We investigate a novel approach for structural shape optimization on the basis of complementary shape and topological sensitivity analysis. As in early approaches to shape optimization, the domain ...variation is specified by modification of boundary nodal points, hence leading to an updated Lagrangian description for the course of optimization. To overcome the formation of oscillating boundaries in the optimal design trials, we employ the traction method to establish smooth descent directions for shape variation. Therein, an auxiliary elastic problem is solved in which the shape sensitivity constitutes the external loading and the deformation of the auxiliary elastic body is used as a descent direction for shape variation rather than the shape sensitivity itself. We complement this method through an evolutionary-type element removal procedure that is based on the topological sensitivity such that an advancing front algorithm is gradually removing elements from the design boundary of the domain. Once the minimum topological sensitivity is no longer encountered at the design boundary, we create a hole in the domain, again using the topological sensitivity to specify its exact location, and resume the element removal procedure for the newly established design boundary. Since this approach yields only a vague estimate of the true optimal shape of newly established holes, the traction method is again used for shape variation of the extended design boundary.
Global climate change is proceeding at an alarming rate with major ecological and genetic consequences for biodiversity, particularly in drylands. The response of species to climate change may differ ...between intraspecific genetic groups, with major implications for conservation. We used molecular data from 10 nuclear and two chloroplast genomes to identify phylogeographic groups within 746 individuals from 29 populations of Senegalia senegal, a savannah tree species in sub-Saharan Africa. Three phylogroups are identified corresponding to Sudano-Sahelian, Zambezian and Southern African biogeographic regions in West, East and Southern Africa. Genetic diversity was highest in Southern and Zambesian and lowest in the Sudano-Sahelian phylogroups. Using species distribution modeling, we infer highly divergent future distributions of the phylogroups under three climate change scenarios. Climate change will lead to severe reductions of distribution area of the genetically diverse Zambezian (- 41-- 54%) and Southern (- 63-- 82%) phylogroups, but to an increase for the genetically depauperate Sudano-Sahelian (+ 7- + 26%) phylogroups. This study improves our understanding of the impact of climate change on the future distribution of this species. This knowledge is particularly useful for biodiversity management as the conservation of genetic resources needs to be considered in complementary strategies of in-situ conservation and assisted migration.
This contribution is concerned with the coupling of finite element based shape optimization to methods of mesh adaptivity. Therein, the nodal points of a finite element mesh serve as design variables ...in an optimization problem that aims to minimize a cost functional with respect to different constraints. In order to avoid the occurrence of oscillating boundaries in the optimal design trials, we generate the respective design updates through solving a series of fictitious boundary value problems on an updated Lagrangian configuration. The design update process is accompanied by adaptive mesh refinement to obtain more accurate results for the structural analysis and the design sensitivity analysis. For the mesh adaptation process, we consider r-adaptive node relocation, h-adaptive mesh refinement and a combination of both approaches. In each case, the derivations rest upon the notion of material residual forces induced by finite element discretization and the coupling of shape optimization and mesh adaptivity is of intermittent type, i.e. mesh adaptivity is invoked once a certain number of design updates has been generated. We examine the benefits of the proposed method on the basis of some numerical examples in comparison to the same shape optimization method not involving adaptive mesh refinement where we evaluate the corresponding numerical costs, the gain in accuracy and the effects on the optimal shapes being obtained.
Climate change is predicted to impact species' genetic diversity and distribution. We used Senegalia senegal (L.) Britton, an economically important species distributed in the Sudano-Sahelian ...savannah belt of West Africa, to investigate the impact of climate change on intraspecific genetic diversity and distribution. We used ten nuclear and two plastid microsatellite markers to assess genetic variation, population structure and differentiation across thirteen sites in West Africa. We projected suitable range, and potential impact of climate change on genetic diversity using a maximum entropy approach, under four different climate change scenarios. We found higher genetic and haplotype diversity at both nuclear and plastid markers than previously reported. Genetic differentiation was strong for chloroplast and moderate for the nuclear genome. Both genomes indicated three spatially structured genetic groups. The distribution of Senegalia senegal is strongly correlated with extractable nitrogen, coarse fragments, soil organic carbon stock, precipitation of warmest and coldest quarter and mean temperature of driest quarter. We predicted 40.96 to 6.34 per cent of the current distribution to favourably support the species' ecological requirements under future climate scenarios. Our results suggest that climate change is going to affect the population genetic structure of Senegalia senegal, and that patterns of genetic diversity are going to influence the species' adaptive response to climate change. Our study contributes to the growing evidence predicting the loss of economically relevant plants in West Africa in the next decades due to climate change.
Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS ...activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.
An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients aged ≤21 years), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001).
Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven 10% of 68 patients in the NTRK fusion-positive safety population and in 18 5% of 355 patients in the overall safety-evaluable population) and anaemia (8 12% and 16 5%). The most common serious treatment-related adverse events were nervous system disorders (three 4% of 68 patients and ten 3% of 355 patients). No treatment-related deaths occurred.
Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.
Ignyta/F Hoffmann-La Roche.
The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of ...actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort.
Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response.
In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6–18.7). Confirmed ORR was 87.4% (95% confidence interval CI: 78.5–93.5) by investigator and 92.0% (95% CI: 84.1–96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6–88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9–98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1–87.7). Safety data were consistent with the known tolerability profile of alectinib.
These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.
Objective
To evaluate the efficacy and safety of tigilanol tiglate (TT) for local intratumoral treatment of mast cell tumors (MCTs) in dogs.
Methods
A randomized controlled clinical study in 2 phases ...involving 123 dogs with cytologically diagnosed MCT. Phase 1 compared 81 TT‐treated dogs with 42 control dogs; phase 2 allowed TT treatment of control dogs and retreatment of dogs that failed to achieve tumor resolution after TT treatment in phase 1. Tigilanol tiglate (1 mg/mL) was injected intratumorally with dose based on tumor volume. Concomitant medications were used to minimize potential for MCT degranulation. Modified response evaluation criteria in solid tumors were used to evaluate treatment response at 28 and 84 days. Adverse events and quality of life were also assessed.
Results
A single TT treatment resulted in 75% complete response (CR) (95% confidence interval CI = 61‐86) by 28 days, with no recurrence in 93% (95% CI = 82‐97) of dogs by 84 days. Eight TT‐treated dogs that did not achieve CR in phase 1 achieved CR after retreatment, increasing the overall CR to 88% (95% CI = 77‐93). Control dogs had 5% CR (95% CI = 1‐17) at 28 days. Wound formation after tumor slough and wound size relative to tumor volume were strongly associated with efficacy. Adverse events typically were low grade, transient, and directly associated with TT's mode of action.
Conclusions
Tigilanol tiglate is efficacious and well tolerated, providing a new option for the local treatment of MCTs in dogs.
Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in ...living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that properties similar to those predicted for the artificial chemistry hold also for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity.
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