Cognitive Impairment and Depression in Mastocytosis: A Synthesis of the Literature.

PURPOSE OF REVIEW: Symptoms of depression and cognitive dysfunction are commonly reported in mastocytosis. The aims of this review paper are to summarize the current literature on cognitive dysfunction and depressive symptoms, elucidate some of the mechanistic pathways underlying depressive symptoms in mastocytosis, identify gaps in the literature, and offer guidance for future research in this area. RECENT FINDINGS: The study of cognition and depression in mastocytosis is in its infancy and the methodological flaws of the current literature limit interpretability. There is preliminary evidence that some individuals with mastocytosis might experience mild deficits in memory. On average, depression symptom scores fell within the mild to moderate or sub-syndromal range. Regrettably, only one study utilized a standardized diagnostic instrument to assess major depressive disorder. The authors' tendency to inaccurately equate depressive symptoms with a diagnosis of major depressive disorder presents a notable issue. The prevalence of cognitive deficits and depression appears to be similar to other chronic illnesses. Future work needs to better characterize cognition and characterize "depression" in this population.

The Importance of Multidisciplinary Trauma-Informed Training in Addressing Campus-Based Sexual Violence.

ABSTRACT: This study investigates the impact of a professional development training series among a multidisciplinary team (MDT) during establishment of a trauma-informed sexual assault response and prevention program at a midsized university in the southeastern United States. MDT members included forensic nurses, advocates, counselors, law enforcement officers, and relevant faculty and staff. After completion of a baseline survey assessing attitudes toward trauma-informed care and perceptions of the team climate within the MDT, team members engaged in a trauma-informed care (TIC) professional development training series consisting of (a) 4-hour-long didactic lectures with incorporated group discussion and (2) one 2-hour in-situ simulation-based training exercise. MDT members subsequently completed 3-month and long-term follow-up surveys to assess the immediate and enduring impacts of the training series.The TIC training series significantly increased MDT members' perceptions of participative safety, task orientation, and support for innovation within the group at the 3-month assessment. No long-term differences were found, likely because of a small sample size and low statistical power.Intensive TIC MDT professional development at the beginning of a campus-wide sexual assault prevention and response initiative enhances psychological safety within the group, evidenced by increased perceptions of participative safety and support for innovation, and builds team cohesiveness around a shared set of tasks. Within the present MDT, the professional development training series also appeared to facilitate adoption of a shared set of values for accomplishing the team's goal of preventing and responding to sexual assault on campus. Recommendations for MDTs with similar goals are discussed.

Transcriptomic Profiling of Upper Tract Urothelial Carcinoma: Bladder Cancer Consensus Classification Relevance, Molecular Heterogeneity, and Differential Immune Signatures.

Analyses of large transcriptomics data sets of muscle-invasive bladder cancer (MIBC) have led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUCs) are less known. Our objective was to determine the relevance of the consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors. Using immunohistochemistry (IHC), subtype markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16, Ki67, mismatch repair system proteins, and PD-L1 were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3'RNA sequencing of each tumor, with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression. Most of the 66 patients were men (77.3%), with pT1 (n = 23, 34.8%) or pT2-4 stage UTUC (n = 43, 65.2%). FGFR3 mutations and mismatch repair-deficient status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as luminal papillary (LumP). Combining our consensus classification results with those of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUCs, which was significantly higher than MIBCs. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology, and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular, if FGFR3 mutated. Our study shows that MIBC consensus classification robustly classified UTUCs and highlighted intratumoral molecular heterogeneity. The proportion of LumP was significantly higher in UTUCs than in MIBCs. Most LumP tumors showed low immune infiltration and PD-L1 expression and high proportion of FGFR3 mutations. These findings suggest differential response to novel therapies between patients with UTUC and those with MIBC.

Epigenomic mapping identifies an enhancer repertoire that regulates cell identity in bladder cancer through distinct transcription factor networks.

Muscle-invasive bladder cancer (BLCA) is an aggressive disease. Consensus BLCA transcriptomic subtypes have been proposed, with two major Luminal and Basal subgroups, presenting distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. We hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of BLCA subtypes. Through integrated RNA-sequencing and epigenomic profiling of histone marks in primary tumours, cancer cell lines, and normal human urothelia, we established the first integrated epigenetic map of BLCA and demonstrated the link between subtype and epigenetic control. We identified the repertoire of activated super-enhancers and highlighted Basal, Luminal and Normal-associated SEs. We revealed super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2, respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation and induced ZBED2 overexpression. In parallel, we showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition. Our study furthers the understanding of epigenetic regulation of muscle-invasive BLCA and identifies a co-regulated network of super-enhancers and associated transcription factors providing potential targets for the treatment of this aggressive disease.

FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias.

BACKGROUND: Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. OBJECTIVE: To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. DESIGN, SETTING, AND PARTICIPANTS: We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. INTERVENTION: Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. RESULTS AND LIMITATIONS: FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3-driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. CONCLUSIONS: Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. PATIENT SUMMARY: By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.

Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies.

Background: Muscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies, or anti-fibroblast growth factor receptor (FGFR) treatments, these tumors are still of a poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating the molecular heterogeneity of MIBC and UTUC, to facilitate the preclinical identification of therapies. Methods: Fresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays), and genomic profiles [targeted Next-Generation Sequencing (NGS)]. Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies [FGFR and epidermal growth factor (EGFR) inhibitors]. Results: A total of 31 PDXs were established from 1 non-MIBC, 25 MIBC, and 5 upper urinary tract tumors, including 28 urothelial (UC) and 3 squamous cell carcinomas (SCCs). Integrated genomic and transcriptomic profiling identified the PDXs of three different consensus molecular subtypes [basal/squamous (Ba/Sq), luminal papillary, and luminal unstable] and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a Ba/Sq patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy, and we did not observe any association between subtypes and the response. Of the three Ba/Sq models treated with anti-EGFR therapy, two models were sensitive, and one model, of the sarcomatoid variant, was resistant. The treatment of three FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone. Conclusions: We developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. The pharmacological characterization of the PDXs suggested that the upper urinary tract and MIBCs, not only UC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.

Failure to Respond to Food Resource Decline Has Catastrophic Consequences for Koalas in a High-Density Population in Southern Australia.

Understanding the ability of koalas to respond to changes in their environment is critical for conservation of the species and their habitat. We monitored the behavioural response of koalas to declining food resources in manna gum (Eucalyptus viminalis) woodland at Cape Otway, Victoria, Australia, from September 2011 to November 2013. Over this period, koala population density increased from 10.1 to 18.4 koalas.ha-1. As a result of the high browsing pressure of this population, manna gum canopy condition declined with 71.4% manna gum being completely or highly defoliated in September 2013. Despite declining food resources, radio collared koalas (N = 30) exhibited high fidelity to small ranges (0.4-1.2 ha). When trees became severely defoliated in September 2013, koalas moved relatively short distances from their former ranges (mean predicted change in range centroid = 144 m) and remained in areas of 0.9 to 1.0 ha. This was despite the high connectivity of most manna gum woodland, and close proximity of the study site (< 3 km) to the contiguous mixed forest of the Great Otway National Park. Limited movement had catastrophic consequences for koalas with 71% (15/21) of radio collared koalas dying from starvation or being euthanased due to their poor condition between September and November 2013.