Transition to turbulence in particle laden flows

Suspended particles can alter the properties of fluids and in particular also affect the transition from laminar to turbulent flow. In the present experimental study, we investigate the impact of neutrally buoyant, spherical inertial particles on transition to turbulence in a pipe flow. At low particle concentrations, like in single phase Newtonian fluids, turbulence only sets in when triggered by sufficiently large perturbations and, as characteristic for this transition localized turbulent regions (puffs) co-exist with laminar flow. In agreement with earlier studies this transition point initially moves to lower Reynolds number (Re) as the particle concentration increases. At higher concentrations however the nature of the transition qualitatively changes: Laminar flow gives way to a globally fluctuating state following a continuous, non-hysteretic transition. A further increase in Re results in a secondary instability where localized puff-like structures arise on top of the uniformly fluctuating background flow. At even higher concentration only the uniformly fluctuating flow is found and signatures of Newtonian type turbulence are no longer observed

Exceeding the asymptotic limit of polymer drag reduction

The drag of turbulent flows can be drastically decreased by addition of small amounts of high molecular weight polymers. While drag reduction initially increases with polymer concentration, it eventually saturates to what is known as the maximum drag reduction (MDR) asymptote; this asymptote is generally attributed to the dynamics being reduced to a marginal yet persistent state of subdued turbulent motion. Contrary to this accepted view we will show in the following that for an appropriate choice of parameters polymers can reduce the drag beyond the suggested asymptotic limit, eliminating turbulence and giving way to laminar flow. However at higher polymer concentrations the laminar state becomes unstable, resulting in a fluctuating flow with the characteristic drag of the MDR asymptote. The asymptotic state is hence dynamically disconnected from ordinary turbulence.Comment: 6 pages, 6 figure

Dynamics of viscoelastic pipe flow in the maximum drag reduction limit

Polymer additives can substantially reduce the drag of turbulent flows and the upper limit, the so called "maximum drag reduction" (MDR) asymptote is universal, i.e. independent of the type of polymer and solvent used. Until recently, the consensus was that, in this limit, flows are in a marginal state where only a minimal level of turbulence activity persists. Observations in direct numerical simulations using minimal sized channels appeared to support this view and reported long "hibernation" periods where turbulence is marginalized. In simulations of pipe flow we find that, indeed, with increasing Weissenberg number (Wi), turbulence expresses long periods of hibernation if the domain size is small. However, with increasing pipe length, the temporal hibernation continuously alters to spatio-temporal intermittency and here the flow consists of turbulent puffs surrounded by laminar flow. Moreover, upon an increase in Wi, the flow fully relaminarises, in agreement with recent experiments. At even larger Wi, a different instability is encountered causing a drag increase towards MDR. Our findings hence link earlier minimal flow unit simulations with recent experiments and confirm that the addition of polymers initially suppresses Newtonian turbulence and leads to a reverse transition. The MDR state on the other hand results from a separate instability and the underlying dynamics corresponds to the recently proposed state of elasto-inertial-turbulence (EIT).Comment: 18 pages, 5 figure

Experimental observation of the origin and structure of elasto-inertial turbulence

Turbulence generally arises in shear flows if velocities and hence inertial forces are sufficiently large. In striking contrast, viscoelastic fluids can exhibit disordered motion even at vanishing inertia. Intermediate between these cases, a novel state of chaotic motion, `elasto-inertial turbulence' (EIT), has been observed in a narrow Reynolds number interval. We here determine the origin of EIT in experiments and show that characteristic EIT structures can be detected across an unexpectedly wide range of parameters. Close to onset a pattern of chevron shaped streaks emerges in excellent agreement with linear theory. However, the instability can be traced to far lower Reynolds numbers than permitted by theory. For increasing inertia, a secondary instability gives rise to a wall mode composed of inclined near wall streaks and shear layers. This mode persists to what is known as the `maximum drag reduction limit' and overall EIT is found to dominate viscoelastic flows across more than three orders of magnitude in Reynolds number

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand–foot syndrome and a combination of grade 1–2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity

Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival