Distribution and Impacts of Tasmanian Devil Facial Tumor Disease

The Tasmanian devil, Sarcophilus harrisii, is the largest extant marsupial carnivore. In 1996, a debilitating facial tumor was reported. It is now clear that this is an invariably lethal infectious cancer. The disease has now spread across the majority of the range of the species and is likely to occur across the entire range within 5 to 10 years. The disease has lead to continuing declines of up to 90% and virtual disappearance of older age classes. Mark-recapture analysis and a preliminary epidemiological model developed for the population with the best longitudinal data both project local extinction in that area over a timeframe of 10 to 15 years from disease emergence. However, the prediction of extinction from the model is sensitive to the estimate of the latent period, which is poorly known. As transmission appears to occur by biting, much of which happens during sexual encounters, the dynamics of the disease may be typical of sexually transmitted diseases. This means that transmission is likely to be frequency-dependent with no threshold density for disease maintenance. Extinction over the entire current range of the devil is therefore a real possibility and an unacceptable risk.     

Conservation Management of Tasmanian Devils in the Context of an Emerging, Extinction-threatening Disease: Devil Facial Tumor Disease

An emerging infectious facial cancer threatens Tasmanian devils with extinction. The disease is likely to occur across the range of the devil within 5 years. This urgent time frame requires management options that can be implemented immediately: the establishment of insurance populations, in captivity, wild-living on islands, and aiming for eradication in areas that can be isolated. The long-term options of the spontaneous or assisted evolution of resistance or development of a field-deliverable vaccine are unlikely to be available in time. The disease’s characteristic allograft transmission through intimate contact simplifies isolation of insurance populations and breaking transmission in suppression trials. Better knowledge of contact matrices in wild devils will help focus timing and demographic targets of removals. A metapopulation approach is needed that integrates captive and wild-living island and peninsula (disease suppression) populations to minimize the loss of genetic diversity over 50 years until either extinction and reintroduction can occur, resistance evolves or a field-deliverable vaccine is developed. Given the importance of the insurance populations and the low genetic diversity of devils, a conservative target for retention of 95% genetic diversity is recommended. Encouraging preliminary results of the first disease-suppression trial on a large peninsula show fewer late stage tumors and no apparent population decline. Limiting geographic spread or suppressing the disease on a broadscale are both unlikely to be feasible. Since the synergy of devil decline and impending fox establishment could have devastating consequences for Tasmanian wildlife, it is crucial to manage the dynamics of new and old predator species together.     

The Immune Response of the Tasmanian Devil (Sarcophilus harrisii) and Devil Facial Tumour Disease

One of the most remarkable aspects of Devil Facial Tumour Disease (DFTD) is its infectious nature, and for successful transmission it must avoid detection by the devil’s immune system. For this to occur, the devil either is severely immunosuppressed or factors produced by the tumor contribute to its avoidance of immune detection. An analysis of the devil’s immune system revealed the presence of normal-looking lymphoid organs and lymphoid cells. At a functional level the lymphocytes proliferated in response to mitogen stimulation. Subcutaneous injection of a cellular antigen produced a strong antibody response, providing compelling evidence that the devil has a competent immune system. Tumor cell analysis demonstrated that the tumor expresses the genes of the major histocompatibility complex; however, there was a limited diversity. Therefore, the most likely explanation for devil-to-devil transmission of DFTD is that the tumor is not recognized by the devil as “non-self” because of the limited genetic diversity. With its consistent morphology and relatively stable genome, this tumor would provide a reasonable target for a vaccine approach, provided the immune system can be coaxed into recognizing the tumor as “non-self.”     

Detecting Selection on Temporal and Spatial Scales: A Genomic Time-Series Assessment of Selective Responses to Devil Facial Tumor Disease

Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cancer—devil facial tumor disease (DFTD)—that since 1996 has ravaged the Tasmanian devil (Sarcophilus harrisii). Using time-series ‘restriction site associated DNA’ (RAD) markers from populations pre- and post DFTD arrival, and DFTD free populations, we infer loci under selection due to DFTD and investigate signatures of selection that are incongruent among methods, populations, and times. The lack of congruence among populations influenced by DFTD with respect to inferred loci under selection, and the direction of that selection, fail to implicate a consistent selective role for DFTD. Instead genetic drift is more likely driving the observed allele frequency changes over time. Our study illustrates the importance of applying methods with different performance optima e.g. accounting for population structure and background selection, and assessing congruence of the results.     

Vincristine in the Treatment of Neoplastic Disease

Seventy-eight patients with advanced malignant disease were treated with vincristine, an alkaloid derived from Vinca rosea Linn. Fifty-nine of these survived one month from the beginning of treatment and could be evaluated. Twenty made a good response, with return to activity and more than 75% regression of tumour deposits. Seven made a fair response with resumption of partial activity and at least a 25% regression of tumour deposits. Favourable results were seen in patients with Hodgkin''s disease, reticulum cell sarcoma, lymphosarcoma, carcinoma of the breast, acute leukemia and choriocarcinoma. The duration of remission was usually brief but in five instances exceeded six months. Toxic reactions include a high incidence of alopecia and neurologic complications. The bone marrow depression is constant and predictable.     

Extreme Telomere Length Dimorphism in the Tasmanian Devil and Related Marsupials Suggests Parental Control of Telomere Length

Telomeres, specialised structures that protect chromosome ends, play a critical role in preserving chromosome integrity. Telomere dynamics in the Tasmanian devil (Sarcophilus harrisii) are of particular interest in light of the emergence of devil facial tumour disease (DFTD), a transmissible malignancy that causes rapid mortality and threatens the species with extinction. We used fluorescent in situ hybridisation to investigate telomere length in DFTD cells, in healthy Tasmanian devils and in four closely related marsupial species. Here we report that animals in the Order Dasyuromorphia have chromosomes characterised by striking telomere length dimorphism between homologues. Findings in sex chromosomes suggest that telomere length dimorphism may be regulated by events in the parental germlines. Long telomeres on the Y chromosome imply that telomere lengthening occurs during spermatogenesis, whereas telomere diminution occurs during oogenesis. Although found in several somatic cell tissue types, telomere length dimorphism was not found in DFTD cancer cells, which are characterised by uniformly short telomeres. This is, to our knowledge, the first report of naturally occurring telomere length dimorphism in any species and suggests a novel strategy of telomere length control. Comparative studies in five distantly related marsupials and a monotreme indicate that telomere dimorphism evolved at least 50 million years ago.     

Residual Tumor Cells That Drive Disease Relapse after Chemotherapy Do Not Have Enhanced Tumor Initiating Capacity

Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs) have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs). We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell’s ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell’s ability to drive disease recurrence.     

EGFR靶向药物与化疗联合治疗恶性肿瘤进展

表皮生长因子受体(epidermal growth factor receptor EGFR)可以在多种恶性肿瘤细胞中表达,针对此靶点的靶向药物主要有单克隆抗体及酪氨酸激酶抑制剂(tyrosine kinase inhibitors TKIs)。本文通过广泛查阅国内外相关文献,对EGFR靶向药物机制及其与传统化疗药物联合应用从基础研究到临床研究进行综述,讨论二者联合应用的前景及研究方向。     

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkin''s disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin''s disease is strongly recommended.     

肠内营养联合复方氨基酸在恶性肿瘤患者化疗中的应用

为了观察肠内营养(EN)支持治疗联合复方氨基酸在恶性肿瘤化疗患者中的临床疗效及并建立相关护理方法,将68例恶性肿瘤化疗患者随机分为治疗组和对照组,每组34例,治疗组给予肠内营养支持治疗联合复方氨基酸治疗,对照组给予常规处理。对两组病人治疗前后进行生化指标监测、记录不良反应以及进行营养评估。研究结果显示,治疗组与对照组比较,人体测量值增加,血清清蛋白升高,两组比较有显著性差异(p<0.05)。本研究表明,肠内营养(EN)支持治疗联合复方氨基酸对于改善恶性肿瘤化疗病人的营养状况效果明显,并且可以提高患者对化疗的耐受力、增强免疫功能。     

Automated Tracking of Quantitative Assessments of Tumor Burden in Clinical Trials

There are two key challenges hindering effective use of quantitative assessment of imaging in cancer response assessment: 1) Radiologists usually describe the cancer lesions in imaging studies subjectively and sometimes ambiguously, and 2) it is difficult to repurpose imaging data, because lesion measurements are not recorded in a format that permits machine interpretation and interoperability. We have developed a freely available software platform on the basis of open standards, the electronic Physician Annotation Device (ePAD), to tackle these challenges in two ways. First, ePAD facilitates the radiologist in carrying out cancer lesion measurements as part of routine clinical trial image interpretation workflow. Second, ePAD records all image measurements and annotations in a data format that permits repurposing image data for analyses of alternative imaging biomarkers of treatment response. To determine the impact of ePAD on radiologist efficiency in quantitative assessment of imaging studies, a radiologist evaluated computed tomography (CT) imaging studies from 20 subjects having one baseline and three consecutive follow-up imaging studies with and without ePAD. The radiologist made measurements of target lesions in each imaging study using Response Evaluation Criteria in Solid Tumors 1.1 criteria, initially with the aid of ePAD, and then after a 30-day washout period, the exams were reread without ePAD. The mean total time required to review the images and summarize measurements of target lesions was 15% (P < .039) shorter using ePAD than without using this tool. In addition, it was possible to rapidly reanalyze the images to explore lesion cross-sectional area as an alternative imaging biomarker to linear measure.We conclude that ePAD appears promising to potentially improve reader efficiency for quantitative assessment of CT examinations, and it may enable discovery of future novel image-based biomarkers of cancer treatment response.     

Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials

The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.     

Disease and the devil: density-dependent epidemiological processes explain historical population fluctuations in the Tasmanian devil

Australia's last mega-carnivore marsupial, the Tasmanian devil Sarcophilus harrisii , Dasyuridae is endemic to the island state of Tasmania. The recent appearance and rapid spread of a debilitating and usually lethal, cancer-like disease has raised concerns regarding the species' future. We used a demographic matrix modelling approach to evaluate the potential long-term implications of epidemics on this population. Both adult survival and temporally autocorrelated re-occurrence of disease were expressed as a function of female abundance. Large fluctuations in abundance resulted when disease outbreaks were conditioned to be density-dependent; however, this resulted in a low probability of quasi-extinction due to the dissipation of disease transmission at low densities. Epidemic stochasticity alone in an otherwise deterministic model resulted in major population cycles occurring every 77–146 yr, consistent with historical reports. Although epidemics in this species may not result in extinction directly, the contemporary presence of additional mortality sources during periods of low abundance may increase extinction risk.