Cooling and aggregation in wet granulates

Wet granular materials are characterized by a defined bond energy in their particle interaction such that breaking a bond implies an irreversible loss of a fixed amount of energy. Associated with the bond energy is a nonequilibrium transition, setting in as the granular temperature falls below the bond energy. The subsequent aggregation of particles into clusters is shown to be a self-similar growth process with a cluster size distribution that obeys scaling. In the early phase of aggregation the clusters are fractals with D_f=2, for later times we observe gelation. We use simple scaling arguments to derive the temperature decay in the early and late stages of cooling and verify our results with event-driven simulations.Comment: 4 pages, 6 figures, suggestions of the referees implemented, EPAPS supplementary material added: http://netserver.aip.org/cgi-bin/epaps?ID=E-PRLTAO-102-00391

Dilute Wet Granulates: Nonequilibrium Dynamics and Structure Formation

We investigate a gas of wet granular particles, covered by a thin liquid film. The dynamic evolution is governed by two-particle interactions, which are mainly due to interfacial forces in contrast to dry granular gases. When two wet grains collide, a capillary bridge is formed and stays intact up to a certain distance of withdrawal when the bridge ruptures, dissipating a fixed amount of energy. A freely cooling system is shown to undergo a nonequillibrium dynamic phase transition from a state with mainly single particles and fast cooling to a state with growing aggregates, such that bridge rupture becomes a rare event and cooling is slow. In the early stage of cluster growth, aggregation is a self-similar process with a fractal dimension of the aggregates approximately equal to D_f ~ 2. At later times, a percolating cluster is observed which ultimately absorbs all the particles. The final cluster is compact on large length scales, but fractal with D_f ~ 2 on small length scales.Comment: 14 pages, 20 figure

Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche’s Endocannabinoid System Projects

: The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples

Evaluation of an iterative model-based CT reconstruction algorithm by intra-patient comparison of standard and ultra-low-dose examinations

Background The explosive growth of computer tomography (CT) has led to a growing public health concern about patient and population radiation dose. A recently introduced technique for dose reduction, which can be combined with tube-current modulation, over-beam reduction, and organ-specific dose reduction, is iterative reconstruction (IR). Purpose To evaluate the quality, at different radiation dose levels, of three reconstruction algorithms for diagnostics of patients with proven liver metastases under tumor follow-up. Material and Methods A total of 40 thorax–abdomen–pelvis CT examinations acquired from 20 patients in a tumor follow-up were included. All patients were imaged using the standard-dose and a specific low-dose CT protocol. Reconstructed slices were generated by using three different reconstruction algorithms: a classical filtered back projection (FBP); a first-generation iterative noise-reduction algorithm (iDose4); and a next generation model-based IR algorithm (IMR). Results The overall detection of liver lesions tended to be higher with the IMR algorithm than with FBP or iDose4. The IMR dataset at standard dose yielded the highest overall detectability, while the low-dose FBP dataset showed the lowest detectability. For the low-dose protocols, a significantly improved detectability of the liver lesion can be reported compared to FBP or iDose4 ( P = 0.01). The radiation dose decreased by an approximate factor of 5 between the standard-dose and the low-dose protocol. Conclusion The latest generation of IR algorithms significantly improved the diagnostic image quality and provided virtually noise-free images for ultra-low-dose CT imaging. </jats:sec

TPLL-1 Protocol of the German CLL Study Group (GCLLSG) - A Prospective Phase II Trial of Fludarabine Phosphate, Mitoxantrone and Cyclophosphamide (FMC) Followed by Alemtuzumab Consolidation in T-PLL.

Abstract Introduction: T-cell prolymphocytic leukemia (T-PLL) is an aggressive disease with a poor median overall survival of &amp;lt;12 months. To improve results in T-PLL, the GCLLSG initiated the T-PLL-1 protocol evaluating the efficacy of induction therapy with fludarabine, mitoxantrone and cyclophosphamide (FCM) followed by antibody therapy with alemtuzumab. Patients (pts) and Methods: Between November 2001 and December 2006 a total of 26 pts were entered in this trial. At the time of analysis eighteen pts. are available with confirmed diagnosis of T-PLL. Twelve patients were untreated and six pretreated. All patients were planned to receive 4 cycles of fludarabine phosphate 25 mg/m2 on Days 1–3, mitoxantrone 8 mg/m2 on Day 1, and cyclophosphamide 200 mg/m2 (FMC) on Days 1–3, which was repeated on Day 29. After 4 courses of chemotherapy, all responding patients were scheduled to receive alemtuzumab 30 mg IV 3 times per week as consolidation therapy for up to 12 weeks. Patients with stable or progressive disease at interim staging, after second cycle of FMC, were treated immediately with alemtuzumab. The median age was 71 years (range 46–75yrs). Median time from diagnosis to study entry was 2 months (range 0.2–6 months). All patients showed a typical marked hyperleukocytosis with a median of 141.600/μl (range 19.9–436.700/μl). Results: A total of 63 cycles of FMC therapy were documented and a total of 129 weeks of Alemtuzumab at 30 mg with a median of duration of 8 weeks therapy per pt (range 2–12 weeks) were administered, which corresponds to a medium Alemtuzumab dose of 720 mg (range 6 mg -1.033 mg). The overall response (OR= complete response (CR) + partial response (PR)) rates following FMC and alemtuzumab therapies were 66% and 86%, respectively. The best response to FMC therapy included 4 pts who achieved a CR, while 8 pts achieved a PR, 5 pts had SD, and 1pt had PD. Alemtuzumab was subsequently administered as consolidation therapy to 15 pts. Of responding pts. with CR 3 of 4 and with PR 7 of 8 received alemtuzumab as consolidation therapy. The pt with PD received alemtuzumab therapy as well, but the disease continued to progress. In addition, 2 pts with SD after FMC subsequently achieved a CR following alemtuzumab therapy and three pts with SD after FMC achieved a PR. One pt with PR after FMC had a progressive disease during Alemtuzumab therapy. The median overall survival (OS) of patients with T-PLL after FMC and alemtuzumab therapy was 19.2 months and progression free survival (PFS) was 10.6 months. Only one fatal adverse event presenting as myocardial infarction during alemtuzumab run-in phase was observed. FISH analysis was performed in 12 of 20 pts showing typical involvement of the chromosome 14 (t (14; 14), t (14q11)). Furthermore, in 12 pts expression of TCL-1 was tested by PCR. However, no correlation to OS or PFS was detected according to the level of expression. Conclusion: The combination of a fludarabine phosphate-containing regimen with subsequent alemtuzumab therapy shows clinical benefit in pts with T-PLL. To increase outcome study evaluating FMC combined with alemtuzumab followed by an alemtuzumab maintenance therapy is currently under investigation.</jats:p

Consolidation with Alemtuzumab in First Remission Induces Pronounced MRD Reduction and Clinical Remissions - Update on a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Abstract The monoclonal antibody alemtuzumab is known to be effective in combination or alone in patients with late stage chronic lymphocytic leukaemia. Flow cytometric studies on minimal residual disease (MRD) showed the high potency beyond clinical response criteria even in late stage chronic lymphocytic leukaemia (CLL). The aim of the phase III trial of the GCLLSG was to investigate the role of alemtuzumab as consolidation therapy in CLL patients in first clinical remission after fludarabin (F) or F plus cyclophosphamide (FC). Patients in partial or complete clinical remission were randomized to either arm A (alemtuzumab 3 x 30 mg i.v. for up to 12 wks) or no further treatment (arm B). From 21 eligible patients 11 (1CR, 1 nPR, 9PR) were randomized to arm A. All patients received standard infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole. Before, at 6 and 12 weeks after start of consolidation therapy and regulary during follow up blood and bone marrow samples were send for molecular MRD assessment by allele specific real time PCR. The PCR allowed MRD assessment with a sensitivity of at least 10E-4 in 11 eligible cases. Results: MRD analysis showed clear reduction of CLL content by first line treatment to a median MRD level of 2.2E-3. Short after alemtuzumab treatment all treated patients showed pronounced MRD reduction to a median MRD level of 5.0E-5. During molecular follow-up median MRD level remained below 1E-4 for one year with a tendency to increase afterwards. After a median follow-up of 31.3 months from start of initial treatment occurred one relapse in the treatment arm compared to 7 of 10 in arm B. The median progression free survival (PFS) calculated from start of consolidation therapy was significantly shorter in the control group versus the treatment group (pfs 25.2; p= 0.04). Nevertheless due to severe acute infections (CTC III and IV) this study had to be stopped prematurely. Conlusion: The addition of alemtuzumab as a consolidation regimen after remission induction by F or FC is highly effective and leads to sustained MRD reduction below 10E-4. This translates into significant improved clinical outcome even in this small patient cohort compared to the control group. Encouraged by the molecular responses the GCLLSG initiated a new phase I/II trial as a dose finding study in CLL patients after F based induction of clinical remission.</jats:p