Pancreatic undifferentiated carcinoma with osteoclast‐like giant cells is genetically similar to,but clinically distinct from,conventional ductal adenocarcinoma

Undifferentiated carcinoma of the pancreas with osteoclast‐like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well‐defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Neural activity patterns evoked by a spouse's incongruent emotional reactions when recalling marriage‐relevant experiences

Resonance with the inner states of another social actor is regarded as a hallmark of emotional closeness. Nevertheless, sensitivity to potential incongruities between one's own and an intimate partner's subjective experience is reportedly also important for close relationship quality. Here, we tested whether perceivers show greater neurobehavioral responsiveness to a spouse's positive (rather than negative) context‐incongruent emotions, and whether this effect is influenced by the perceiver's satisfaction with the relationship. Thus, we used fMRI to scan older long‐term married female perceivers while they judged either their spouse's or a stranger's affect, based on incongruent nonverbal and verbal cues. The verbal cues were selected to evoke strongly polarized affective responses. Higher perceiver marital satisfaction predicted greater neural processing of the spouse's (rather than the strangers) nonverbal cues. Nevertheless, across all perceivers, greater neural processing of a spouse's (rather than a stranger's) nonverbal behavior was reliably observed only when the behavior was positive and the context was negative. The spouse's positive (rather than negative) nonverbal behavior evoked greater activity in putative mirror neuron areas, such as the bilateral inferior parietal lobule (IPL). This effect was related to a stronger inhibitory influence of cognitive control areas on mirror system activity in response to a spouse's negative nonverbal cues, an effect that strengthened with increasing perceiver marital satisfaction. Our valence‐asymmetric findings imply that neurobehavioral responsiveness to a close other's emotions may depend, at least partly, on cognitive control resources, which are used to support the perceiver's interpersonal goals (here, goals that are relevant to relationship stability). Hum Brain Mapp 36:4164–4183, 2015. © 2015 Wiley Periodicals, Inc.     

Dynamics of gene circuits shapes evolvability

To what extent does the dynamical mechanism producing a specific biological phenotype bias the ability to evolve into novel phenotypes? We use the interpretation of a morphogen gradient into a single stripe of gene expression as a model phenotype. Although there are thousands of three-gene circuit topologies that can robustly develop a stripe of gene expression, the vast majority of these circuits use one of just six fundamentally different dynamical mechanisms. Here we explore the potential for gene circuits that use each of these six mechanisms to evolve novel phenotypes such as multiple stripes, inverted stripes, and gradients of gene expression. Through a comprehensive and systematic analysis, we find that circuits that use alternative mechanisms differ in the likelihood of reaching novel phenotypes through mutation. We characterize the phenotypic transitions and identify key ingredients of the evolutionary potential, such as sensitive interactions and phenotypic hubs. Finally, we provide an intuitive understanding on how the modular design of a particular mechanism favors the access to novel phenotypes. Our work illustrates how the dynamical mechanism by which an organism develops constrains how it can evolve. It is striking that these dynamical mechanisms and their impact on evolvability can be observed even for such an apparently simple patterning task, performed by just three-node circuits.Evolution occurs through mutations on existing genotypes, potentially transforming the original phenotype or trait into a novel one, with latent beneficial consequences. It is a fundamental problem in biology to understand the relationship between a genotype and the associated phenotypes accessible through mutations, in other words, its evolvability. From the many definitions of evolvability (1, 2), we refer here to the ability of genotypes to access novel phenotypes, irrespective of the subsequent process of natural selection.To understand how a phenotype evolves we need to consider that a huge number of distinct genotypes can achieve that same phenotype. For example, hundreds of distinct RNA sequences fold in the same secondary structure (3), as do proteins in their 3D structure (4). Similarly, distinct gene regulatory architectures can produce the same gene expression pattern (5, 6) or temporal behavior (7, 8). However, among these genotypes, some are more evolvable than others. The existing studies have targeted two key drivers of evolvability: a genotype’s design and a genotype’s location within a neutral space.A first class of studies focuses on a circuit’s general architectural features, such as feed-back or feed-forward loops, revealing that these distinct families of designs or motifs differ in their evolvability (9, 10). The second class of studies centers not on single designs but on the whole collection of genotypes capable of producing the same phenotype. These genotypes with a common phenotype form a region in genotype space termed a neutral space or neutral network (3), as mutations within this region produce no change in the phenotype.As revealed by many studies, the existence of neutral spaces has two major consequences to the evolutionary process. First, these neutral spaces often appear as fully connected and dense regions (11–13). Therefore, although genotypes internal to the neutral space are highly robust to mutations (i.e., not evolvable), only genotypes close to the edges of the neutral space might access novel phenotypes. From this perspective, neutral mutations and thus the process of neutral drift can generate cryptic genetic variation (14) by moving a species closer to the edges of the neutral space into a more evolvable state (12, 15). Second, different positions in genotype space give access to distinct novel phenotypes. Large neutral spaces percolate through genotype space, providing access to a diversity of novel phenotypes from different genotypes (11–13). In a nutshell, the accessible innovations are critically determined by a genotype’s position in genotype space (16) (Fig. 1).Open in a separate windowFig. 1.Phenotype-based view on evolvability. (A) Evolvability accounts for the accessible novel phenotypes, whereas developmental constraints imply that certain hypothetical forms are not possible: phenotype 2 (purple) is not available by gradual mutation. (B) Innovations accessible from a given genotype constitute its phenotypic neighborhood. The arrangement and diversity of this neighborhood is a measure of the genotype’s evolvability (16). Genotype space is high dimensional, but we schematically represent it here in 2D for illustrative purposes.Although the abovementioned features of genotype-phenotype maps have been much studied, another important aspect of the system has thus far been neglected. None of the existing studies addressed the impact of the underlying dynamical mechanism of a gene circuit on its evolvability. By mechanism, we mean the causal dynamics responsible for the trajectory of the system (i.e., the spatiotemporal course of gene expression) resulting in the final phenotype. In addition to the increasing awareness that dynamics itself is a decisive property of gene circuits (17), several specific observations led us to hypothesize that dynamics does impact on evolvability.First, to achieve a given biological function, a gene circuit uses one of few fundamental solutions referred to as dynamical mechanisms (5–7, 18–20). More specifically, circuits with the same underlying dynamical mechanism share a common arrangement of phase portraits (20, 21). Second, Cotterell and Sharpe (6) revealed that, for a simple patterning function, it is not possible to smoothly and functionally transition from one mechanism to another. That is, in contrast to the common view (11–13), this particular neutral space does not form a single fully connected region when the underlying mechanism is taken into account. Instead, the neutral space for the simple patterning function studied by Cotterell and Sharpe (6) breaks up into scattered islands of genotypes characterized by distinct underlying mechanisms. These observations suggest that evolvability may be constrained specifically by the dynamical mechanism of the gene circuit. As neutral spaces can be broken up into a discrete collection of separated islands, the process of neutral drift may be limited to these mechanism-specific regions.To assess the impact of dynamical mechanisms, we chose to study circuits that control spatial (multicellular) gene expression patterns. It is well established in developmental biology that the spatial organization of gene expression orchestrates cell differentiation. Their diversification causes evolution of both modest morphological traits, such as novel pigmentation patterns (22), and major evolutionary breakthroughs, such as new body structures (23). Here we chose to address the interpretation of a morphogen gradient by a field of cells into different cell fates (5–7, 18, 24–27) (Fig. 2A), a critical patterning event in embryo’s morphogenesis (28). We build on the work of Cotterell and Sharpe (6), who extracted six fundamental mechanisms for this patterning task: Bistable, Incoherent feed-forward, Mutual Inhibition, Overlapping Domains, Classical, and Frozen Oscillator (Fig. 2B and SI Appendix, Fig. S1).Open in a separate windowFig. 2.Alternative mechanisms to achieve a single phenotype. (A) Within the French Flag conceptual framework, a preestablished fixed concentration gradient (input) is interpreted by a one-dimensional row of cells into different cell fates through a threshold-dependent mechanism. Additionally, cells communicate to one another through diffusive gene products (dashed arrows). We exhaustively enumerate all possible three-gene circuit topologies and sample large numbers of genotypes (i.e., parameter values; SI Appendix, Methods). Solutions of our search are genotypes able to interpret the morphogen gradient into a band of gene expression (6). Similar exhaustive approaches have being adopted for exploring a variety of biological functions, such as temporal behaviors (7, 25) or other spatial patterning functions (5, 18). (B) A stripe-forming circuit uses one of six distinct mechanisms (6), each mechanism uses a distinct gene expression dynamics in space and time to reach the same phenotype. Importantly, Mutual Inhibition (bicoid-hunchback-knirps), Incoherent feed-forward (caudal-knirps-giant), and Classical (hunchback-krüppel-knirps) are involved in Drosophila anterior-posterior patterning (26), whereas Incoherent feed-forward controls the mesoderm inducer Xenopus Brachyury (27).For the current study, we analyzed each of these six mechanisms independently and obtained a mechanism-specific measure of evolvability. We found that, indeed, the likelihood of accessing distinct phenotypic innovations is different for each dynamical mechanism, despite the fact that they all produce the same phenotype. Our analysis uncovers key features of the mechanistic neutral spaces and provides useful insight into how phenotypic transitions and thus innovations occur.     

Molecular Confirmation of t(6;11)(p21;q12) Renal Cell Carcinoma in Archival Paraffin-embedded Material Using a Break-apart TFEB FISH Assay Expands its Clinicopathologic Spectrum

A subset of renal cell carcinomas (RCCs) is characterized by t(6;11)(p21;q12), which results in fusion of the untranslated Alpha (MALAT1) gene to the TFEB gene. Only 21 genetically confirmed cases of t(6;11) RCCs have been reported. This neoplasm typically demonstrates a distinctive biphasic morphology, comprising larger epithelioid cells and smaller cells clustered around basement membrane material; however, the full spectrum of its morphologic appearances is not known. The t(6;11) RCCs differ from most conventional RCCs in that they consistently express melanocytic immunohistochemical (IHC) markers such as HMB45 and Melan A and the cysteine protease cathepsin K but are often negative for epithelial markers such as cytokeratins. TFEB IHC has been proven to be useful to confirm the diagnosis of t(6;11) RCCs in archival material, because native TFEB is upregulated through promoter substitution by the gene fusion. However, IHC is highly fixation dependent and has been proven to be particularly difficult for TFEB. A validated fluorescence in situ hybridization (FISH) assay for molecular confirmation of the t(6;11) RCC in archival formalin-fixed, paraffin-embedded material has not been previously reported. We report herein the development of a break-apart TFEB FISH assay for the diagnosis of t(6;11)(p21;q12) RCCs. We validated the assay on 4 genetically confirmed cases and 76 relevant expected negative control cases and used the assay to report 8 new cases that expand the clinicopathologic spectrum of t(6;11) RCCs. An additional previously reported TFEB IHC-positive case was confirmed by TFEB FISH in 46-year-old archival material. In conclusion, TFEB FISH is a robust, clinically validated assay that can confirm the diagnosis of t(6;11) RCC in archival material and should allow a more comprehensive clinicopathologic delineation of this recently recognized neoplastic entity.     

Hantavirus infection—Hemorrhagic fever with renal syndrome: the first case series reported in Romania and review of the literature

Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic infectious disease caused by Hantaviruses, a group of RNA viruses belonging to the Bunyaviridae family. Humans may get the disease by contamination with excreta of carrier rodents. The disease typically manifests with the triad fever-thrombocytopenia-acute kidney injury (AKI). Although its global prevalence seems to be increasing, Hantavirus infection is still commonly overlooked, because of its clinical polymorphism and non-specific symptoms, particularly in mild cases. Until recently, the disease was virtually unknown in Romania, due to lack of physicians' awareness and of adequate laboratory diagnostic techniques. In this article, we present the first six cases of HFRS diagnosed in our country, based on serology testing. We review the existing literature on HFRS and discuss our findings in comparison with other reports. All our patients presented with fever, flu syndrome, bleeding, gastrointestinal symptoms, and oliguria. Among laboratory abnormalities, elevated serum creatinine and liver enzymes, high C-reactive protein, leukocytosis, low platelet count, and hematuria were constantly seen. Five patients required hemodialysis. All patients survived and five of them completely recovered their renal function, while only one patient retained a mild impairment of the glomerular filtration rate. From a clinical viewpoint, we believe that Hantavirus infection should be considered in all patients presenting with fever, thrombocytopenia, and AKI, when specific serology testing would be indicated. From a public health perspective, we suggest that future efforts in our country should be directed toward (1) increasing the understanding and the awareness of this disease among health care professionals, (2) educating the population at risk on the application of prophylactic measures, (3) expanding the availability of diagnostic laboratory tools, and (4) developing research on national zoonotic virus reservoirs.