Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer

Tubulin is the target for very widely used anti-tumor drugs, including Vinca alkaloids, taxanes, and epothilones, which are an important component of chemotherapy in breast cancer and other malignancies. Paclitaxel and other tubulin-targeting drugs bind to the β subunit of tubulin, which is a heterodimer of α and β subunits. β-Tubulin exists in the form of multiple isotypes, which are differentially expressed in normal and neoplastic cells and differ in their ability to bind to drugs. Among them, the βIII isotype is overexpressed in many aggressive and metastatic cancers and may serve as a prognostic marker in certain types of cancer. The underpinning mechanisms accounting for the overexpression of this isotype in cancer cells are unclear. To better understand the role of β-tubulin isotypes in cancer, we analyzed over 1000 clones from 90 breast cancer patients, sequencing their β-tubulin isotypes, in search of novel mutations. We have elucidated two putative emerging molecular subgroups of invasive breast cancer, each of which involve mutations in the βI-, βIIA-, or βIVB isotypes of tubulin that increase their structural, and possibly functional, resemblance to the βIII isotype. A unifying feature of the first of the two subgroups is the mutation of the highly reactive C239 residue of βI- or βIVB-tubulin to L239, R239, Y239, or P239, culminating in probable conversion of these isotypes from ROS-sensitive to ROS-resistant species. In the second subgroup, βI, βIIA, and βIVB have up to seven mutations to the corresponding residues in βIII-tubulin. Given that βIII-tubulin has emerged as a pro-survival factor, overexpression of this isotype may confer survival advantages to certain cancer cell types. In this mini-review, we bring attention to a novel mechanism by which cancer cells may undergo adaptive mutational changes involving alternate β-tubulin isotypes to make them acquire some of the pro-survival properties of βIII-tubulin. These “hybrid” tubulins, combining the sequences and/or properties of two wild-type tubulins (βIII and either βI, βIIA, or βIVB), are novel isotypes expressed solely in cancer cells and may contribute to the molecular understanding and stratification of invasive breast cancer and provide novel molecular targets for rational drug development.     

Family Life and Social Medicine: Discourses and Discontents Surrounding Puebla’s Psychiatric Care

Drawing on clinical data from 15 months of on-site participant observation in the only public psychiatric hospital in the state of Puebla, Mexico, this article advances our understanding of globalization in relation to psychiatry. I challenge the construction of psychiatry as only treating the individual patient and provide grounded doctor-patient-family member interaction in a Mexican psychiatric clinic in order to review what happens when doctors cannot interact with patients as atomized individuals even though in theory they are trained to think of patients that way. Challenged by severe structural constraints and bolstered by lessons from other nations’ efforts at deinstitutionalization, psychiatrists in Puebla push to keep patients out of the inpatient wards and in their respective communities. To this end, psychiatrists call upon co-present kin who are identified both as the customer and part of the caretaking system outside the clinic. This modification to the visit structure changes the dynamic and content of clinical visits while doctors seamlessly respond to unspoken beliefs and values that are central to local life, ultimately showing that efforts to define a “global psychiatry” informed by global policy will fail because it cannot exist in a uniform way—interpersonal interaction and personal experience matters.     

Intracoronary allogeneic cardiosphere‐derived stem cells are safe for use in dogs with dilated cardiomyopathy

Cardiosphere‐derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non‐ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c‐kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.     

Ecosystem size predicts eco‐morphological variability in a postglacial diversification

Identifying the processes by which new phenotypes and species emerge has been a long‐standing effort in evolutionary biology. Young adaptive radiations provide a model to study patterns of morphological and ecological diversification in environmental context. Here, we use the recent radiation (ca. 12k years old) of the freshwater fish Arctic charr (Salvelinus alpinus) to identify abiotic and biotic environmental factors associated with adaptive morphological variation. Arctic charr are exceptionally diverse, and in postglacial lakes there is strong evidence of repeated parallel evolution of similar morphologies associated with foraging. We measured head depth (a trait reflecting general eco‐morphology and foraging ecology) of 1,091 individuals across 30 lake populations to test whether fish morphological variation was associated with lake bathymetry and/or ecological parameters. Across populations, we found a significant relationship between the variation in head depth of the charr and abiotic environmental characteristics: positively with ecosystem size (i.e., lake volume, surface area, depth) and negatively with the amount of littoral zone. In addition, extremely robust‐headed phenotypes tended to be associated with larger and deeper lakes. We identified no influence of co‐existing biotic community on Arctic charr trophic morphology. This study evidences the role of the extrinsic environment as a facilitator of rapid eco‐morphological diversification.     

DIFFERENTIAL MOVEMENTS BY HARBOR SEAL PUPS IN CONTRASTING ALASKA ENVIRONMENTS

Movement patterns of Alaska harbor seal pups were studied using satellite telemetry during 1997–2000. Mean tracking duration was 277.3 d (SD = 105.8) for Tugidak Island pups ( n = 26) and 171.2 d (108.3) for Prince William Sound (PWS) pups ( n = 27). Movements were similar for males and females and were largely restricted to the continental shelf. Multiple return trips of > 75 km from the natal area and up to ∼3 wk duration were most common, followed by movements restricted to <25 km from the natal area; one way movements from the natal site were rare. Distances moved and home range sizes remained relatively stable or increased gradually from July through winter, then decreased markedly through spring. Monthly movements (maximum distance from tagging location, mean distance from haul-outs to at-sea locations, and home range size) were significantly greater for Tugidak vs . PWS pups. Six of seven pups from each region that traveled farthest and were tracked the longest had returned to their tagging site when their last location was recorded, indicating philopatry or limited dispersal during their first year of life. Seal pups exhibited similar movement patterns in the distinct habitats of the two regions, but differed in the spatial extent of their movements.     

Heterologous expression of Mytilus californianus foot protein three (Mcfp-3) in Kluyveromyces lactis

Mytilus californianus foot protein three (Mcfp-3) was successfully expressed in the yeast, Kluyveromyces lactis. The first nine amino acids (YPYDVPDYA) from the human-influenza-virus hemagglutinin (HA) protein were fused to the amino terminus of Mcfp-3 (HA-Mcfp-3) to facilitate identification and purification. HA-Mcfp-3 was purified to a concentration of 1mg/L using HA affinity chromatography. The recovered polypeptide was resolved by SDS-PAGE and migrated primarily at 36 kDa, an increase of approximately 29 kDa over the calculated molecular weight of a HA-Mcfp-3 monomer. Significantly, release of Mcfp-3 by enterokinase treatment coincided with the formation of high molecular weight complexes. It is noteworthy that the complexes mimicked the previously reported insolubility of Mcfps found in vivo to denaturing and reducing conditions. These data demonstrate the successful expression of Mcfp-3 in K. lactis and show an intrinsic ability of Mcfp-3 to self-assemble into stable, higher molecular weight forms.