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Epithelial to mesenchymal transition (EMT) has been hypothesized as a mechanism by which cells change phenotype during carcinogenesis, as well as tumor metastasis. Whether EMT is involved in cancer metastasis has a specific, practical impact on the field of circulating tumor cells (CTCs). Since the generally accepted definition of a CTC includes the expression of epithelial surface markers, such as EpCAM, if a cancer cell loses its epithelial surface markers (which is suggested in EMT), it will not be separated and/or identified as a CTC. We have developed, and previously reported on the use of, a purely negative enrichment technology enriching for CTCs in the blood of squamous cell carcinoma of the head and neck (SCCHN). This methodology does not depend on the expression of surface epithelial markers. Using this technology, our initial data on SCCHN patient blood indicates that the presence of CTCs correlates with worse disease-free survival. Since our enrichment is not dependent on epithelial markers, we have initiated investigation of the presence of mesenchymal markers in these CTC cells to include analysis of: vimentin, epidermal growth factor receptor, N-cadherin, and CD44. With the aid of confocal microscopy, we have demonstrated not only presumed CTCs that express and/or contain: a nucleus, cytokeratins, vimentin, and either EGFR, CD44, or N-cadherin, but also cells that contain all of the aforementioned proteins except cytokeratins, suggesting that the cells have undergone the EMT process. We suggest that our negative depletion enrichment methodology provides a more objective approach in identifying and evaluating CTCs, as opposed to positive selection approaches, as it is not subjective to a selection bias and can be tailored to accommodate a variety of cytoplasmic and surface markers which can be evaluated to identify a multitude of phenotypic patterns within CTCs from individual patients, including so-called EMT as presented here.

It has been argued that disproportionately larger ornaments in bigger males—positive allometry—is the outcome of sexual selection operating on the size of condition dependent traits. We reviewed the literature and found a general lack of empirical testing of the assumed link between female preferences for large ornaments and a pattern of positive allometry in male ornamentation. We subsequently conducted a manipulative experiment by leveraging the unusual terrestrial fish, Alticus sp. cf. simplicirrus, on the island of Rarotonga. Males in this species present a prominent head crest to females during courtship, and the size of this head crest in the genus more broadly exhibits the classic pattern of positive allometry. We created realistic male models standardized in body size but differing in head crest size based on the most extreme allometric scaling recorded for the genus. This included a crest size well outside the observed range for the study population (super-sized). The stimuli were presented to free-living females in a manner that mimicked the spatial distribution of courting males. Females directed greater attention to the male stimulus that exhibited the super-sized crest, with little difference in attention direct to other size treatments. These data appear to be the only experimental evidence from the wild of a female preference function that has been implicitly assumed to drive selection that results in the evolution of positive allometry in male ornamentation.

Background Whether natural selection can erase the imprint of past evolutionary history from phenotypes has been a topic of much debate. A key source of evidence that present-day selection can override historically contingent effects comes from the repeated evolution of similar adaptations in different taxa. Yet classic examples of repeated evolution are often among closely related taxa, suggesting the likelihood that similar adaptations evolve is contingent on the length of time separating taxa. To resolve this, we performed a meta-analysis of published reports of repeated evolution. Results Overall, repeated evolution was far more likely to be documented among closely related than distantly related taxa. However, not all forms of adaptation seemed to exhibit the same pattern. The evolution of similar behavior and physiology seemed frequent in distantly related and closely related taxa, while the repeated evolution of morphology was heavily skewed towards closely related taxa. Functionally redundant characteristics—alternative phenotypes that achieve the same functional outcome—also appeared less contingent. Conclusions If the literature provides a reasonable reflection of the incidence of repeated evolution in nature, our findings suggest that natural selection can overcome contingent effects to an extent, but it depends heavily on the aspect of the phenotype targeted by selection.

The increasing potential for accidental radiation exposure from either nuclear accidents or terrorist activities has escalated the need for radiation countermeasure development. We previously showed that a 30-day course of high-dose captopril, an ACE inhibitor, initiated 1–4 h after total body irradiation (TBI), improved Hematopoietic Acute Radiation Syndrome (H-ARS) and increased survival in mice. However, because of the time likely required for the deployment of a stockpiled radiation countermeasure to a radiation mass casualty site, there is a need for therapies that can be administered 24–48 hours after initial exposure. Using C57BL/6 mice exposed to an LD 50-80/30 of 60 Co TBI (7.75–7.9 Gy, 0.615 Gy/min), we show that low-dose captopril administration, initiated as late as 48 h post-TBI and continued for 14 days, significantly enhanced overall survival similarly to high-dose, rapid administration. Captopril treatment did not affect radiation-induced cell cycle arrest genes or the immediate loss of hematopoietic precursors. Reduced mortality was associated with the recovery of bone marrow cellularity and mature blood cell recovery at 21–30 days post-irradiation. Captopril reduced radiation-induced cytokines EPO, G-CSF, and SAA in the plasma. Finally, delayed captopril administration mitigated brain micro-hemorrhage at 21 days post-irradiation. These data indicate that low dose captopril administered as late as 48 h post-TBI for only two weeks improves survival that is associated with hematopoietic recovery and reduced inflammatory response. These data suggest that captopril may be an ideal countermeasure to mitigate H-ARS following accidental radiation exposure.

The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M:F ratio; 20:13) and a median age of 32 years (range, 16–91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkin's lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations.

An ecological release from competition or predation is a frequent adaptive explanation for the colonization of novel environments, but empirical data are limited. On the island of Rarotonga, several blenny fish species appear to be in the process of colonizing land. Anecdotal observations have implied that aquatic predation is an important factor in prompting such amphibious fish behavior. We provide evidence supporting this hypothesis by demonstrating that amphibious blennies shift their abundance up and down the shoreline to remain above predatory fishes that periodically move into intertidal areas during high tide. A predation experiment using blenny mimics confirmed a high risk of aquatic predation for blennies, significantly higher than predation experienced on land. These data suggest that predation has played an active role in promoting terrestrial activity in amphibious blennies and provide a rare example of how ecological release from predation could drive the colonization of a novel environment.

The present studies evaluate the in vivo prophylactic radioprotective effects of 1-bromoacetyl-3, 3-dinitroazetidine (RRx-001), a phase III anticancer agent that inhibits c-myc and downregulates CD-47, after total body irradiation (TBI), in lethally and sublethally irradiated CD2F1 male mice. A single dose of RRx-001 was administered by intraperitoneal (IP) injection 24 h prior to a lethal or sublethal radiation dose. When irradiated with 9.35 Gy, the dose lethal to 70% of untreated mice at 30 days (LD 70/30 ), only 33% of mice receiving RRx-001 (10 mg/kg) 24 h prior to total body irradiation (TBI) died by day 30, compared to 67% in vehicle-treated mice. The same pretreatment dose of RRx-001 resulted in a significant dose reduction factor of 1.07. In sublethally TBI mice, bone marrow cellularity was increased at day 14 in the RRx-001-treated mice compared to irradiated vehicle-treated animals. In addition, significantly higher numbers of lymphocytes, platelets, percent hematocrit and percent reticulocytes were observed on days 7 and/or 14 in RRx-001-treated mice. These experiments provide proof of principle that systemic administration of RRx-001 prior to TBI significantly improves overall survival and bone marrow regeneration.

Anaplastic large cell lymphomas constitute a heterogeneous group of hematopoietic neoplasms that are characterized by immunopositivity for CD30 and the presence, in varying degrees, of large, pleomorphic “hallmark” cells. Primary systemic anaplastic lymphoma kinase-positive anaplastic large cell lymphomas are a subset of this group. Numerous heterogeneous histomorphologic patterns have been described in anaplastic lymphoma kinase-positive anaplastic large cell lymphomas, and all patterns tend to have a better prognosis than that found in anaplastic lymphoma kinase-negative cases. We provide a short review of the small cell variant of anaplastic large cell lymphoma to facilitate the diagnosis of this difficult-to-recognize entity, which may be confused with reactive processes, commonly presents with disseminated disease, and pursues an aggressive clinical course.

Allogeneic stem cell transplantation is currently the only curative therapy for primary myelofibrosis (MF), while the JAK2 inhibitor, ruxolitinib. Has been approved only for palliation. Other therapies are desperately needed to reverse life‐threatening MF. However, the cell(s) and cytokine(s) that promote MF remain unclear. Several reports have demonstrated that captopril, an inhibitor of angiotensin‐converting enzyme that blocks the production of angiotensin II (Ang II), mitigates fibrosis in heart, lung, skin and kidney. Here, we show that captopril can mitigate the development of MF in the Gata1low mouse model of primary MF. Gata1low mice were treated with 79 mg/kg/d captopril in the drinking water from 10 to 12 months of age. At 13 months of age, bone marrows were examined for fibrosis, megakaryocytosis and collagen expression; spleens were examined for megakaryocytosis, splenomegaly and collagen expression. Treatment of Gata1low mice with captopril in the drinking water was associated with normalization of the bone marrow cellularity; reduced reticulin fibres, splenomegaly and megakaryocytosis; and decreased collagen expression. Our findings suggest that treating with the ACE inhibitors captopril has a significant benefit in overcoming pathological changes associated with MF.