TERT promoter mutations increase tumor aggressiveness by altering TERT mRNA splicing in papillary thyroid carcinoma.

CONTEXT: Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis compared with TERT-p mutation-positive tumors. OBJECTIVE: TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. METHODS: We investigated the expression of two major variants, α deletion (dA) and ß deletion (dB), in a series of 207 PTCs operated between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. RESULTS: The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into three groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A + B/dB ratio in mut+/exp + was significantly higher than that in mut-/exp + PTCs. Analysis with clinicopathological data revealed that +A + B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor suppressive role. CONCLUSION: These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Pathotype characterization of Aphanomyces euteiches isolates collected from pea breeding nurseries.

Introduction: Aphanomyces euteiches Drechsler is an oomycete pathogen that affects legume crops, causing root rot, a severe disease of peas (Pisum sativum L.) worldwide. While significant research progress has been made in breeding pea-resistant varieties, there is still a need for a deeper understanding of the diversity of pathogen populations present in breeding nurseries located in various legume-growing regions around the world. Methods: We analysed the diversity of 51 pea-infecting isolates of A. euteiches, which were recovered from four American (Athena, OR; Le Sueur, MN; Mount Vernon, WA; Pullman, WA) and three French (Riec-sur-Belon, Templeux-le-Guérard, Dijon) resistance screening nurseries. Our study focused on evaluating their aggressiveness on two sets of differential hosts, comprising six pea lines and five Medicago truncatula accessions. Results: The isolates clustered into three groups based on their aggressiveness on the whole pea set, confirming the presence of pathotypes I and III. Pathotype I was exclusive to French isolates and American isolates from Athena and Pullman, while all isolates from Le Sueur belonged to pathotype III. Isolates from both pathotypes were found in Mount Vernon. The M. truncatula set clustered the isolates into three groups based on their aggressiveness on different genotypes within the set, revealing the presence of five pathotypes. All the isolates from the French nurseries shared the same Fr pathotype, showing higher aggressiveness on one particular genotype. In contrast, nearly all-American isolates were assigned to four other pathotypes (Us1, Us2, Us3, Us4), differing in their higher aggressiveness on two to five genotypes. Most of American isolates exhibited higher aggressiveness than French isolates within the M. truncatula set, but showed lower aggressiveness than French isolates within the P. sativum set. Discussion: These results provide valuable insights into A. euteiches pathotypes, against which the QTL and sources of resistance identified in these nurseries displayed effectiveness. They also suggest a greater adaptation of American isolates to alfalfa, a more widely cultivated host in the United States.

Prediction of prostate cancer aggressiveness using magnetic resonance imaging radiomics: a dual-center study.

PURPOSE: The Gleason score (GS) and positive needles are crucial aggressive indicators of prostate cancer (PCa). This study aimed to investigate the usefulness of magnetic resonance imaging (MRI) radiomics models in predicting GS and positive needles of systematic biopsy in PCa. MATERIAL AND METHODS: A total of 218 patients with pathologically proven PCa were retrospectively recruited from 2 centers. Small-field-of-view high-resolution T2-weighted imaging and post-contrast delayed sequences were selected to extract radiomics features. Then, analysis of variance and recursive feature elimination were applied to remove redundant features. Radiomics models for predicting GS and positive needles were constructed based on MRI and various classifiers, including support vector machine, linear discriminant analysis, logistic regression (LR), and LR using the least absolute shrinkage and selection operator. The models were evaluated with the area under the curve (AUC) of the receiver-operating characteristic. RESULTS: The 11 features were chosen as the primary feature subset for the GS prediction, whereas the 5 features were chosen for positive needle prediction. LR was chosen as classifier to construct the radiomics models. For GS prediction, the AUC of the radiomics models was 0.811, 0.814, and 0.717 in the training, internal validation, and external validation sets, respectively. For positive needle prediction, the AUC was 0.806, 0.811, and 0.791 in the training, internal validation, and external validation sets, respectively. CONCLUSIONS: MRI radiomics models are suitable for predicting GS and positive needles of systematic biopsy in PCa. The models can be used to identify aggressive PCa using a noninvasive, repeatable, and accurate diagnostic method.

Anaplasia in Wilms tumor: A critical review.

Anaplasia in Wilms tumor is recognized as the most important prognostically unfavorable histological feature. It is subtyped as focal anaplastic Wilms tumor (FAWT) and diffuse anaplastic Wilms tumor (DAWT). Outcomes of patients with DAWT remain poor in patients with stage III and IV tumors. Important issues relevant to anaplasia in Wilms tumor, including prevalence, treatment, outcomes, biomarkers, anaplasia, and chemotherapy, and the concept of tumor aggressiveness, are reviewed and discussed here. We also consider the differences in clinical approaches to anaplasia in Wilms tumor between the two major renal tumor clinical research groups: the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group and the Children's Oncology Group (COG) Renal Tumor Group. We emphasize the importance and implications of recognizing FAWT and DAWT as separate clinico-pathological entities.

Emotional, coping factors and personality traits that influenced alcohol consumption in Romanian students during the COVID-19 pandemic. A cross-sectional study.

BACKGROUND: During the COVID-19 pandemic, after 3 months from the installation of the state of emergency on the territory of Romania, data were collected from 677 students and master's students, to explore the problematic alcohol consumption (AC). METHODS: The evaluation was done with: Alcohol Use Disorders Identification Test, Depression, Anxiety and Stress Scales, Strategic Coping Approach Scale and The Freiburg Personality Inventory. The statistical methods used were linear regression with bootstrap procedure, Spearman's rank correlation, and the Mann-Whitney U test. RESULTS: More than half were affected by depression or anxiety of moderate to extremely severe intensity. The prevalence of problematic alcohol consumption was low: (Hazardous and Extremely Hazardous (2.3) and Medium Risk (10.2). Early onset increases the subsequent risk of problematic AC, compared to women, men recorded a higher AC (p <.01). Anxiety, antisocial action, personality traits Aggressiveness and Somatic complaints had the effect of increasing the alcohol consumption score (p <.01). Significant but weak positive correlations between AC on one hand, and depression, anxiety, stress and antisocial action on the other hand were found (p <.01). CONCLUSIONS: Probably the prevalence of AC was low as a result of the fact that most respondents were studying in the field of health promotion and as a result of the closure of entertainment venues. This study advocates for the education of youngsters to clearly express their opinions without violating the boundaries of others' feelings (assertive action) and to act prudently in dangerous or uncertain situations (cautious action) since these coping mechanisms were not associated with problematic alcohol consumption. The promotion of positive, achievement-oriented, life attitudes is equally important, as these characteristics of the Life Satisfaction personality dimensions were also found as non-determinants of alcohol-induced problems. The association of problematic AC with antisocial actions as a coping mechanism and high scores on Aggressiveness calls for interventions to educate the younger generation how to acquire and adopt healthy mechanisms to control tensions without resorting to alcohol consumption, more so as the two variables reinforce each other. Drinking as a means of gaining courage must be carefully reconsidered since anxiety generally hits back, often in increased levels.

Aggressiveness in systemic anticancer therapy at the end of life in an oncology center.

Introduction: An increasing aggressiveness in cancer treatment at the end of life (EoL) has been reported in several, but not all, countries. This study aimed to see how aggressive cancer treatment is at the EoL in an oncology center. Methods: Retrospective study of patients 18 years or older with a solid cancer diagnosis who died in 2017. The focus was systemic anticancer therapy (SACT), excluding hormonotherapy. Results: In 2017, 2024 patients with solid tumors died. Of those patients, 1262 (62%) were male, and the median age was 69 (range 19-97) years. The most frequent primary cancer was lung cancer, followed by colorectal and stomach cancers, and 740 (37%) patients had metastatic disease. The median interval between SACT and death was 61 days. Of the patients undergoing SACT, 216 (27%) did it in the last month of life, 174 (22%) between 8 and 30 days from death, and 42 (5%) in the last week. On multivariable analysis, head and neck, colorectal, breast, and melanoma primaries; age group (older than 65 years); and metastatic disease had statistical significance associated with SACT. Of these variables, only metastatic disease is more likely to undergo SACT. Conclusion: This study confirms the relatively frequent aggressiveness in cancer treatment at the EoL. Taking into consideration previously published data, it can be tentatively concluded that the use of SACT increased in the last month and the last week of life.

Cross-cultural perception of strength, attractiveness, aggressiveness and helpfulness of Maasai male faces calibrated to handgrip strength.

Previous research has demonstrated that Maasai and Europeans tend to align in their ratings of the physical strength and aggressiveness of Maasai male faces, calibrated to hand grip strength (HGS). However, perceptions of attractiveness of these faces differed among populations. In this study, three morphs of young Maasai men created by means of geometric morphometrics, and depicting the average sample and two extrema (± 4 SD of HGS), were assessed by men and women from Tanzania, Czech Republic, Russia, Pakistan, China, and Mexico (total sample = 1540). The aim of this study was to test cross-cultural differences in the perception of young Maasai men's composites calibrated to HGS, focusing on four traits: physical strength, attractiveness, aggressiveness, and helpfulness. Individuals from all six cultures were able to distinguish between low, medium, and high HGS portraits. Across all study populations, portrait of Maasai men with lower HGS was perceived as less attractive, more aggressive, and less helpful. This suggests that people from diverse populations share similar perceptions of physical strength based on facial shape, as well as attribute similar social qualities like aggressiveness and helpfulness to these facial images. Participants from all samples rated the composite image of weak Maasai men as the least attractive.

A field approach to observing changes in behavioural welfare indicators over 2 years in stabled horses.

In stabled horses, several behaviours are considered to be important indicators of the state of welfare at the individual level: stereotypies, aggressive behaviours towards humans and the "withdrawn", alert, sternal, lateral and observation postures. Until now, these behaviours have been extensively studied in relation to different horse management practices. However, little is known about their changes or consistency over time. This study aimed to investigate differences in the expression of these behaviours assessed on 44 stabled horses during an initial 3-month period and then again on the same individuals 2 years later. Out of the six behaviours studied, two showed significant differences between the 2 years with medium effect sizes: the levels of aggressiveness towards humans increased (Wilcoxon signed-rank test: V = 65, P = 0.005) and those of recumbent rest during the day decreased (V = 416, P < 0.001) over time. The results also suggested limited evidence of major changes over time in the expression of stereotypies, the "withdrawn", alert and observation postures. However, the principal component analyses carried out on all the behaviours showed that alert and observation postures may slightly decrease over time for some individuals. Regarding stereotypies and the "withdrawn" posture, the results mainly suggested a change at the individual level in the expression of these behaviours over time. This study provided new insights into the dynamic nature of several behaviours when the horses' living conditions are not fundamentally altered and raised hypotheses about the state of welfare of stabled individuals over a 2-year period.

Activation of astrocytes by ANXA2-derived extracellular vesicles from lung cancer cells affects aggressiveness, immunotherapy response and microenvironment of lung cancer.

Background: ANXA2 has been extensively documented in relation to cancer. Nevertheless, the involvement of ANXA2 in lung carcinoma remains uncertain. Methods: Data from The Cancer Genome Atlas (TCGA) database was downloaded using open-access methods. The examination of publicly available data was conducted utilizing the R software. The mRNA level of specific molecules was detected using Real-time Quantitative PCR (qPCR). The protein level of specific molecules was detected using the Western blot assay. The cell proliferation ability of cancer cells was assessed using the CCK8 assay. The invasion and migration capability of cancer cells was assessed using the Transwell assay. Validation of exosomes extraction was conducted using electron microscopy and particle size analysis. Results: In this study, based on series experiments, we found that ANXA2 can promote the activation of neuroastrocytes cells CP-H122 through the exosome pathway. Also, we found that ANXA2 can be transmitted from A549 cells to CP-H122 through the exosomes pathway and further promote the activation of CP-H122. Activated CP-H122 cells further enhance the proliferation, invasion and metastasis of A549 cells. Meanwhile, we performed transcriptome sequencing to explore the downstream genes of ANXA2 to screen potential targets for follow-up studies. Analysis based on public data showed that ANXA2 was related to the worse survival performance and clinical features of lung cancer. Gene set enrichment analysis based on the Hallmark gene set indicated that the patient with high ANXA2 expression might have a higher activity of the apical surface, reactive oxygen species pathway, angiogenesis, TGF-ß signaling, MYC target, but lower activity of pancreas-ß cells. More important, our results showed that ANXA2 can affects immunotherapy response and reshape immune microenvironment of lung cancer. Conclusions: This study demonstrates that ANXA2 activates CP-H122 cells, affects A549 cell behavior, and impacts lung cancer prognosis and immunotherapy response.

Gene Expression and Prognostic Value of NADPH Oxidase Enzymes in Breast Cancer.

NADPH oxidase enzymes (NOX) are involved in all stages of carcinogenesis, but their expression levels and prognostic value in breast cancer (BC) remain unclear. Thus, we aimed to assess the expression and prognostic value of NOX enzymes in BC samples using online databases. For this, mRNA expression from 290 normal breast tissue samples and 1904 BC samples obtained from studies on cBioPortal, Kaplan-Meier Plotter, and The Human Protein Atlas were analyzed. We found higher levels of NOX2, NOX4, and Dual oxidase 1 (DUOX1) in normal breast tissue. NOX1, NOX2, and NOX4 exhibited higher expression in BC, except for the basal subtype, where NOX4 expression was lower. DUOX1 mRNA levels were lower in all BC subtypes. NOX2, NOX4, and NOX5 mRNA levels increased with tumor progression stages, while NOX1 and DUOX1 expression decreased in more advanced stages. Moreover, patients with low expression of NOX1, NOX4, and DUOX1 had lower survival rates than those with high expression of these enzymes. In conclusion, our data suggest an overexpression of NOX enzymes in breast cancer, with certain isoforms showing a positive correlation with tumor progression.

Identification and Pathogenicity of Fusarium Fungi Associated with Dry Rot of Potato Tubers.

Dry rot of potato tubers is a harmful disease caused by species of the Fusarium genus. Studies on the composition and features of Fusarium spp. that cause the disease in Russia are limited. Thirty-one Fusarium strains belonging to the F. sambucinum species complex (FSAMSC) and F. solani species complex (FSSC) were accurately identified using multilocus phylogenetic analysis of the tef and rpb2 loci, and their physiological characteristics were studied in detail. As a result, 21 strains of F. sambucinum s. str. and 1 strain of F. venenatum within the FSAMSC were identified. Among the analyzed strains within the FSSC, one strain of F. mori, four strains of F. noneumartii, and two strains of both F. stercicola and F. vanettenii species were identified. This is the first record of F. mori on potato as a novel host plant, and the first detection of F. noneumartii and F. stercicola species in Russia. The clear optimal temperature for the growth of the strains belonging to FSAMSC was noted to be 25 °C, with a growth rate of 11.6-15.0 mm/day, whereas, for the strains belonging to FSSC, the optimal temperature range was between 25 and 30 °C, with a growth rate of 5.5-14.1 mm/day. The distinctive ability of F. sambucinum strains to grow at 5 °C has been demonstrated. All analyzed Fusarium strains were pathogenic to potato cv. Gala and caused extensive damage of the tuber tissue at an incubation temperature of 23 °C for one month. Among the fungi belonging to the FSAMSC, the F. sambucinum strains were more aggressive and caused 23.9 ± 2.2 mm of necrosis in the tubers on average compared to the F. venenatum strain-17.7 ± 1.2 mm. Among the fungi belonging to the FSSC, the F. noneumartii strains were the most aggressive and caused 32.2 ± 0.8 mm of necrosis on average. The aggressiveness of the F. mori, F. stercicola, and especially the F. vanettenii strains was significantly lower: the average sizes of damage were 17.5 ± 0.5 mm, 17.2 ± 0.2 mm, and 12.5 ± 1.7 mm, respectively. At an incubation temperature of 5 °C, only the F. sambucinum strains caused tuber necroses in the range of 6.7 ± 0.5-15.9 ± 0.8 mm.

IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/ß-catenin signaling pathway.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/ß-catenin pathway associated proteins (ß-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/ß-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/ß-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/ß-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.

Moral injury and pre-deployment personality factors as contributors to psychiatric symptomatology among combatants: a two-year prospective study.

Background: Combatants who are exposed to events that transgress deeply held moral beliefs might face lasting psychopathological outcomes, referred to as Moral Injury (MI). However, knowledge about pre-deployment factors that might moderate the negative consequences of MI is sparse. In this prospective study, we examined pre-enlistment characteristics and pre-deployment personality factors as possible moderators in the link between exposure to potentially morally injurious events (PMIEs) and psychiatric symptomatology among Israeli active-duty combatants.Methods: A sample of 335 active-duty Israeli combatants participated in a 2.5-year prospective study with three waves of measurements (T1: 12 months before enlistment, T2: Six months following enlistment - pre-deployment, and T3: 18 months following enlistment - post-deployment). Participants' characteristics were assessed via semi-structured interviews (T1) and validated self-report measures of personality factors: emotional regulation, impulsivity, and aggression (T2) and combat exposure, PMIEs, psychiatric symptomology and posttraumatic symptoms (T3) between 2019 and 2021.Results: Pre-enlistment psychiatric difficulties and negative life events contributed to higher exposure to PMIEs post-deployment. Higher levels of pre-deployment aggression and lower levels of emotional regulation and impulsivity moderated the association between betrayal, PMIEs and psychiatric symptomology post-deployment, above and beyond pre-enlistment psychiatric difficulties and life events.Conclusions: Our results highlight that pre-deployment emotional regulation, impulsivity and aggressiveness levels should be assessed, screened, and identified among combatants, as they all facilitate psychiatric symptomology (and PTSS) after combatants are exposed to PMIEs of betrayal. Such pre-assessment will enable the identification of at-risk combatants and might provide them with tailor-made preparation regarding moral and ethical situations that should be investigated in future research.

Pre-enlistment psychiatric difficulties contributed to higher exposure to PMIEs post-deployment.Pre-deployment personality moderated the associations between PMIEs and psychiatric symptomatology among combatants.Higher levels of pre-deployment emotional regulation moderated the association between betrayal PMIEs and post-deployment PTSS symptoms.

[Retracted] Tunicamycin inhibits colon carcinoma growth and aggressiveness via modulation of the ERK­JNK­mediated AKT/mTOR signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion and migration assay data shown in Fig. 1B and C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had either already been published or were under consideration for publication at around the same time. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 4203­4212, 2018; DOI: 10.3892/mmr.2018.8444].

The Utility of 18F-FDG-PET-CT Metabolic Parameters in Evaluating the Primary Tumor Aggressiveness and Lymph Node Metastasis of Nasopharyngeal Carcinoma.

Background: Following changes in primary tumor (T) and lymph node (N) staging for nasopharyngeal carcinoma (NPC) in the Eighth Edition AJCC Cancer Staging Manual, simplification of T staging has been proposed. However, a limited range of 2-deoxy-2-[fluorine-18] fluoro-D-glucose positron emission tomography-computed tomography (18F-FDG PET-CT) metabolic parameters has been investigated. Therefore, we aimed to evaluate the primary tumor invasiveness and the lymph node metastasis (LNM) of NPC from a metabolic perspective. Methods: A total of 435 NPC patients underwent 18F-FDG PET/CT before treatment were retrospectively examined. The primary endpoint was differences in standard uptake value (SUV), lean body mass-normalized SUV (SUL), body surface area-normalized SUV (SUS), glucose-normalized SUV (GN), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and glucose-normalized total lesion glycolysis (GNTLG) of primary tumors and LNM between different T and N stages. The metabolic parameters associated with T and N staging were identified. Results: There were significant differences between all parameters relative to the primary tumor but no significant differences in any parameter relative to the LNM and T stages. Higher mean values of TGNmax, TGNmean, TSUVpeak, and TSUSmax were associated with advanced T stages. Higher mean values of all the LNM parameters were associated with more advanced N stages. Only primary tumor metabolic tumor volume (TMTV), TSUVpeak, TSULmax, and TSUSmax showed a significant positive association with T staging, while lymph node metabolic tumor volume (LNMTV) and TSUSmax were significantly positive in N staging. Conclusions: Our findings suggest that metabolic parameters are useful indicators of tumor invasiveness and LNM based on the Eighth Edition manual. Compared with volume-dependent parameters, TGNmax, TGNmean, TSUVpeak, and TSUSmax may be better indicators of local tumor aggressiveness. SUSmax of the primary tumor was associated with LNM. In addition to SUVmax, other metabolic parameters (eg, SULmax, SUSmax, GNmax, and GNmean) could evaluate tumor aggressiveness and LNM better.

PRADclass: Hybrid Gleason Grade-Informed Computational Strategy Identifies Consensus Biomarker Features Predictive of Aggressive Prostate Adenocarcinoma.

BACKGROUND: Prostate adenocarcinoma (PRAD) is a common cancer diagnosis among men globally, yet large gaps in our knowledge persist with respect to the molecular bases of its progression and aggression. It is mostly indolent and slow-growing, but aggressive prostate cancers need to be recognized early for optimising treatment, with a view to reducing mortality. METHODS: Based on TCGA transcriptomic data pertaining to PRAD and the associated clinical metadata, we determined the sample Gleason grade, and used it to execute: (i) Gleason-grade wise linear modeling, followed by five contrasts against controls and ten contrasts between grades; and (ii) Gleason-grade wise network modeling via weighted gene correlation network analysis (WGCNA). Candidate biomarkers were obtained from the above analysis and the consensus found. The consensus biomarkers were used as the feature space to train ML models for classifying a sample as benign, indolent or aggressive. RESULTS: The statistical modeling yielded 77 Gleason grade-salient genes while the WGCNA algorithm yielded 1003 trait-specific key genes in grade-wise significant modules. Consensus analysis of the two approaches identified two genes in Grade-1 (SLC43A1 and PHGR1), 26 genes in Grade-4 (including LOC100128675, PPP1R3C, NECAB1, UBXN10, SERPINA5, CLU, RASL12, DGKG, FHL1, NCAM1, and CEND1), and seven genes in Grade-5 (CBX2, DPYS, FAM72B, SHCBP1, TMEM132A, TPX2, UBE2C). A RandomForest model trained and optimized on these 35 biomarkers for the ternary classification problem yielded a balanced accuracy ∼ 86% on external validation. CONCLUSIONS: The consensus of multiple parallel computational strategies has unmasked candidate Gleason grade-specific biomarkers. PRADclass, a validated AI model featurizing these biomarkers achieved good performance, and could be trialed to predict the differentiation of prostate cancers. PRADclass is available for academic use at: https://apalania.shinyapps.io/pradclass (online) and https://github.com/apalania/pradclass (command-line interface).

Frequent expression of PD-L1 in BLS-type diffuse large B-cell lymphoma: implications for aggressiveness and immunotherapy.

BLS-type diffuse large B-cell lymphoma (DLBCL) denotes an uncommon, aggressive variant of DLBCL presenting initially in bone marrow, liver and spleen without lymphadenopathy or mass lesion. Patients with BLS-type DLBCL present frequently with haemophagocytic syndrome which often leads to early patient demise. Programmed death ligand 1 (PD-L1) plays a negative regulatory role on effector T cells and is an important target of immunotherapy. Assessment of PD-L1 expression in BLS-type DLBCL may carry therapeutic implications and provide mechanistic insights. Standard immunohistochemical analysis for PD-L1 was performed in seven cohorts for this study: (1) DLBCL-not otherwise specified (NOS) (n=201); (2) Epstein-Barr virus (EBV)-positive DLBCL (n=26); (3) thymic (primary mediastinal) DLBCL (n=12); (4) intravascular LBCL (n=3); (5) high-grade B-cell lymphoma, NOS (n=12); (6) BLS-type DLBCL (n=37); and (7) systemic DLBCL involving bone marrow (n=28). We found that PD-L1 was positive in 12.9% of DLBCL-NOS cases, 46.2% of EBV-positive DLBCL, 91.7% of thymic LBCL, none of intravascular LBCL, 8.3% of high-grade B-cell lymphoma-NOS, and 56.8% of BLS-type DLBCL. By comparison, only 14.3% of bone marrow cases involved by systemic DLBCL were positive for PD-L1 (p<0.001). Interestingly, BLS-type DLBCL more frequently showed activated B-cell phenotype (86.5% vs 65.2%, p=0.010), a high Ki-67 proliferative index (97.1% vs 63.3%, p<0.001), MYC overexpression (90.9% vs 56.2%, p=0.023), presence of haemophagocytic syndrome (86.5% vs 4.0%, p<0.001), and poorer overall survival (p<0.001) than DLBCL-NOS. These data suggest that the poor prognosis of BLS-type DLBCL may be explained by both extrinsic tumour microenvironment factors and intrinsic genetic factors of tumour cells, such as PD-L1-associated inactivation of anti-tumour immunity for the former, and MYC pathway activation-related aggressiveness for the latter.

A nomogram to preoperatively predict the aggressiveness of non-functional pancreatic neuroendocrine tumors based on CT features.

OBJECTIVES: To develop a nomogram to predict the aggressiveness of non-functional pancreatic neuroendocrine tumors (NF-pNETs) based on preoperative computed tomography (CT) features. METHODS: This study included 176 patients undergoing radical resection for NF-pNETs. These patients were randomly divided into the training (n = 123) and validation sets (n = 53). A nomogram was developed based on preoperative predictors of aggressiveness of the NF-pNETs which were identified by univariable and multivariable logistic regression analysis. The aggressiveness of NF-pNETs was defined as a composite measure including G3 grading, N+, distant metastases, and/ or disease recurrence. RESULTS: Altogether, the number of patients with highly aggressive NF-pNETs was 37 (30.08 %) and 15 (28.30 %) in the training and validation sets, respectively. Multivariable logistic regression analysis identified that tumor size, biliopancreatic duct dilatation, lymphadenopathy, and enhancement pattern were preoperative predictors of aggressiveness. Those variables were used to develop a nomogram with good concordance statistics of 0.89 and 0.86 for predicting aggressiveness in the training and validation sets, respectively. With a nomogram score of 59, patients with NF-pNETs were divided into low-aggressive and high-aggressive groups. The high-aggressive group had decreased overall survival (OS) and disease-free survival (DFS). Moreover, the nomogram showed good performance in predicting OS and DFS at 3, 5, and 10 years. CONCLUSION: The nomogram integrating CT features helped preoperatively predict the aggressiveness of NF-pNETs and could potentially facilitate clinical decision-making.

Genetic evaluation of crossbred Bos indicus cow temperament at parturition.

Cow temperament at parturition may be mostly a measure of aggressiveness. The heritability of cow temperament at parturition in Bos taurus cows has been reported to be low. The objectives of this study were to estimate the heritability of cow temperament at parturition, conduct a genome-wide association analysis of cow temperament at the time of parturition, and estimate the correspondence of cow temperament at the time of parturition with cow productive performance and early-life temperament traits in Bos indicus crossbreds. Cow temperament was assessed from 1 to 5 indicating increasing levels of aggressiveness of cows (937 cows and 4,337 parturitions) from 2005 to 2022. Estimates of heritability and repeatability were 0.12 ±â€…0.024 and 0.24 ±â€…0.018. The estimates of proportion of phenotypic variance were 0.13 ±â€…0.019 and 0.02 ±â€…0.011 for permanent and maternal permanent environmental components, respectively. Estimates of heritability for maximum lifetime temperament score and proportions of temperament scores >1 were 0.18 ±â€…0.07 and 0.13 ±â€…0.072. Within cycles (generations), 2-yr-old cows had lower temperament score means than cows in most other age categories. There were low to moderate positive estimates of unadjusted correlation coefficients (r = 0.22 to 0.29; P < 0.05) of unadjusted temperament score with temperament measured on the same females when they were 8 mo old. There were low to moderate positive estimates of correlation coefficients (r = 0.09 to 0.37; P < 0.05) of unadjusted temperament score with calving rate, weaning rate, weaning weight per cow exposed, and weaning weight per 454 kg cow weight at weaning. Cows with the lowest temperament score had lower (P < 0.05) calving and weaning rate than cows in other temperament categories. Within 3 of 5 cycles, cows with the lowest temperament score (totally docile) had lower (P < 0.05) weaning weight per cow exposed than cows in other temperament categories. There were 2 SNP on BTA 4 associated with maximum lifetime temperament score (FDR < 0.05). The non-genetic influence of a cow's mother was documented in her own temperament measured at the time of calving; this may be a consequence of learned behavior. Less aggressiveness displayed by cows at the time of calving may be accompanied by lower reproductive and maternal performance.

Cow temperament was evaluated in 1/2 Nellore 1/2 Angus cows from four distinct generations (five herds) from 2005 to 2022. Cows were scored when their calves were processed (1 d age) as 1 = totally docile, 2 = protective, but not aggressive, 3 = moderately aggressive when calf is disturbed, 4 = very aggressive when calf is disturbed, and 5 = very aggressive even when calf is not disturbed. Similar to results in Bos taurus cows, the heritability of this trait was low. The repeatability was more moderate, indicating that additional records from a cow would be beneficial for selection purposes. Young cows had lower scores, indicating more docile behavior. This may be because a strong maternal protective instinct develops and strengthens over time. Temperament measured when cows were 8 mo old was moderately associated with their temperament as mature cows at the time of parturition. Cows with low temperament scores (more docile) had, in several cases, lower reproductive performance and production. Experiential accumulation appears to be important for cow temperament near the time of calving, including the cow's experience as a calf from her dam.