Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Molecular characterization of ESR1 variants in breast cancer.

PURPOSE: Estrogen receptor 1 (ESR1) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize ESR1 variants among molecularly profiled advanced breast cancers. METHODS: DNA next-generation sequencing (592-gene panel) data from 9860 breast cancer samples were retrospectively reviewed. Gene fusions were detected using the ArcherDx fusion assay or whole transcriptome sequencing (n = 344 and n = 4305, respectively). Statistical analyses included Chi-square and Fisher's exact tests. RESULTS: An ESR1 ligand-binding domain (LBD) mutation was detected in 8.6% of tumors evaluated and a pathogenic ESR1 fusion was detected in 1.6%. Most ESR1 LBD mutations/fusions were from estrogen receptor (ER)-positive samples (20.1% and 4.9%, respectively). The most common ESR1 LBD mutations included D538G (3.3%), Y537S (2.3%), and E380Q (1.1%) mutations. Among biopsy sites, ESR1 LBD mutations were most observed in liver metastases. Pathogenic ESR1 fusions were identified in 76 samples (1.6%) with 40 unique fusion partners. Evaluating co-alterations, ESR1 variant (mutation/fusion) samples more frequently expressed androgen receptor (78.0% vs 58.6, P < 0.0001) and less frequently immune checkpoint proteins than ESR1 wild-type (PD-1 20.0% vs 53.4, P < 0.05; immune cell PD-L1 10.0% vs 30.2, P < 0.0001). CONCLUSION: We have described one of the largest series of ESR1 fusions reported. ESR1 LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of ESR1 fusions, which could be an area for future therapeutic exploration.

Seven-tesla susceptibility-weighted analysis of hippocampal venous structures: Application to magnetic-resonance-normal focal epilepsy.

OBJECTIVE: Vascular structures may play a significant role in epileptic pathology. Although previous attempts to characterize vasculature relative to epileptogenic zones and hippocampal sclerosis have been inconsistent, an in vivo method of analysis would assist in resolving these inconsistencies and facilitate a comparison against healthy controls in a human model. Magnetic resonance imaging is a noninvasive technique that provides excellent soft tissue contrast, and the relatively recent development of susceptibility-weighted imaging has dramatically improved the visibility of small veins. METHODS: We built and tested a Hessian-based segmentation technique, which takes advantage of the increased signal and contrast available at 7 T to detect venous structures in vivo. We investigate the ability of this technique to quantify vessels in the brain and apply it to an asymmetry analysis of vessel density in the hippocampus in patients with mesial temporal lobe epilepsy (MTLE) and neocortical epilepsy. RESULTS: Vessel density was highly symmetric in the hippocampus in controls (mean asymmetry = 0.080 ± 0.076, median = 0.05027), whereas average vessel density asymmetry was greater in neocortical (mean asymmetry = 0.23 ± 0.17, median = 0.14) and MTLE (mean asymmetry = 0.37 ± 0.46, median = 0.26) patients, with the decrease in vessel density ipsilateral to the suspected seizure onset zone. Post hoc testing with one-way analysis of variance and Tukey post hoc test indicated significant differences in the group means (P < .02) between MTLE and the control group only. SIGNIFICANCE: Asymmetry in vessel density in the hippocampus is visible in patients with MTLE, even when qualitative and quantitative measures of hippocampal asymmetry show little volumetric difference between epilepsy patients and healthy controls.

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases.

We profiled nine pure clear cell carcinomas of the breast using massively parallel DNA and RNA sequencing (NGS), in situ hybridization (ISH), and immunohistochemistry (IHC). All cases were primary mammary clear cell carcinomas that were diagnosed in female patients (mean age: 53.4 years; range: 31-69 years). Based on our findings, we conclude that the majority of clear cell carcinomas are ER/PR positive and consequently amenable to anti-ER treatment modalities. A subset of clear cell carcinomas also harbored alterations in PIK3CA/PTEN/AKT pathway, particularly PTEN, indicating a potential benefit of PI3K/Akt/mTOR inhibitors. The status of I-O biomarkers in clear cell carcinomas indicates a limited therapeutic benefit of immune checkpoint inhibitors (against PD-1/PD-L1).

Correction to: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

In the original publication, the sixth author name was published incorrectly as Matthew Stein. The correct author name should read as Matthew K Stein.

Immunohistochemistry-Enabled Precision Medicine.

Immunohistochemistry (IHC) can be applied to diagnostic aspects of pathologic examination to provide aid in assignment of lineage and histologic type of cancer. Increasingly, however, IHC is widely used to provide prognostic and predictive (theranostic) information about the neoplastic disease. A refinement of theranostic application of IHC can be seen in the use of "genomic probing" where antibody staining results are directly correlated with an underlying genetic alteration in the tumor (somatic mutations) and/or the patient (germline constitution). All these aspects of IHC find their best use in guiding the oncologists in the optimal use of therapy for the patients.

How chimpanzees cooperate in a competitive world.

Our species is routinely depicted as unique in its ability to achieve cooperation, whereas our closest relative, the chimpanzee (Pan troglodytes), is often characterized as overly competitive. Human cooperation is assisted by the cost attached to competitive tendencies through enforcement mechanisms, such as punishment and partner choice. To examine if chimpanzees possess the same ability to mitigate competition, we set up a cooperative task in the presence of the entire group of 11 adults, which required two or three individuals to pull jointly to receive rewards. This open-group set-up provided ample opportunity for competition (e.g., freeloading, displacements) and aggression. Despite this unique set-up and initial competitiveness, cooperation prevailed in the end, being at least five times as common as competition. The chimpanzees performed 3,565 cooperative acts while using a variety of enforcement mechanisms to overcome competition and freeloading, as measured by (attempted) thefts of rewards. These mechanisms included direct protest by the target, third-party punishment in which dominant individuals intervened against freeloaders, and partner choice. There was a marked difference between freeloading and displacement; freeloading tended to elicit withdrawal and third-party interventions, whereas displacements were met with a higher rate of direct retaliation. Humans have shown similar responses in controlled experiments, suggesting shared mechanisms across the primates to mitigate competition for the sake of cooperation.

Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma.

BACKGROUND: Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers. METHODS: In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel. RESULTS: In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B-Raf proto-oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF-mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD-L1 (56%) and PD-1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had KIT mutations, wild-type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A). CONCLUSIONS: The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333-1344. © 2016 American Cancer Society.

Identification of molecular targets in vulvar cancers.

OBJECTIVES: To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment. METHODS: After retrospective analysis of a database of molecularly-profiled gynecologic cancer patients, 149 vulvar cancer patients were included and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (C/FISH). A Fisher's exact test was used when indicated with a p-value≤0.05 indicating significance. RESULTS: Median age was 65. 85% had squamous cell carcinoma (SCC) and 15% adenocarcinoma (ADC) histologies. 46% had metastatic (Stage IV) disease. Targeted hot-spot sequencing identified variants in the following genes: TP53 (33%), PIK3CA/BRCA2 (8%, 10%, respectively), HRAS/FBXW7 (5%, 4%, respectively) and ERBB4/GNAS (3%, 3% respectively). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS (n=1, respectively) and BRAF (n=2) also occurred. Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancers (e.g. PIK3CA: exon 9 [E545K], RAS: G13D, Q61L, BRCA2: S1667X, BRAF: R443T, FBXW7: E471fs, etc.). Drug targets identified by IHC and ISH methodologies include cMET (32% IHC, 2% ISH), PDL1 (18%), PTEN loss (56%), HER2 (4% IHC, 2% ISH) and hormone receptors (AR, 4%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2 and GNAS with an increased presence in ADC (p-values all <0.05). CONCLUSIONS: Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.

Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.

A semiadiabatic spectral-spatial spectroscopic imaging (SASSI) sequence for improved high-field MR spectroscopic imaging.

PURPOSE: MR spectroscopic imaging (MRSI) benefits from operation at 7T due to increased signal-to-noise ratio (SNR) and spectral separation. The 180° radiofrequency (RF) pulses used in the conventional MRSI sequences are particularly susceptible to the variation in the transmitted RF (B1 ) field and severe chemical shift localization errors at 7T. RF power deposition, as measured by specific absorption rate (SAR), also increases with field strength. Adiabatic 180° RF pulses may mitigate the effects of B1 variation. We designed and implemented a semiadiabatic spectral-spatial spectroscopic imaging (SASSI) pulse sequence to provide more uniform spectral data at 7T with reduced SAR. METHODS: The adiabatic Shinnar-Le Roux algorithm was used to generate a high bandwidth 180° adiabatic spectral-spatial (SPSP) pulse that captured a spectral range containing the main metabolites of interest. A pair of 180° SPSP pulses was used to refocus the signal excited by a 90° SPSP pulse in order to select a 3D volume of interest in the SASSI sequence. RESULTS: The SASSI pulse sequence produced spectra with more uniform brain metabolite SNR when compared with the conventional nonadiabatic MRSI sequence. CONCLUSION: SASSI achieved comparable SNR to the current adiabatic alternative, semi-LASER, but with 1/3 of the SAR. Magn Reson Med 76:1071-1082, 2016. © 2015 Wiley Periodicals, Inc.

A SEmi-Adiabatic matched-phase spin echo (SEAMS) PINS pulse-pair for B1 -insensitive simultaneous multislice imaging.

PURPOSE: Simultaneous multislice (SMS) imaging is a powerful technique that can reduce image acquisition time for anatomical, functional, and diffusion weighted magnetic resonance imaging. At higher magnetic fields, such as 7 Tesla, increased radiofrequency (RF) field inhomogeneity, power deposition, and changes in relaxation parameters make SMS spin echo imaging challenging. We designed an adiabatic 180° Power Independent of Number of Slices (PINS) pulse and a matched-phase 90° PINS pulse to generate a SEmi-Adiabatic Matched-phase Spin echo (SEAMS) PINS sequence to address these issues. METHODS: We used the adiabatic Shinnar Le-Roux (SLR) algorithm to generate a 180° pulse. The SLR polynomials for the 180° pulse were then used to create a matched-phase 90° pulse. The pulses were sub-sampled to produce a SEAMS PINS pulse-pair and the performance of this pulse-pair was validated in phantoms and in vivo. RESULTS: Simulations as well as phantom and in vivo results, demonstrate multislice capability and improved B1 -insensitivity of the SEAMS PINS pulse-pair when operating at RF amplitudes of up to 40% above adiabatic threshold. CONCLUSION: The SEAMS PINS approach presented here achieves multislice spin echo profiles with improved B1 -insensitivity when compared with a conventional spin echo.

Cervical Cancer Screening Among Homeless Women of New York City Shelters.

Introduction Homeless persons have minimal opportunities to complete recommended cancer screening. The rates and predictors of cervical cancer screening are understudied among homeless women in the US. Methods We enrolled 297 homeless women 21-65 years old residing in 6 major New York City shelters from 2012 to 2014. We used a validated national survey to determine the proportion and predictors of cervical cancer screening using cytology (Pap test). Results Mean age was 44.72 (±11.96) years. Majority was Black, heterosexual, single, with high school or lower education; 50.9 % were smokers and 41.7 % were homeless more than a year. Despite a 76.5 % proportion of self-reported Pap test within the past 3 years, 65 % of women assumed their Pap test results were normal or did not get proper follow up after abnormal results. Forty-five-point-nine percent of women did not know about frequency of Pap test or causes of cervical cancer. Lower proportion of up-to-date Pap test was associated with lack of knowledge of recommended Pap test frequency (p < 0.01) and relationship between HPV and an abnormal Pap test (p < 0.01). Conclusions Self-reported Pap testing in homeless women was similar to a national sample. However, the majority of women surveyed were not aware of their results, received limited if any follow up and had significant education gaps about cervical cancer screening. We recommend improved counseling and patient education, patient navigators to close screening loops, and consideration of alternative test-and-treat modalities to improve effective screening.

Arboviral diseases and malaria in Australia, 2013-14: Annual report of the National Arbovirus and Malaria Advisory Committee.

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2013-14 season (1 July 2013 to 30 June 2014) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 8,898 cases of disease transmitted by mosquitoes during the 2013-14 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 6,372 (72%) total notifications. However, over-diagnosis and possible false positive diagnostic test results for these 2 infections mean that the true burden of infection is likely overestimated, and as a consequence, the case definitions have been amended. There were 94 notifications of imported chikungunya virus infection and 13 cases of imported Zika virus infection. There were 212 notifications of dengue virus infection acquired in Australia and 1,795 cases acquired overseas, with an additional 14 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia (51%). No cases of locally-acquired malaria were notified during the 2013-14 season, though there were 373 notifications of overseas-acquired malaria. In 2013-14, arbovirus and mosquito surveillance programs were conducted in most jurisdictions. Surveillance for exotic mosquitoes at international ports of entry continues to be a vital part of preventing the spread of vectors of mosquito-borne diseases such as dengue to new areas of Australia, with 13 detections of exotic mosquitoes at the ports of entry in 2013-14.

Arboviral diseases and malaria in Australia, 2012-13: Annual report of the National Arbovirus and Malaria Advisory Committee.

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2012-13 season (1 July 2012 to 30 June 2013) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 9,726 cases of disease transmitted by mosquitoes during the 2012-13 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 7,776 (80%) of total notifications. However, over-diagnosis and possible false positive diagnostic test results for these 2 infections mean that the true burden of infection is likely overestimated, and as a consequence, the case definitions were revised, effective from 1 January 2016. There were 96 notifications of imported chikungunya virus infection. There were 212 notifications of dengue virus infection acquired in Australia and 1,202 cases acquired overseas, with an additional 16 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia. No locally-acquired malaria was notified during the 2012-13 season, though there were 415 notifications of overseas-acquired malaria. There were no cases of Murray Valley encephalitis virus infection in 2012-13. In 2012-13, arbovirus and mosquito surveillance programs were conducted in most jurisdictions with a risk of vectorborne disease transmission. Surveillance for exotic mosquitoes at the border continues to be a vital part of preventing the spread of mosquito-borne diseases such as dengue to new areas of Australia, and in 2012-13, there were 7 detections of exotic mosquitoes at the border.

Arboviral diseases and malaria in Australia, 2011-12: annual report of the National Arbovirus and Malaria Advisory Committee.

The National Notifiable Diseases Surveillance System received notifications for 7,875 cases of disease transmitted by mosquitoes during the 2011-12 season (1 July 2011 to 30 June 2012). The alphaviruses Barmah Forest virus and Ross River virus accounted for 6,036 (77%) of these. There were 18 notifications of dengue virus infection acquired in Australia and 1,390 cases that were acquired overseas, while for 38 cases, the place of acquisition was unknown. Imported cases of dengue in Australia were most frequently acquired in Indonesia. There were 20 imported cases of chikungunya virus. There were no notifications of locally-acquired malaria in Australia during the 2011-12 season. There were 314 notifications of overseas-acquired malaria and 41 notifications where the place of acquisition was unknown. Sentinel chicken, mosquito surveillance, viral detection in mosquitoes and climate modelling are used to provide early warning of arboviral disease activity in Australia. In 2011-12, sentinel chicken programs for the detection of flavivirus activity were conducted in most states with the risk of arboviral transmission. Other surveillance activities to detect the presence of arboviruses in mosquitoes or mosquito saliva or for surveying mosquito abundance included honey-baited trap surveillance, surveys of household containers that may provide suitable habitat for the dengue vector, Aedes aegypti, and carbon dioxide baited traps. Surveillance for exotic mosquitoes at the border continues to be a vital part of preventing the spread of mosquito-borne diseases to new areas of Australia.

Emotional clarity in daily life is associated with reduced indecisiveness and greater goal pursuit.

Affect-as-information theory posits that understanding of one's emotions (i.e., emotional clarity) can be leveraged to make decisions and attain goals. Furthermore, recent work has emphasized the dynamic nature of emotional clarity and its fluctuations in daily life. Therefore, we sought to test how momentary emotional clarity, experienced in everyday life, would be associated with levels of indecisiveness and goal pursuit. Following affect-as-information, we hypothesized that emotional clarity would be associated with lower indecisiveness but greater goal pursuit. We also hypothesized that indecisiveness would be associated with less goal pursuit with momentary emotional clarity being a potential moderator of this association. Adults (N = 215, Mage = 44.3) experiencing a range of depression, a disorder characterized by indecisiveness, completed a self-report measure of indecisiveness and 2 weeks of experience sampling assessing momentary emotional clarity, goal pursuit, and negative affect. Momentary emotional clarity showed robust links to lower indecisiveness and greater goal pursuit that were not accounted for by negative affect. We did not observe a link between indecisiveness and goal pursuit. Emotional clarity appears to play a role in motivational and cognitive processes that unfold in daily life. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Genomic Landscape of Breast Cancer in Young and Older Women.

BACKGROUND: Young women with breast cancer (YWBC; ≤40 years) often have a poorer prognosis than older women with breast cancer (OWBC; ≥65 years). We explored molecular features of tumors from YWBC and OWBC to identify a biologic connection for these patterns. MATERIALS AND METHODS: We retrospectively analyzed the molecular profiles of 1879 breast tumors. Testing included immunohistochemistry (IHC), in situ hybridization (ISH), and next-generation sequencing. Statistical analyses included Pearson's chi2 test for comparisons, with significance defined as FDR (false discovery rate)-P < .05. RESULTS: TP53 and BRCA1 somatic mutations were more common in YWBC tumors than in OWBC tumors (53%, 42%; P = .0001, FDR-P = .0025 and 7%, 2%; P = .0001, FDR-P = .0025; respectively). Conversely, OWBC tumors had higher androgen receptor expression (55%, 45%; P = .0002, FDR-P = .0025) higher PD-L1 expression detected by IHC (8%, 5%; P = .0476, FDR-P = .2754), and more frequent PIK3CA mutations (33%, 17%; P = < .0001, FDR-P = < .0001). Among HR+/HER2- samples, YWBC had more gene amplifications in FGF3 (27%, 10%; P = .0353, FDR-P = .2462), FGF4 (27%, 9%; P = .0218, FDR-P = .1668), FGF19 (30%, 12%; P = .034, FDR-P = .2462) and CCND1 (37%, 18%; P = .0344, FDR-P = .2462) than OWBC. CONCLUSIONS: Our data suggest distinct molecular aberrations exist between YWBC and OWBC. Exploiting these molecular changes could refine our treatment strategies in YWBC and OWBC.

Mosquitoes provide a transmission route between possums and humans for Buruli ulcer in southeastern Australia.

Buruli ulcer, a chronic subcutaneous infection caused by Mycobacterium ulcerans, is increasing in prevalence in southeastern Australia. Possums are a local wildlife reservoir for M. ulcerans and, although mosquitoes have been implicated in transmission, it remains unclear how humans acquire infection. We conducted extensive field survey analyses of M. ulcerans prevalence among mosquitoes in the Mornington Peninsula region of southeastern Australia. PCR screening of trapped mosquitoes revealed a significant association between M. ulcerans and Aedes notoscriptus. Spatial scanning statistics revealed overlap between clusters of M. ulcerans-positive Ae. notoscriptus, M. ulcerans-positive possum excreta and Buruli ulcer cases, and metabarcoding analyses showed individual mosquitoes had fed on humans and possums. Bacterial genomic analysis confirmed shared single-nucleotide-polymorphism profiles for M. ulcerans detected in mosquitoes, possum excreta and humans. These findings indicate Ae. notoscriptus probably transmit M. ulcerans in southeastern Australia and highlight mosquito control as a Buruli ulcer prevention measure.