Phylodynamics for cell biologists.

Multicellular organisms are composed of cells connected by ancestry and descent from progenitor cells. The dynamics of cell birth, death, and inheritance within an organism give rise to the fundamental processes of development, differentiation, and cancer. Technical advances in molecular biology now allow us to study cellular composition, ancestry, and evolution at the resolution of individual cells within an organism or tissue. Here, we take a phylogenetic and phylodynamic approach to single-cell biology. We explain how "tree thinking" is important to the interpretation of the growing body of cell-level data and how ecological null models can benefit statistical hypothesis testing. Experimental progress in cell biology should be accompanied by theoretical developments if we are to exploit fully the dynamical information in single-cell data.

An intact bony tympanic facial canal does not protect from secondary facial paresis in adult acute otitis media.

OBJECTIVE: To investigate the prevalence of bony dehiscence in the tympanic facial canal in patients with acute otitis media with facial paresis compared to those without facial paresis. METHOD: A retrospective case-control study was conducted on acute otitis media patients with facial paresis undergoing high-resolution temporal bone computed tomography. RESULTS: Forty-eight patients were included (24 per group). Definitive determination of the presence of a bony dehiscence was possible in 44 out of 48 patients (91.7 per cent). Prevalence of bony dehiscence in acute otitis media patients with facial paresis was not different from that in acute otitis media patients without facial paresis (p = 0.21). Presence of a bony dehiscence was associated with a positive predictive value of 66.7 per cent in regard to development of facial paresis. However, an intact bony tympanic facial canal did not prevent facial paresis in 44.8 per cent of cases (95 per cent confidence interval = 34.6-55.6). CONCLUSION: Prevalence of bony dehiscence in acute otitis media patients with facial paresis did not differ from that in acute otitis media patients without facial paresis. An intact tympanic bony facial canal does not protect from facial paresis development.

Advanced Rotator Cuff Tear Score (ARoCuS): a multi-scaled tool for the classification and description of rotator cuff tears.

BACKGROUND: To introduce a (semi-)quantitative surgical score for the classification of rotator cuff tears. MATERIAL AND METHODS: A total of 146 consecutive patients underwent rotator cuff repair and were assessed using the previously defined Advanced Rotator Cuff Tear Score (ARoCuS) criteria: muscle tendon, size, tissue quality, pattern as well as mobilization of the tear. The data set was split into a training (125 patients) and a testing set (21 patients). The training data set fitted a nonlinear predictive model of the tear score based on the ARoCuS criteria, while the testing data served as control. Based on the scoring results, rotator cuff tears were assigned to one of four categories (ΔV I-IV) and received a stage-adapted treatment. For statistical analysis, mean values ± standard deviation, interclass correlation coefficients (ICC) and kappa values were calculated. RESULTS: Overall, 32 patients were classified as ΔV I, 68 as ΔV II and 37 as ΔV III. Nine patients showed ΔV IV tears. Patients of all ΔV groups improved significantly their Constant scores (p < 0.001) and profited from significant pain reduction after surgery (p < 0.001). To date, ten patients have undergone revision surgery with five of them primarily classified as ΔV IV. Kappa values for the interobserver reliability ranged between 0.69 and 0.95. ICC scores for the ΔV category were 0.95 for interobserver reliability. CONCLUSIONS: The ARoCuS facilitates intra-operative decision-making and enables surgeons and researches to document rotator cuff tears in a standardized and reproducible manner.

Outbreak investigation for toxigenic Corynebacterium diphtheriae wound infections in refugees from Northeast Africa and Syria in Switzerland and Germany by whole genome sequencing.

Toxigenic Corynebacterium diphtheriae is an important and potentially fatal threat to patients and public health. During the current dramatic influx of refugees into Europe, our objective was to use whole genome sequencing for the characterization of a suspected outbreak of C. diphtheriae wound infections among refugees. After conventional culture, we identified C. diphtheriae using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and investigated toxigenicity by PCR. Whole genome sequencing was performed on a MiSeq Illumina with >70×coverage, 2×250 bp read length, and mapping against a reference genome. Twenty cases of cutaneous C. diphtheriae in refugees from East African countries and Syria identified between April and August 2015 were included. Patients presented with wound infections shortly after arrival in Switzerland and Germany. Toxin production was detected in 9/20 (45%) isolates. Whole genome sequencing-based typing revealed relatedness between isolates using neighbour-joining algorithms. We detected three separate clusters among epidemiologically related refugees. Although the isolates within a cluster showed strong relatedness, isolates differed by >50 nucleotide polymorphisms. Toxigenic C. diphtheriae associated wound infections are currently observed more frequently in Europe, due to refugees travelling under poor hygienic conditions. Close genetic relatedness of C. diphtheriae isolates from 20 refugees with wound infections indicates likely transmission between patients. However, the diversity within each cluster and phylogenetic time-tree analysis suggest that transmissions happened several months ago, most likely outside Europe. Whole genome sequencing offers the potential to describe outbreaks at very high resolution and is a helpful tool in infection tracking and identification of transmission routes.

Recovering speciation and extinction dynamics based on phylogenies.

Phylogenetic trees of only extant species contain information about the underlying speciation and extinction pattern. In this review, I provide an overview over the different methodologies that recover the speciation and extinction dynamics from phylogenetic trees. Broadly, the methods can be divided into two classes: (i) methods using the phylogenetic tree shapes (i.e. trees without branch length information) allowing us to test for speciation rate variation and (ii) methods using the phylogenetic trees with branch length information allowing us to quantify speciation and extinction rates. I end the article with an overview on limitations, open questions and challenges of the reviewed methodology.

Preliminary studies of effectiveness and selectivity of Movento on Bemisia tabaci and its parasitoid Eretmocerus mundus.

The Bemisia tabaci Gennadius (Homoptera:Aleyrodidae) biotype complex is a key pest of several worldwide crops. The management and control of this pest has become difficult mainly due to its high reproductive rate and capacity to develop resistance to broad spectrum insecticides. In Argentina B. tabaci whitefly, causes economic losses in most areas of agricultural production. Eretmocerus mundus Mercet (Hymenoptera:Aphelinidae) is the most important parasitoid of B. tabaci and is commercialized as a biocontrol agent, mainly in Europe. Conservation of this biological control agent in Argentinean orchards requires the adoption of sustainable pest management practices due the negative impact of traditional pesticides on non-target organisms. Spirotetramat (Movento) belongs to a new class of pesticides that acts as a lipid biosynthesis inhibitor and claims to be selective towards natural enemies. The objectives of this work were 1) to evaluate the effectiveness of spirotetramat on eggs and nymphs of B. tabaci and 2) to determine the selectivity of spirotetramat towards E. mundus. Whitefly's eggs and nymphs (first nymphal settled instar) were exposed to the insecticide by foliar immersion whereas parasitoid adults (6 days old) were exposed to the insecticide by residual method for one hour, to simulate exposure of the parasitoid to the insecticide in the field. Lethal and sublethal effects of the insecticide were recorded daily. These preliminary studies have shown a high effectiveness of spirotetramat on the first nymphal instar of B. tabaci as well as a high selectivity for the pest in comparison to the parasitoid adults showing a low acute toxicity to them. These results suggest Movento could be included in Integrated Pest Management programs although more studies are required to complete its ecotoxicological profile.

Fitness effects of derived deleterious mutations in four closely related wild tomato species with spatial structure.

A key issue in evolutionary biology is an improved understanding of the genetic mechanisms by which species adapt to various environments. Using DNA sequence data, it is possible to quantify the number of adaptive and deleterious mutations, and the distribution of fitness effects of new mutations (its mean and variance) by simultaneously taking into account the demography of a given species. We investigated how selection functions at eight housekeeping genes of four closely related, outcrossing species of wild tomatoes that are native to diverse environments in western South America (Solanum arcanum, S. chilense, S. habrochaites and S. peruvianum). We found little evidence for adaptive mutations but pervasive evidence for strong purifying selection in coding regions of the four species. In contrast, the strength of purifying selection seems to vary among the four species in non-coding (NC) regions (introns). Using F(ST)-based measures of fixation in subdivided populations, we suggest that weak purifying selection has affected the NC regions of S. habrochaites, S. chilense and S. peruvianum. In contrast, NC regions in S. arcanum show a distribution of fitness effects with mutations being either nearly neutral or very strongly deleterious. These results suggest that closely related species with similar genetic backgrounds but experiencing contrasting environments differ in the variance of deleterious fitness effects.

Amazonia through time: Andean uplift, climate change, landscape evolution, and biodiversity.

The Amazonian rainforest is arguably the most species-rich terrestrial ecosystem in the world, yet the timing of the origin and evolutionary causes of this diversity are a matter of debate. We review the geologic and phylogenetic evidence from Amazonia and compare it with uplift records from the Andes. This uplift and its effect on regional climate fundamentally changed the Amazonian landscape by reconfiguring drainage patterns and creating a vast influx of sediments into the basin. On this "Andean" substrate, a region-wide edaphic mosaic developed that became extremely rich in species, particularly in Western Amazonia. We show that Andean uplift was crucial for the evolution of Amazonian landscapes and ecosystems, and that current biodiversity patterns are rooted deep in the pre-Quaternary.

[Pyrosequencing in uro-oncology: applications in prostate cancer]. / Pyrosequenzierung in der Uroonkologie : Anwendungsmöglichkeiten am Beispiel des Prostatakarzinoms.

Changes in the methylation pattern in particular gene promoters as well as genetic sequence mutations play an important role in carcinogenesis. Molecular methods like pyrosequencing provide the specific analysis of these epigenetic and genetic modifications. In this review the relevance of these alterations for prostate cancer and the function of pyrosequencing will be described and explained on the basis of a search of the PubMed literature database. At present, in uro-oncology only a few studies outlining methylation in prostate cancer and pyrosequencing have been published. Nevertheless, it becomes evident that epigenetic mechanisms as well as specific gene sequence alterations have an impact on the carcinogenesis of prostate cancer and knowledge of these factors might open perspectives in diagnostic approaches of the future.

Sorafenib after combination therapy with gemcitabine plus doxorubicine in patients with sarcomatoid renal cell carcinoma: a prospective evaluation.

BACKGROUND: Sarcomatoid renal cell cancer (RCC) is a distinct histological variant of RCC that is associated with rapid progression and a poor prognosis. The optimal treatment for patients with sarcomatoid RCC remains to be defined. Gemcitabine plus doxorubicine (GD) has shown some efficacy, however durability of response is limited. We carried out a prospective, open-label study to investigate the efficacy and safety of sorafenib in patients after GD failure in sarcomatoid RCC. METHODS: Fifteen patients with pure sarcomatoid RCC and objective progressive disease were treated with GD (gemcitabine 1500 mg/m², doxorubicine 50 mg/m² administered by weekly intravenous infusion) until progression of disease. Subsequently 9 patients were switched to sorafenib (400 mg twice daily). Tumor response was measured by physical examination and computerized tomography scans and evaluated according to Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Median time to progression (TTP) under GD was 6.6 months (range 0.8 - 8 months). During GD treatment there were no remissions and 6 patients died from progressive disease. Median TTP for the 9 patients switched to sorafenib was 10.9 months (range 0.6 - 25.5 months). During sorafenib therapy one patient had a partial remission lasting for 3 months and 4 patients experienced stable disease with a duration of 3 to 9 months. Four patients immediately progressed on sorafenib treatment but had a slower dynamic of tumor progression than under GD. Dosing in both treatment phases was generally well tolerated with manageable toxicities and no requirement for dose reduction. CONCLUSIONS: Chemotherapy with GD was ineffective in our patients with pure sarcomatoid RCC. Subsequent anti-angiogenic treatment using the multi-tyrosine kinase inhibitor sorafenib resulted in additional progression-free survival in 5 of 9 patients. Further evaluation of targeted anti-angiogenic agents for the treatment of sarcomatoid RCC is warranted.

[Prostatic inflammation and prostate cancer]. / Prostatitis und Prostatakarzinom.

Chronic inflammation seems of importance in multiple types of cancer. Numerous reports have revealed a potential link between chronic prostatatic inflammation and prostate cancer. The aim of this paper is to review the epidemiological, moprphological, molecular and clinical aspects of prostattic inflammation and prostate cancer.

[Erectile dysfunction after radical prostatectomy]. / Erektile Dysfunktion nach radikaler Prostatektomie.

In the age of nerve-sparing radical prostatectomy, rates of postoperative erectile dysfunction (ED) have significantly decreased. However, on comparing open retropubic, laparoscopic and robot-assisted procedures, none of these techniques seem to show specific advantages in this respect. PDE5 inhibitors are considered to be the gold standard in the first-line therapy of postoperative ED, as far as relevant contraindications can be excluded. Intraurethral and intracavernosal injections with prostaglandin E1 represent the second-line treatment. Implantation of penile prostheses still remains as the third-line and ultima ratio. Meanwhile, the administration of PDE5 inhibitors has been proven to be most effective. When applying this therapy regimen, these substances are highly useful when they are administered early after the intervention. After curative treatment of prostate cancer, testosterone substitution can be an efficient way to reduce hypo-gonadal symptoms in patients with manifest testosterone deficiency. It may even contribute to the improvement of post- interventional erectile disorders. According to the recent literature, testosterone substitution therapy is safe and does not show any additional risk of recurrence when there is a well considered indication and when patients are carefully selected.

Carcinoma of the collecting ducts of Bellini of the kidney: adjuvant chemotherapy followed by multikinase-inhibition with sunitinib.

INTRODUCTION: Carcinoma of the collecting ducts of Bellini of the kidney (CDC) is very rare but among the most aggressive urological entities. Standard therapy is not well defined with questionable efficacy. METHODS: We present two cases of male patients (49 and 66 years old) with pT3a pN2 CDC treated with a combination of cisplatin plus gemcitabine in an adjuvant setting. Following recurrence the multi-kinase inhibitor sunitinib was administered. RESULTS: Radical nephrectomy with lymphadenectomy revealed CDC in stage pT3a pN2 M0 G3 R0 in both patients. 4 courses of adjuvant chemotherapy with cisplatin 70 mg/m superset2 and gemcitabine 1,500 mg/m superset2 were given. Side effects according to the NCI 3.0 common toxicity criteria were limited to grade 2 asthenia and grade 2 thrombozytopenia/leucopenia. Restaging revealed local recurrence and lymph node metastases. Both patients were re-operated and metastatic CDC was found. Second line therapy with sunitinb malatat (Sutent superset, Pfizer Inc. U.S.) at 50mg p.o. was given. Grade 3 leucopenia and thrombocytopenia and grade 2 asthenia and mucositis were not dose-limiting. After two cycles multiple liver, lung and bone metastases and mediastinal lymphopathy occured. 8 weeks later the patients died with a survival of 8 months from initial diagnosis. CONCLUSIONS: Adjuvant gemcitabine plus cisplatin did not delay recurrence of CDC after surgery. Metastasectomy either had no influence on the course of disease. Anti-angiogenetic therapy with sunitinib treatment was not effective, possibly related to a low vascular density (CD31 expression) in CDC.

[Systemic therapy of metastasizing renal cell carcinoma]. / Systemische Therapie des metastasierten Nierenzellkarzinoms.

Once surgical options have been exhausted, systemic therapy is indicated for metastasizing renal cell carcinoma. Until recently this was carried out using mainly immunotherapeutic concepts with unsatisfactory results. Since the majority of clear cell renal cell carcinomas are well vascularised, angiogenetic inhibition offered an alternative therapy goal. To date, four substances have been approved to control angiogenesis in the therapy of renal cell carcinoma: sunitinib, sorafenib, temsirolimus, as well as a combination of bevacizumab and interferon alpha. Other substances, such as everolimus, pazopanib and axitinib, are currently the subject of clinical trials. Initial data on tolerance and efficacy was presented at this years annual conference of the American Society of Clinical Oncology (ASCO). This article examines current therapy options and ASCO data and discusses future trends.

[Managing the side effects of angiogenetic inhibitors in metastatic renal cell carcinoma]. / Antiangiogenetische Therapie beim Nierenzellkarzinom. Management der Nebenwirkungen.

Sunitinib and Sorafenib are both effective angiogenetic inhibitors for the treatment of renal cell carcinoma. With these drugs of a new class of chronic therapy is performed. During chronic treatment, the inherent side effects may necessitate stopping the application of these drugs thus preventing the required effective therapy. Most of the effects can be avoided or attenuated by prophylaxis. In this paper the published data are reviewed and added with our experience in 138 patients over up to two and a half years.

[Therapy strategies for advanced renal cell carcinoma]. / Therapiestrategien des fortgeschrittenen Nierenkarzinoms.

The therapeutic regimen for metastatic renal cell cancer has changed substantially in the last years. Formerly, metastatic disease was regarded as being inoperable and had a disastrous prognosis. Nowadays, radical nephrectomy is the accepted urologic-oncologic standard therapy in metastatic primaries, if technically feasible. A complete resection of metastases may be curative, or can achieve a substantial palliative benefit. A better understanding of prognostic parameters helps in the selection of patients with a chance of benefiting from systemic immunochemotherapy. For patients with rapidly progressing tumors or sarcomatoid dedifferentiation, new effective chemotherapy regimens are available. New angiogenesis inhibitors such as sutent, avastin or sorafenib can potentially be effectively used in future therapeutic regimens.