The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA ...gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Abiraterone is an important agent in the treatment of advanced prostate cancer. Early changes in prostate-specific antigen while on abiraterone in patients with metastatic castrate-resistant prostate ...cancer potentially have financial and health implications for patients. Limited data is available on early prostate-specific antigen change and subsequent survival given phase III trials did not measure prostate-specific antigen changes before 12 weeks.
A single-center retrospective study was performed. Metastatic castrate-resistant prostate cancer patients treated with abiraterone (without prior enzalutamide) at Tulane Cancer Center were reviewed with a focus on early prostate-specific antigen decline and relationship to overall survival.
A total of 110 patients were analyzed for prostate-specific antigen response of ≥ 30 and > 50% at 4, 8, and 12 weeks. A prostate-specific antigen response of either > 30% or > 50% at 4, 8, or 12 weeks was associated with improved overall survival at all time points except > 50% decline at 8 weeks. Multivariate analysis indicated, for all time points, that early prostate-specific antigen declines were predictive of overall survival. The neutrophil to lymphocyte ratio and docetaxel pretreatment also were predictive in many, but not all, of the multivariate analyses.
A > 30% or > 50% prostate-specific antigen decline at 4, 8, or 12 weeks provides important information regarding subsequent overall survival for patients with metastatic castrate-resistant prostate cancer. While these data require validation with a large, multi-institutional trial, they can provide physicians with information regarding prognosis and the timing of expected outcomes. These data affirms the notion that prostate-specific antigen responses as early as 4 weeks after abiraterone initiation can be used to inform both patients and physicians about metastatic castrate-resistant prostate cancer outcomes after initiating treatment with this important but costly therapeutic choice.
Biological confirmation of the presence of Vibrio cholerae in clinical and environmental samples is often constrained due to resource- and labor-intensive gold standard methods. To develop low-cost, ...simple, and sustainable surveillance techniques, we modified previously published specimen sampling and culture techniques and applied the use of enriched dipstick testing in conjunction with the use of filter paper for DNA specimen preservation during clinical and environmental surveillance in the Far North of Cameroon from August 2013 to October 2014. The enriched dipstick methodology during routine use in a remote setting demonstrated a specificity of 99.8% compared with polymerase chain reaction (PCR). The novel application of filter paper as a preservation method for cholera DNA specimens reduced the need for cold chain storage and allowed for PCR characterization and confirmation of V. cholerae. The application of basic technologies such as the enriched dipstick, the use of simplified gauze filtration for environmental sample collection, and the use of filter paper for sample preservation enabled early case identification with reduced logistics and supply cost while reporting minimal false-positive results. Simplified laboratory and epidemiological methodologies can improve the feasibility of cholera surveillance in rural and resource-constrained areas, facilitating early case detection and rapid response implementation.
Circulating tumor DNA (ctDNA), which can be assessed by liquid biopsy, can provide valuable genomic information that may affect treatment response in prostate cancer. The aim of this study was to ...characterize TP53 mutations and treatment history in prostate cancer.
This study included 143 patients with metastatic castration-resistant prostate cancer who had undergone ctDNA sequencing via Guardant360 testing. The presence or absence of TP53 mutations was analyzed along with treatment history for this group. TP53 mutations were further classified as gain of function (GOF) or not GOF, and analyzed with prior therapies.
Chi-square analysis was performed for treatment history and TP53 status (further specified as all TP53 mutations or only TP53 GOF mutations). There were no associations between prior receipt of abiraterone/enzalutamide therapy and all TP53 mutations, or between docetaxel therapy and all TP53 mutations. However, TP53 GOF mutations had a positive association with prior abiraterone/enzalutamide therapy (P = .047). There was no association of TP53 GOF mutations with prior docetaxel therapy. The most frequent alterations co-occurring with all TP53 mutations were in AR, BRAF, EGFR, MYC, and PIK3CA. Common coalterations with TP53 GOF mutations included AR, BRAF, EGFR, RB1, NF1, and PIK3CA. There was an association of RB1 mutations with TP53 GOF mutations, versus RB1 mutations and no TP53 GOF mutations (P = .0036).
TP53 GOF mutations may provide a valuable pathway to delineate metastatic castration-resistant prostate cancer TP53 mutations into therapeutic categories. Association with disease progression while receiving abiraterone/enzalutamide therapy was apparent in this study; however, further studies are needed to elaborate the therapeutic and prognostic implications.
Of the many genes involved in metastatic castration-resistant prostate cancer (mCRPC), TP53 is commonly altered and has a broad mutational landscape. We investigated TP53 in mCRPC using circulating tumor DNA from 143 patients with a variety of annotated treatment histories. TP53 gain-of-function mutations were associated with disease progression while receiving abiraterone/enzalutamide therapy, suggesting a potentially valuable therapeutic category of TP53 mutations in mCRPC.
Regulatory CD4+ T cells are important for the homeostasis of the immune system and their absence correlates with autoimmune disorders. Here, we investigate the capacity of IL-27, a cytokine with pro- ...and anti-inflammatory properties, to regulate the generation of transforming growth factor β (TGFβ)-inducible forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3, CD25 and CTLA-4 (CD152) expression as well as the suppressive function. In contrast to TGFβ-induced Treg cells, the cells generated after differentiation in the presence of TGFβ and IL-27 maintained the ability for IL-2 and tumour necrosis factor α (TNFα) production. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA), while STAT1-dependent signals seemed to oppose the STAT3 signals. In turn, TGFβ blocked IL-27-induced Th1 differentiation. Thus, IL-27 and TGFβ mutually control their effects on CD4+ T-cell differentiation, whereby IL-27 favours inflammatory conditions through a STAT3-dependent inhibition of Treg generation.
Like some species of pika (Ochotona) and tree squirrel (Tamiasciurus), the banner-tailed kangaroo rat (Dipodomys spectabilis) is a solitary, philopatric larder-hoarder that practices unisexual ...territoriality. Seeking to understand how this unusual combination of traits might influence the mating system, we used systematic trapping at mounds (burrows) and spool-and-line tracking to examine male and female visits to each other. Where genetic data exist, unisexual larder-hoarders such as D. spectabilis have been found to be polygynandrous. We asked whether the fact that females sometimes mate with more than 1 male is a passive side effect of imperfect mate defense by males, or whether females actively engage in behaviors that encourage multiple mating. During the nonbreeding season, adults of both sexes were rarely captured at mounds other than their own. In contrast, during the breeding season females as well as males were significantly more likely to be captured away from their home mounds, most often at mounds belonging to adults of the opposite sex. Spool-and-line tracking during the breeding season confirmed these results. Consistent with the expectation that they engage in competitive mate searching, adult males visited adult females' mounds significantly more than expected by chance and without regard to age, size, or relatedness. More surprisingly, adult females exhibited similar behavior, expanding their home ranges and disproportionately visiting the mounds of large adult males during the nights preceding estrus. Increased (and apparently directed) female mobility during the days preceding estrus may serve as a means of shaping the pool of competing mates and is worthy of more attention in this and other, ecologically similar species.
Spool-and-line tracking is an innovative and inexpensive way to record the movements of small mammals in a variety of habitats, and could have important applications for conservation related studies. ...However, the potential negative effects of the method have not been investigated. We document the effects of spool-and-line tracking on short-term change in body mass, recapture, and survival probability of banner-tailed kangaroo rats, Dipodomys spectabilis, in southeastern Arizona. We attached spools to D. spectabilis adults of both sexes during 3 y of varying environmental conditions, with total sample sizes of 90 experimental and 81 control animals. We did not attach spools to females in late pregnancy, and, to avoid entanglement, we did not attach spools to kangaroo rats located within 25 m of each other on the same night. We found no significant negative effects of spool attachment on body mass, survival, or recapture probability in either sex in any year.
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