) clinically insignificant carcinoma (Gleason 3+3). SB detected 140 carcinomas, hereof 64% (90/140) csPCA and 36% (50/140) nsPCA. Forty-one of the overall 143 detected carcinoma were only found by SB, hereof 46% (19/41) csPCA and 54% (22/41) nsPCA. Tumor locations overlapped in 44% (63/143) between TB and SB. In 25% (36/143), SB detected additional tumor foci outside the target lesions. 70/143 patients subsequently underwent RP. The detection of tumor foci was congruent between mpMRI and prostatectomy specimen in 79% (55/70) of cases. Tumor foci were mpMRI occult in 21% (15/70) of cases. In the group with negative mpMRI (n = 111), biopsy was performed in 81 cases. Gleason ≥ 3+4 carcinoma was detected in 7% and Gleason 3+3 in 24% cases. CONCLUSION: There was a notable number of cases in which SB detected tumor foci that were mpMRI occult and could have been missed by TB alone. Therefore, additional systematic random biopsy is still required. A supplemental random biopsy should be considered depending on the overall clinical suspicion in negative mpMRI.

Comparative Analysis of Swine Antibody Responses following Vaccination with Live-Attenuated and Killed African Swine Fever Virus Vaccines.

African swine fever virus (ASFV) is circulating in many swine-producing countries, causing significant economic losses. It is observed that pigs experimentally vaccinated with a live-attenuated virus (LAV) but not a killed virus (KV) vaccine develop solid homologous protective immunity. The objective of this study was to comparatively analyze antibody profiles between pigs vaccinated with an LAV vaccine and those vaccinated with a KV vaccine to identify potential markers of vaccine-induced protection. Thirty ASFV seronegative pigs were divided into three groups: Group 1 received a single dose of an experimental LAV, Group 2 received two doses of an experimental KV vaccine, and Group 3 was kept as a non-vaccinated (NV) control. At 42 days post-vaccination, all pigs were challenged with the parental virulent ASFV strain and monitored for 21 days. All pigs vaccinated with the LAV vaccine survived the challenge. In contrast, eight pigs from the KV group and seven pigs from the NV group died within 14 days post-challenge. Serum samples collected on 41 days post-vaccination were analyzed for their reactivity against a panel of 29 viral structural proteins. The sera of pigs from the LAV group exhibited a strong antibody reactivity against various viral structural proteins, while the sera of pigs in the KV group only displayed weak antibody reactivity against the inner envelope (p32, p54, p12). There was a negative correlation between the intensity of antibody reactivity against five ASFV antigens, namely p12, p14, p15, p32, and pD205R, and the viral DNA titers in the blood of animals after the challenge infection. Thus, antibody reactivities against these five antigens warrant further evaluation as potential indicators of vaccine-induced protection.

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

TEAD Proteins Associate With DNA Repair Proteins to Facilitate Cellular Recovery From DNA Damage.

Transcriptional enhanced associate domain family members 1 to 4 (TEADs) are a family of four transcription factors and the major transcriptional effectors of the Hippo pathway. In order to activate transcription, TEADs rely on interactions with other proteins, such as the transcriptional effectors Yes-associated protein and transcriptional co-activator with PDZ-binding motif. Nuclear protein interactions involving TEADs influence the transcriptional regulation of genes involved in cell growth, tissue homeostasis, and tumorigenesis. Clearly, protein interactions for TEADs are functionally important, but the full repertoire of TEAD interaction partners remains unknown. Here, we employed an affinity purification mass spectrometry approach to identify nuclear interacting partners of TEADs. We performed affinity purification mass spectrometry experiment in parallel in two different cell types and compared a wildtype TEAD bait protein to a nuclear localization sequence mutant that does not localize to the nucleus. We quantified the results using SAINT analysis and found a significant enrichment of proteins linked to DNA damage including X-ray repair cross-complementing protein 5 (XRCC5), X-ray repair cross-complementing protein 6 (XRCC6), poly(ADP-ribose) polymerase 1 (PARP1), and Rap1-interacting factor 1 (RIF1). In cellular assays, we found that TEADs co-localize with DNA damage-induced nuclear foci marked by histone H2AX phosphorylated on S139 (γH2AX) and Rap1-interacting factor 1. We also found that depletion of TEAD proteins makes cells more susceptible to DNA damage by various agents and that depletion of TEADs promotes genomic instability. Additionally, depleting TEADs dampens the efficiency of DNA double-stranded break repair in reporter assays. Our results connect TEADs to DNA damage response processes, positioning DNA damage as an important avenue for further research of TEAD proteins.

Machine-Learning and Chemicogenomics Approach Defines and Predicts Cross-Talk of Hippo and MAPK Pathways.

Hippo pathway dysregulation occurs in multiple cancers through genetic and nongenetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defining tumors that are Hippo pathway-dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type-agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage-independent signature for the Hippo pathway in cancers. Evaluating transcriptional profiles using a machine-learning method led to identification of a relationship between YAP/TAZ dependency and MAPK pathway activity. The results help to nominate potential combination therapies with Hippo pathway inhibition.This article is highlighted in the In This Issue feature, p. 521.

Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae.

FACT (FAcilitates Chromatin Transcription/Transactions) is a histone chaperone that can destabilize or assemble nucleosomes. Acetylation of histone H3-K56 weakens a histone-DNA contact that is central to FACT activity, suggesting that this modification could affect FACT functions. We tested this by asking how mutations of H3-K56 and FACT affect nucleosome reorganization activity in vitro, and chromatin integrity and transcript output in vivo Mimics of unacetylated or permanently acetylated H3-K56 had different effects on FACT activity as expected, but the same mutations had surprisingly similar effects on global transcript levels. The results are consistent with emerging models that emphasize FACT's importance in establishing global chromatin architecture prior to transcription, promoting transitions among different states as transcription profiles change, and restoring chromatin integrity after it is disturbed. Optimal FACT activity required the availability of both modified and unmodified states of H3-K56. Perturbing this balance was especially detrimental for maintaining repression of genes with high nucleosome occupancy over their promoters and for blocking antisense transcription at the +1 nucleosome. The results reveal a complex collaboration between H3-K56 modification status and multiple FACT functions, and support roles for nucleosome reorganization by FACT before, during, and after transcription.

The tumor suppressor BAP1 cooperates with BRAFV600E to promote tumor formation in cutaneous melanoma.

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk of mesothelioma and melanocytic tumors. Here, we show that Bap1 deletion in melanocytes cooperates with the constitutively active, oncogenic form of BRAF (BRAFV600E ) and UV to cause melanoma in mice, albeit at very low frequency. In addition, Bap1-null melanoma cells derived from mouse tumors are more aggressive and colonize and grow at distant sites more than their wild-type counterparts. Molecularly, Bap1-null melanoma cell lines have increased DNA damage measured by γH2aX and hyperubiquitination of histone H2a. Therapeutically, these Bap1-null tumors are completely responsive to BRAF- and MEK-targeted therapies. Therefore, BAP1 functions as a tumor suppressor and limits tumor progression in melanoma.

Administration of oral chemotherapy: results from three rounds of the quality oncology practice initiative.

PURPOSE: Although use of oral chemotherapy is becoming more prevalent, little is known about the quality of care that patients receive when these agents are prescribed. Moreover, few practice-level systems are in place to ensure safe management of oral chemotherapy in the vulnerable population of patients with cancer. METHODS: We analyzed results from 155 practices that were voluntarily participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) program on 17 test measures of oral chemotherapy administration and management in at least one of three collection periods: spring or fall of 2012, or spring of 2013. The 17 test measures cover three domains: treatment plan documentation, patient education, and adherence/toxicity monitoring. We defined composite scores for each of the three domains. We analyzed the composite scores by secular trend and tested the difference in composite scores for the three domains. Additionally, we tested change in scores over time among practices that participated at least twice. RESULTS: The majority of data was provided by QOPI-certified practices. Overall, mean practice composite scores ranged from 66% to 68% for treatment plan documentation, 51% to 57% for patient education, and 75% to 81% for adherence/toxicity monitoring. Composite scores for practices that participated more than once did not improve significantly. CONCLUSION: The collection of oral chemotherapy test measure data is feasible. Composite scores for treatment plan documentation and patient education were not only lower, but had greater variability compared with adherence/toxicity monitoring. Improvement opportunities exist for patients who are prescribed oral chemotherapy.

Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the American Society of Clinical Oncology Quality Oncology Practice Initiative.

PURPOSE: Family history of cancer (CFH) is important for identifying individuals to receive genetic counseling/testing (GC/GT). Prior studies have demonstrated low rates of family history documentation and referral for GC/GT. METHODS: CFH quality and GC/GT practices for patients with breast (BC) or colon cancer (CRC) were assessed in 271 practices participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative in fall 2011. RESULTS: A total of 212 practices completed measures regarding CFH and GC/GT practices for 10,466 patients; 77.4% of all medical records reviewed documented presence or absence of CFH in first-degree relatives, and 61.5% of medical records documented presence or absence of CFH in second-degree relatives, with significantly higher documentation for patients with BC compared with CRC. Age at diagnosis was documented for all relatives with cancer in 30.7% of medical records (BC, 45.2%; CRC, 35.4%; P ≤ .001). Referall for GC/GT occurred in 22.1% of all patients with BC or CRC. Of patients with increased risk for hereditary cancer, 52.2% of patients with BC and 26.4% of those with CRC were referred for GC/GT. When genetic testing was performed, consent was documented 77.7% of the time, and discussion of results was documented 78.8% of the time. CONCLUSION: We identified low rates of complete CFH documentation and low rates of referral for those with BC or CRC meeting guidelines for referral among US oncologists. Documentation and referral were greater for patients with BC compared with CRC. Education and support regarding the importance of accurate CFH and the benefits of proactive high-risk patient management are clearly needed.

Measles Epidemics Among Children in Vietnam: Genomic Characterization of Virus Responsible for Measles Outbreak in Ho Chi Minh City, 2014.

BACKGROUND: Measles remains poorly controlled in Southeast Asia, including Vietnam. OBJECTIVES: The aim of this study was to characterize genes of virus responsible for a measles outbreak among children in Vietnam in 2014. STUDY DESIGN: Throat swab samples were collected from 122 pediatric patients with suspected measles. Furthermore, peripheral blood mononuclear cells (PBMCs) from 31 of these cases were also collected. Measles virus (MV) RNA was obtained directly from the clinical specimens, amplified by PCR, and then the N and H genes were sequenced. RESULTS: MV RNA was detectable in throat swabs from all 122 patients tested. Positive-strand viral RNA, which indicates the intermediate replicative form of MV, was also detected in PBMCs from all 31 cases from whom these cells were collected. One hundred and eighteen strains with the N gene were obtained by RT-PCR and sequenced. Using phylogenetic analysis with measles reference sequences, all of the Vietnamese strains were found to be genotype D8. However, all strains formed a distinct cluster within the genotype D8 group (D8-VNM) suggesting their own lineage. This distinct cluster was supported by a branch with a 99% bootstrap value and 3.3% nucleotide divergence in the N-450 region of the N gene from the D8 reference strain. Notably, all of the D8-VNM variant strains represented unique amino acid sequences consisting of R442, S451 and G452 in the N-450 region of the N gene. CONCLUSIONS: Measles viruses responsible for outbreaks in Southern Vietnam belonged to a genotype D8 variant group which had unique amino acid sequences in the N gene. Our report provides important genomic information about the virus for measles elimination in Southeast Asia.

The association between acanthosis nigricans and dysglycemia in an ethnically diverse group of eighth grade students.

OBJECTIVE: The purpose of this study was to describe the prevalence of acanthosis nigricans (AN) and to quantify its association with dysglycemia in an ethnically diverse group of eighth-grade students. DESIGN AND METHODS: Data were collected in 2003 from a cross-sectional study of students from 12 middle schools in three US states. Sex, race/ethnicity, and pubertal status were self-reported. Anthropometric measures were recorded. Trained staff identified the presence and severity of AN by inspection of the back of the neck. Fasting and 2 h blood samples were analyzed for impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and high-risk glycated hemoglobin (A1C), respectively, defined as ≥100 mg/dl, ≥140 mg/dl, and ≥ 5.7-6.4%. RESULTS: Overall, 25.0%, 58.2%, and 16.8% were Black, Hispanic, and White, respectively. AN was present among 406/1,438 (28.2%) of students: 39% among Black, 30% among Hispanic, and 5.4% among White. IGT and high-risk A1C were present among 2.1%, and 12.4%, respectively. In multivariate logistic modeling after adjusting for gender, family history of diabetes, BMI percentile, and pubertal staging, the presence (vs. absence) of AN was associated with a 59% increased likelihood of high-risk A1C: (P = 0.04), twice the likelihood of IGT (P = 0.06), and 47% greater likelihood of IGT/IFG combined (P < 0.0001). Adjustment for insulin attenuated the ORs by 25-70%. CONCLUSION: In a racially/ethnically diverse sample of US adolescents, AN was common, occurring in 28% of the sample. AN was associated with a 50-100% increased likelihood of dysglycemia even after consideration of established diabetes risk factors.

HEALTHY intervention: fitness, physical activity, and metabolic syndrome results.

PURPOSE: This study aimed to assess the effect of the HEALTHY intervention on the metabolic syndrome (Met-S), fitness, and physical activity levels of US middle-school students. METHODS: Cluster randomized controlled trial conducted in 42 (21 intervention) US middle schools. Participants were recruited at the start of sixth grade (2006) when baseline assessments were made, with post-assessments made 2.5 yr later at the end of eighth grade (2009). The HEALTHY intervention had four components: 1) improved school food environment, 2) physical activity and eating educational sessions, 3) social marketing, and 4) revised physical education curriculum. Met-S risk factors, 20-m shuttle run (fitness), and self-reported moderate to vigorous physical activity (MVPA) were assessed at each time point. Ethnicity and gender were self-reported. Obesity status (normal weight, overweight, or obese) was also assessed. RESULTS: At baseline, 5% of the participants were classified with Met-S, with two-thirds of the males and one-third of the females recording below average baseline fitness levels. Control group participants reported 96 min of MVPA at baseline with 103 min reported by the intervention group. There were no statistically significant (P < 0.05) differences in Met-S, fitness, or MVPA levels at the end of the study after adjustment for baseline values and confounders. There were no differences in any ethnic, obesity, or ethnic × obesity subgroups for either gender. CONCLUSIONS: The HEALTHY intervention had no effect on the Met-S, fitness, or physical activity levels. Approaches that focus on how to change physical activity, fitness, and Met-S using nonschool or perhaps in addition to school based components need to be developed.

Fatness, fitness, and cardiometabolic risk factors among sixth-grade youth.

PURPOSE: Examine whether cardiometabolic risk factors are predicted by fitness or fatness among adolescents. METHODS: Participants are 4955 (2614 female) sixth-grade students with complete data from 42 US middle schools. Fasting blood samples were analyzed for total cholesterol, HDL- and LDL-cholesterol, triglyceride, glucose, and insulin concentrations. Waist circumference and blood pressure were assessed. Body mass index (BMI) was categorized as normal weight, overweight, or obese as a measure of fatness. Fitness was assessed using the multistage shuttle test and was converted into gender-specific quintiles. Gender-specific regression models, adjusted for race, pubertal status, and household education, were run to identify whether BMI group predicted risk factors. Models were repeated with fitness group and both fitness and fatness groups as predictors. RESULTS: Means for each risk factor (except HDL, which was the reverse) were significantly higher (P < 0.0001) with increased fatness and differed across all BMI groups (P < 0.001). Waist circumference, LDL-cholesterol, triglycerides, diastolic blood pressure, and insulin were inversely associated with fitness (P < 0.001). When both fatness and fitness were included in the model, BMI was associated (P < 0.001) with almost all cardiometabolic risk factors; fitness was only associated with waist circumference (both genders), LDL-cholesterol (males), and insulin (both genders). Other associations between fitness and cardiometabolic risk factors were attenuated after adjustment for BMI group. CONCLUSIONS: Both fatness and fitness are associated with cardiometabolic risk factors among sixth-grade youth, but stronger associations were observed for fatness. Although maintaining high levels of fitness and preventing obesity may positively affect cardiometabolic risk factors, greater benefit may be obtained from obesity prevention.

Measurement of static and vibration-induced phase noise in UHF thin-film resonator (TFR) filters.

Measurements of the static phase noise and vibration sensitivity of thin-film resonator (TFR) filters operating at 640 and 2110 MHz have been made. They show that the short-term frequency instability of the filters is small compared with that induced in the oscillator signal by the sustaining stage amplifier PM (phase modulation) noise. In-oscillator measurement of filter performance under vibration indicates that fractional frequency vibration sensitivities (deltafo/fo) are on the order of several parts in 10(-9)/g. Because the percentage bandwidth and order (number of poles) of the filters was fairly constant, so was the product of the center frequency and group delay. Thus, the fractional frequency vibration sensitivity of the filters can be expressed alternatively as carrier signal phase sensitivity to vibration. The tau-omega0 product for the filters that were tested was on the order of 300 rad, so that the equivalent phase sensitivity to vibration was approximately 1 microrad/g.