Ribociclib-induced liver injury: a case report.

Background: Idiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US. Ribociclib is a potent Cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor administered for advanced hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Previous reports have shown hepatotoxicity without liver necrosis related to ribociclib. Case presentation: A 41-year-old female patient with primary metastatic HR-positive, HER2-negative breast cancer developed liver enzyme elevation under treatment with ribociclib. Ribociclib was withdrawn 8 weeks after initiation due to liver enzyme elevation. A liver biopsy, performed due to further enzyme increase (peak ALT 2836 U/l), onset of jaundice (peak bilirubin 353 µmol/l) and coagulopathy (INR 1.8) two weeks later, revealed acute hepatitis with 30% parenchymal necrosis. Roussel Uclaf Causality Assessment Method (RUCAM) score was 7 points (probable). Under treatment with prednisone (60mg), initiated 2 weeks after drug withdrawal, and subsequently N-acetylcysteine (Prescott regimen) liver enzymes normalized within 8 weeks along with prednisone tapering. Conclusion: This case illustrates the development of a severe idiosyncratic hepatocellular pattern DILI grade 3 (International DILI Expert Working Group) induced by ribociclib. Routine liver enzyme testing during therapy, immediate hepatologic work-up and treatment interruption in case of liver enzyme elevation are highly recommended. Corticosteroid treatment should be considered in cases of severe necroinflammation.

Drilling Sequence Optimization Using Evolutionary Algorithms to Reduce Heat Accumulation for Femtosecond Laser Drilling with Multi-Spot Beam Profiles.

We report on laser drilling borehole arrays using ultrashort pulsed lasers with a particular focus on reducing the inadvertent heat accumulation across the workpiece by optimizing the drilling sequence. For the optimization, evolutionary algorithms are used and their results are verified by thermal simulation using Comsol and experimentally evaluated using a thermal imaging camera. To enhance process efficiency in terms of boreholes drilled per second, multi-spot approaches are employed using a spatial light modulator. However, as higher temperatures occur across the workpiece when using simultaneous multi-spot drilling as compared to a single-spot process, a subtle spatial distribution and sequence of the multi-spot approach has to be selected in order to limit the resulting local heat input over the processing time. Different optimization approaches based on evolutionary algorithms aid to select those drilling sequences which allow for the combination of a high efficiency of multi-spot profiles, a low-generated process temperature and a high-component quality. In particular, using a 4 × 4 laser spot array allows for the drilling of 40,000 boreholes in less than 76 s (526 boreholes/s) with a reduced temperature increase by about 35%, as compared to a single spot process when employing an optimized drilling sequence.

Lateral cortical notching facilitates dynamization of proximal femoral nailing - A finite element analysis.

INTRODUCTION: Dynamization of proximal femoral nailing by removal of distal interlocking is one of the recommended treatment options for nonunions of femur fractures. However, in certain inter-/subtrochanteric fractures, gliding of the nail along the femoral shaft is blocked by lateral femoral cortical support of the lag screw. For these cases, Biber et al. proposed lateral cortical notching (LCN), in which the supporting lateral bone is removed. This study investigates the biomechanical effect of LCN on gliding of proximal femoral nailing and stress distribution at the bone/implant interface. MATERIALS AND METHODS: In this finite element analysis a three-dimensional model of an unstable intertrochanteric fracture with proximal femoral nailing without distal interlocking was simulated using the FebioStudio software suite. To simulate LCN, the lag screw hole was lengthened to 15.34 mm at the lateral cortex. Displacement of the nail along the femoral shaft axis and von Mises stress distribution were compared between LCN model and standard implantation model. RESULTS: Displacement of the nail along the femoral shaft axis was higher in the LCN model than in the standard implantation model (0.48 mm vs. 0.07 mm). Highest von Mises stresses of 176-178 MPa at the implant and of 52-81 MPa at the proximal femur were detected. Maximum von Mises stresses of the implant were comparable at all sides, except for a reduced von Mises stress at the lateral inferior side in the LCN model (80 vs. 102 MPa). At the inferior lateral screw hole and the anterior/posterior lateral screw hole maximum von Mises stress was reduced in the LCN model (2 vs. 49 MPa and 52 vs. 81 MPa), whereas the maximum von Mises stress at the inferior medial screw hole was higher in the LCN model than in the standard implantation model (53 vs. 27 MPa). CONCLUSIONS: Lateral cortical notching facilitates gliding of a distally dynamized proximal femoral nail along the femoral shaft axis in intertrochanteric fractures. Additionally, the lack of lateral cortical bone support at the lag screw reduces von Mises stress at the bone/implant interface and thus could lower the risk for implant breakage and peri­implant fractures.

Optimization of Heat Accumulation during Femtosecond Laser Drilling Borehole Matrices by Using a Simplex Algorithm.

We report on an optimization study of percussion drilling thin metal sheets employing a high repetition rate, high power femtosecond laser with respect to the resulting heat accumulation. A specified simplex algorithm was employed to optimize the spatial drilling sequence, whereas a simplified thermal simulation using COMSOL was validated by comparing its results to the temperature measurements using an infrared camera. Optimization for drilling borehole matrices was aspired with respect to the generated temperature across the processed specimen, while the drilling strategy was altered in its spatial drilling sequence and by using multi-spot approaches generated by a spatial light modulator. As a result, we found that an optimization strategy based on limited consecutive holes in a Moore neighborhood led to reduced temperatures and the shortest process times.

Biomechanical in vitro analysis of a novel flexible implant for pubic symphysis disruption using an ultra-high molecular weight polyethylene fiber cord.

BACKGROUND: Plate osteosynthesis depicts the gold standard to surgically treat pubic symphysis disruptions. However, high rates of implant failure after plate osteosynthesis are reported, probably because of the iatrogenic arthrodesis of this fibrocartilaginous joint. Therefore, flexible implants for treatment of pubic symphysis disruptions appear to be a sensible solution. METHODS: In this biomechanical screening study, we designed and investigated a flexible implant, which consists of two plates connected with an ultra-high molecular weight polyethylene fiber cord. We mechanically tested eye splices as a possible fixation method of the cords by performing tensile load to failure tests. Afterwards, we developed a biomechanically appropriate plate design and cord routing between the plates. Finally, we biomechanically tested the flexible implant under tensile and shear loading until failure. FINDINGS: When fixing a 1 mm ultra-high molecular weight polyethylene fiber cord with eye splices, a load at failure of 1570.74 N was detected under tensile loading. None of the eye splices failed but the cords itself ruptured. The load at failure of the designed cord routing in criss-cross technique and fixation within the plates amounts 4742.09 N under tensile and 2699.77 N under shear load. INTERPRETATION: We developed a novel flexible implant for repair of pubic symphysis disruptions using ultra-high molecular weight polyethylene fiber cords connected to osteosynthesis plates. We identified eye splices as a mechanically optimal fixation method and proved that the ultra-high molecular weight polyethylene fiber cord routing and fixation of the flexible implant clearly withstands physiological forces acting on the pubic symphysis.

Iliotibial band autograft is a suitable alternative graft for anterior cruciate ligament reconstruction: a systematic review and meta-analysis of outcomes.

PURPOSE: Despite encouraging clinical, biomechanical and histological results, ACL reconstruction using the ITB was slowly abandoned. The hypothesis was that the current literature supports the use of ITB as the graft of choice for ACL reconstruction because of its good outcomes. METHODS: A systematic search of the literature was performed in the PubMed, MEDLINE, Cochrane, and Ovid databases to identify published clinical studies relevant to ACL reconstruction with ITB autograft and studies comparing ITB autograft with bone-patellar tendon-bone (BPTB) and hamstring (HT) autografts (none were found). The results of the eligible studies were analyzed in terms of graft failure, instrumented knee laxity measurements, Lachman test, pivot-shift test, Lysholm score, objective and subjective International Knee Documentation committee (IKDC) scores, Tegner activity score, return to sports rate, return to sports at pre-injury level and complications. RESULTS: Nineteen clinical studies including 1,210 patients with ACL reconstruction met the inclusion criteria. Graft failure occurred after ITB autograft in 4.2% of patients. Postoperative mean side-to-side laxity was 1.41 mm with 21% of patients having greater than 3 mm side-to-side difference. Lachman test and pivot-shift test were negative (grade 0) in 57% and 85%, respectively, and were grade 0 or 1 in 95% and 97%, respectively. Functional outcomes were satisfactory in 84% of patients with good to excellent results (Lysholm score > 84). Mean postoperative Lysholm score was 93.3 and 84% of patients had an objective IKDC grade of A or B. Mean postoperative Tegner score was 6.8. The return to sports rate was 89% and 61% of patients returned to their pre-injury level. A comparison of 89 ITB versus 80 BPTB autografts revealed no significant differences in graft failure (n.s.), instrumented mean side-to-side knee laxity difference (n.s.) or Tegner score (n.s.). CONCLUSION: The graft survival rate and clinical and functional outcomes for ITB autograft are satisfactory. By allowing ACL reconstruction and lateral tenodesis to be done with a single, continuous, pedicled graft through an outside-in femoral tunnel, this technique may become the preferred alternative for primary or secondary ACL surgery. LEVEL OF EVIDENCE: Level IV.

Determination of the through-plane profile of vanadium species in hydrated Nafion studied with micro X-ray absorption near-edge structure spectroscopy - proof of concept.

Vanadium-ion transport through the polymer membrane results in a significant decrease in the capacity of vanadium redox flow batteries. It is assumed that five vanadium species are involved in this process. Micro X-ray absorption near-edge structure spectroscopy (micro-XANES) is a potent method to study chemical reactions during vanadium transport inside the membrane. In this work, protocols for micro-XANES measurements were developed to enable through-plane characterization of the vanadium species in Nafion 117 on beamline P06 of the PETRA III synchrotron radiation facility (DESY, Hamburg, Germany). A Kapton tube diffusion cell with a diameter of 3 mm was constructed. The tube diameter was chosen in order to accommodate laminar flow for cryogenic cooling while allowing easy handling of the cell components by hand. A vertical step size of 2.5 µm and a horizontal step size of 5 µm provided sufficient resolution to resolve the profile and good statistics after summing up horizontal rows of scan points. The beam was confined in the horizontal plane to account for the waviness of the membrane. The diffusion of vanadium ions during measurement was inhibited by the cryogenic cooling. Vanadium oxidation, e.g. by water radiolysis (water percentage in the hydrated membrane ∼23 wt%), was mitigated by the cryogenic cooling and by minimizing the dwell time per pixel to 5 ms. Thus, the photo-induced oxidation of V3+ in the focused beam could be limited to 10%. In diffusion experiments, Nafion inside the diffusion cell was exposed on one side to V3+ electrolyte and on the other side to VO2+. The ions were allowed to diffuse across the through-plane orientation of the membrane during one of two short defrost times (200 s and 600 s). Subsequent micro-XANES measurements showed the formation of VO2+ from V3+ and VO2+ inside the water body of Nafion. This result proves the suitability of the experimental setup as a powerful tool for the determination of the profile of vanadium species in Nafion and other ionomeric membranes.

Analysis of the optical properties of the silvery spots on the wings of the Gulf Fritillary, Dione vanillae.

The ventral face of the wings of the butterfly Dione vanillae is covered with bright and shiny silvery spots. These areas contain densely packed ground- and coverscales with a bright metallic appearance reflecting more than 50% of light uniformly over the visible range. Our analysis shows that this optically attractive feature is caused by the inner microstructure of the scales located in these areas. Electron microscopy of cross sections through the scales shows that upper and lower lamina, supporting trabeculae, and topping ridges can be approximated by a 'circus tent'-like geometry. By simulating its optical properties, we show that a moderate disorder of this geometry is important for the uniform reflection of light resulting in the silvery appearance.

Iodine-Mediated Tryptathionine Formation Facilitates the Synthesis of Amanitins.

Synthetic methods on the macrocyclization of peptides are of high interest since they facilitate the synthesis of various types of potentially bioactive compounds, e.g. addressing targets like protein-protein-interactions. Herein, we report on an efficient method to construct tryptathionine-cross-links in peptides between the amino acids Trp and Cys. This reaction not only is the basis for the total synthesis of the death cap toxin α-amanitin but also provides rapid access to various new amanitin analogues. This study for the first time presents a systematic compilation of structure-activity relations (SAR) of amatoxins with regard to RNA polymerase II inhibition and cytotoxicity with one amanitin derivative of superior RNAP II inhibition. The present approach paves the way for the synthesis of structurally diverse amatoxins as future payloads for antibody-toxin conjugates in cancer therapy.

Characterization of Dimeric Vanadium Uptake and Species in Nafion™ and Novel Membranes from Vanadium Redox Flow Batteries Electrolytes.

A core component of energy storage systems like vanadium redox flow batteries (VRFB) is the polymer electrolyte membrane (PEM). In this work, the frequently used perfluorosulfonic-acid (PFSA) membrane Nafion™ 117 and a novel poly (vinylidene difluoride) (PVDF)-based membrane are investigated. A well-known problem in VRFBs is the vanadium permeation through the membrane. The consequence of this so-called vanadium crossover is a severe loss of capacity. For a better understanding of vanadium transport in membranes, the uptake of vanadium ions from electrolytes containing Vdimer(IV-V) and for comparison also V(II), V(III), V(IV), and V(V) by both membranes was studied. UV/VIS spectroscopy, X-ray absorption near edge structure spectroscopy (XANES), total reflection X-ray fluorescence spectroscopy (TXRF), inductively coupled plasma optical emission spectrometry (ICP-OES), and micro X-ray fluorescence spectroscopy (microXRF) were used to determine the vanadium concentrations and the species inside the membrane. The results strongly support that Vdimer(IV-V), a dimer formed from V(IV) and V(V), enters the nanoscopic water-body of Nafion™ 117 as such. This is interesting, because as of now, only the individual ions V(IV) and V(V) were considered to be transported through the membrane. Additionally, it was found that the Vdimer(IV-V) dimer partly dissociates to the individual ions in the novel PVDF-based membrane. The Vdimer(IV-V) dimer concentration in Nafion™ was determined and compared to those of the other species. After three days of equilibration time, the concentration of the dimer is the lowest compared to the monomeric vanadium species. The concentration of vanadium in terms of the relative uptake λ = n(V)/n(SO3) are as follows: V(II) [λ = 0.155] > V(III) [λ = 0.137] > V(IV) [λ = 0.124] > V(V) [λ = 0.053] > Vdimer(IV-V) [λ = 0.039]. The results show that the Vdimer(IV-V) dimer needs to be considered in addition to the other monomeric species to properly describe the transport of vanadium through Nafion™ in VRFBs.

HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells.

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.

Variation of the frictional anisotropy on ventral scales of snakes caused by nanoscale steps.

The ventral scales of most snakes feature micron-sized fibril structures with nanoscale steps oriented towards the snake's tail. We examined these structures by microtribometry as well as atomic force microscopy (AFM) and observed that the nanoscale steps of the micro-fibrils cause a frictional anisotropy, which varies along the snake's body in dependence of the height of the nanoscale steps. A significant frictional behavior is detected when a sharp AFM tip scans the nanoscale steps up or down. Larger friction peaks appear during upward scans (tail to head direction), while considerably lower peaks are observed for downward scans (head to tail direction). This effect causes a frictional anisotropy on the nanoscale, i.e. friction along the head to tail direction is lower than in the opposite direction. The overall effect increases linearly with the step height of the micro-fibrils. Although the step heights are different for each snake, the general step height distribution along the body of the examined snakes follows a common pattern. The frictional anisotropy, induced by the step height distribution, is largest close to the tail, intermediate in the middle, and lower close to the head. This common distribution of frictional anisotropy suggests that snakes even optimized nanoscale features like the height of micro-fibrils through evolution in order to achieve optimal friction performance for locomotion. Finally, ventral snake scales are replicated by imprinting their micro-fibril structures into a polymer. As the natural prototype, the artificial surface exhibits frictional anisotropy in dependence of the respective step height. This feature is of high interest for the design of tribological surfaces with artificial frictional anisotropy.

Total Synthesis of α- and ß-Amanitin.

α-Amanitin and related amatoxins have been studied for more than six decades mostly by isolation from death cap mushrooms. The total synthesis, however, remained challenging due to unique structural features. α-Amanitin is a potent inhibitor of RNA polymerase II. Interrupting the basic transcription processes of eukaryotes leads to apoptosis of the cell. This unique mechanism makes the toxin an ideal payload for antibody-drug conjugates (ADCs). Only microgram quantities of toxins, when delivered selectively to tumor sites through conjugation to antibodies, are sufficient to eliminate malignant tumor cells of almost every origin. By solving the stereoselective access to dihydroxyisoleucine, a photochemical synthesis of the tryptathion precursor, solid-phase peptide synthesis, and macrolactamization we obtained a scalable synthetic route towards synthetic α-amanitin. This makes α-amanitin and derivatives now accessible for the development of new ADCs.

Locally Controlled Growth of Individual Lambda-Shaped Carbon Nanofibers.

The locally defined growth of carbon nanofibers with lambda shape in an open flame process is demonstrated. Via the growth time, the geometry of the structures can be tailored to a Λ- or λ-type shape. Microchannel cantilever spotting and dip-pen nanolithography are utilized for the deposition of catalytic salt NiCl2 · 6H2 O for locally controlled growth of lambda-shaped carbon nanofibers. Rigorous downscaling reveals a critical catalytic salt volume of 0.033 µm³, resulting in exactly one lambda-shaped carbon nanofiber at a highly predefined position. An empirical model explains the observed growth process.

Amanitins and their development as a payload for antibody-drug conjugates.

Amanitin-based ADCs represent a new class of ADCs using a novel mode of action. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA Polymerase II. The high potency of the toxin leads to highly efficacious ADCs. The development of the technology around this toxin will be described. These developments support the clinical development of amanitin-based ADCs by using a toxin with a new mode of action and with a favorable therapeutic index. HDP-101 is an Amanitin based ADC directed against BCMA and will be advancing to the clinical phase in 2019.

Percutaneous Medial Ligament Reconstruction for Valgus and Rotational Knee Instability.

The following surgical technique is intended for patients with chronic valgus laxity and rotational knee instability. It is a percutaneous 2-bundle ligament reconstruction method that uses the semitendinosus tendon, allowing it to remain pedicled to its distal tibial insertion. The aim is to correct the laxity without otherwise limiting the motion of the knee.

Characterization of the microscopic tribological properties of sandfish (Scincus scincus) scales by atomic force microscopy.

Lizards of the genus Scincus are widely known under the common name sandfish due to their ability to swim in loose, aeolian sand. Some studies report that this fascinating property of sandfish is accompanied by unique tribological properties of their skin such as ultra-low adhesion, friction and wear. The majority of these reports, however, is based on experiments conducted with a non-standard granular tribometer. Here, we characterise microscopic adhesion, friction and wear of single sandfish scales by atomic force microscopy. The analysis of frictional properties with different types of probes (sharp silicon tips, spherical glass tips and sand debris) demonstrates that the tribological properties of sandfish scales on the microscale are not exceptional if compared to snake scales or technical surfaces such as aluminium, Teflon, or highly oriented pyrolytic graphite.

Percutaneous Medial Ligament Reconstruction for Valgus Knee Instability.

Injuries to stabilizing elements on the medial side of the knee are one of the most common knee ailments. Because of the good healing capacity of these structures, acute injuries are typically treated conservatively. However, valgus laxity near full extension can persist in some patients. This laxity may be the source of instability due to medial joint space opening, which then requires surgical treatment. Various procedures have been described that aim to reproduce the anatomy of the medial collateral ligament (MCL) and the posterior oblique ligament (POL), which work together to stabilize the medial aspect of the knee. However, these are complex open surgical procedures, technically demanding to achieve the favorable isometry, which prevent joint contracture or recurrence of laxity. The purpose of this study was to describe a short construct that minimizes the risk of secondary loss of tension and complies with the principle of favorable anisometry. The graft is positioned in the joint opening axis, between the deep bundle of the MCL and the POL.

Dry adhesives from carbon nanofibers grown in an open ethanol flame.

Based on magnetic-field-assisted growth of carbon nanofibers in an open ethanol flame we fabricated arrays of carbon nanofibers with different degrees of orientation. Inspired by the dry adhesive system of geckos we investigated the adhesive properties of such carbon nanofiber arrays with ordered and random orientation. AFM-based force spectroscopy revealed that adhesion force and energy rise linear with preload force. Carbon nanofibers oriented by a magnetic field show a 68% higher adhesion (0.66 N/cm2) than the randomly oriented fibers. Endurance tests revealed that the carbon nanofiber arrays withstand 50.000 attachment/detachment cycles without observable wear.