Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness-femaleness" continuum are rare. Rather, most brains are comprised of unique "mosaics" of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.gender differences | sex differences | brain structure | brain connectivity | behavior T he question of whether males and females form two distinct categories has attracted thinkers from ancient times to this day. Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved (for a historical overview, see refs. 1 and 2). Documented sex/gender* differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" vs. "male brain"), and consequently, of a sexually dimorphic view of human behavior, cognition, personality, attitudes, and other gender characteristics (3). Joel (4, 5) has recently argued that the existence of sex/gender differences in the brain is not sufficient to conclude that human brains belong to two distinct categories. Rather, such a distinction requires the fulfillment of two conditions: one, the form of the elements that show sex/gender differences should be dimorphic, that is, with little overlap between the forms of the elements in males and females. Two, there should be a high degree of internal consistency in the form of the different elements of a single brain (e.g., all elements have the "male" form).Previous criticisms of the dichotomous view of human brain have focused on the fact that most sex/gender differences are nondimorphic popul...

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Gastric cancer is the third most lethal cancer worldwide, and evaluation of the genomic status of gastric cancer cells has not translated into effective prognostic or therapeutic strategies.We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), in particular, cancerassociated fibroblasts (CAF). However, very little is known about the role of CAFs in gastric cancer. To address this, we mapped the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from patients with gastric cancer. A stromal gene signature was associated with poor disease outcome, and the transcription factor heat shock factor 1 (HSF1) regulated the signature. HSF1 upregulated inhibin subunit beta A and thrombospondin 2, which were secreted in CAF-derived extracellular vesicles to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment. Significance: This study shows how HSF1 regulates a stromal transcriptional program associated with aggressive gastric cancer and identifies multiple proteins within this program as candidates for therapeutic intervention. better understand the molecular basis of this disease, and to identify 48 biomarkers that may predict outcome and guide therapy.49 Gastric cancer is a heterogeneous disease. Traditionally, anatomical 50 location (true gastric vs. gastro-esophageal) and histologic character-51 istics (diffuse vs. intestinal; tubular vs. papillary) have been used to 52 classify gastric cancer subtypes (2). Recent advances in molecular 53 understanding have enabled classification of gastric cancer into dif-54 ferent subtypes based on chromosomal instability, microsatellite 55 instability, genomic stability, presence of Epstein-Barr virus, and 56 epithelial-mesenchymal transition (EMT), which were associated with 57 different survival outcomes (3-6). Mutations in CDH1 and KRAS, and 58 overexpression of HER2, EGFR, FGFR2, VEGF, were shown to 59 contribute to disease progression and correlate with poor out-60 come (7, 8). Despite serving as valuable guides in deciphering the 61 complexity of gastric cancer, there has been little success in applying 62 these molecular classifiers to treatment stratification and development 63 of targeted therapies (3). Prognosis in the clinic is still mostly evaluated 64 on the basis of TNM staging (tumor size, lymph node involvement, and 65 metastasis), and the standard of care for localized gastric cancer is 66 surgical intervention combined with chemotherapy (7). 67 Increasing evidence over the past decade highlighted the indispens-68 able contribution of the tumor microenvironment (TME) to disease 69 progression and treatment resistance (9). The TME is comprised of 70 various cell types, including endothelial cells, fibroblasts, macro-71 phages, and lymphocytes, as well as extracellular matrix co...

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.

Estimating VE using a moving age window as well as weekly VE analysis may provide more detailed information regarding the relationship between VE and age.