Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury.

Traumatic brain injury (TBI) is a debilitating disease with no current therapies outside of acute clinical management. While acute, controlled inflammation is important for debris clearance and regeneration after injury, chronic, rampant inflammation plays a significant adverse role in the pathophysiology of secondary brain injury. Immune cell therapies hold unique therapeutic potential for inflammation modulation, due to their active sensing and migration abilities. Macrophages are particularly suited for this task, given the role of macrophages and microglia in the dysregulated inflammatory response after TBI. However, maintaining adoptively transferred macrophages in an anti-inflammatory, wound-healing phenotype against the proinflammatory TBI milieu is essential. To achieve this, we developed discoidal microparticles, termed backpacks, encapsulating anti-inflammatory interleukin-4, and dexamethasone for ex vivo macrophage attachment. Backpacks durably adhered to the surface of macrophages without internalization and maintained an anti-inflammatory phenotype of the carrier macrophage through 7 days in vitro. Backpack-macrophage therapy was scaled up and safely infused into piglets in a cortical impact TBI model. Backpack-macrophages migrated to the brain lesion site and reduced proinflammatory activation of microglia in the lesion penumbra of the rostral gyrus of the cortex and decreased serum concentrations of proinflammatory biomarkers. These immunomodulatory effects elicited a 56% decrease in lesion volume. The results reported here demonstrate, to the best of our knowledge, a potential use of a cell therapy intervention for a large animal model of TBI and highlight the potential of macrophage-based therapy. Further investigation is required to elucidate the neuroprotection mechanisms associated with anti-inflammatory macrophage therapy.

A framework for robotic excavation and dry stone construction using on-site materials.

Automated building processes that enable efficient in situ resource utilization can facilitate construction in remote locations while simultaneously offering a carbon-reducing alternative to commonplace building practices. Toward these ends, we present a robotic construction pipeline that is capable of planning and building freeform stone walls and landscapes from highly heterogeneous local materials using a robotic excavator equipped with a shovel and gripper. Our system learns from real and simulated data to facilitate the online detection and segmentation of stone instances in spatial maps, enabling robotic grasping and textured 3D scanning of individual stones and rubble elements. Given a limited inventory of these digitized stones, our geometric planning algorithm uses a combination of constrained registration and signed-distance-field classification to determine how these should be positioned toward the formation of stable and explicitly shaped structures. We present a holistic approach for the robotic manipulation of complex objects toward dry stone construction and use the same hardware and mapping to facilitate autonomous terrain-shaping on a single construction site. Our process is demonstrated with the construction of a freestanding stone wall (10 meters by 1.7 meters by 4 meters) and a permanent retaining wall (65.5 meters by 1.8 meters by 6 meters) that is integrated with robotically contoured terraces (665 square meters). The work illustrates the potential of autonomous heavy construction vehicles to build adaptively with highly irregular, abundant, and sustainable materials that require little to no transportation and preprocessing.

Transcriptomic changes across vitellogenesis in the black tiger prawn (Penaeus monodon), neuropeptides and G protein-coupled receptors repertoire curation.

The black tiger prawn (Penaeus monodon) is one of the most commercially important prawn species world-wide, yet there are currently key issues that hinder aquaculture of this species, such as low spawning capacity of captive-reared broodstock females and lack of globally available fully domesticated strains. In this study, we analysed the molecular changes that occur from vitellogenesis to spawning of a fully domesticated population of P.monodon (Madagascar) using four tissues [brain and thoracic ganglia (central nervous system - CNS), eyestalks, antennal gland, and ovary] highlighting differentially expressed genes that could be involved in the sexual maturation. In addition, due to their key role in regulating multiple physiological processes including reproduction, transcripts encoding P.monodon neuropeptides and G protein-coupled receptors (GPCRs) were identified and their expression pattern was assessed. A few neuropeptides and their putative GPCRs which were previously implicated in reproduction are discussed. We identified 573 differentially expressed transcripts between previtellogenic and vitellogenic stages, across the four analysed tissues. Multiple transcripts that have been linked to ovarian maturation were highlighted throughout the study, these include vitellogenin, Wnt, heat shock protein 21, heat shock protein 90, teneurin, Fs(1)M3, hemolymph clottable proteins and some other candidates. Seventy neuropeptide transcripts were also characterized from our de novo assembly. In addition, a hybrid approach that involved clustering and phylogenetics analysis was used to annotate all P. monodon GPCRs, revealing 223 Rhodopsin, 100 Secretin and 27 Metabotropic glutamate GPCRs. Given the key commercial significance of P.monodon and the industry requirements for developing better genomic tools to control reproduction in this species, our findings provide a foundation for future gene-based studies, setting the scene for developing innovative tools for reproduction and/or sexual maturation control in P. monodon.

Closed rupture of flexor digitorum profundus in zone III.

Closed ruptures of the flexor digitorum profundus (FDP) tendon cause a loss of active flexion at the distal interphalangeal joint. Commonly referred to as a 'jersey finger' because of its association with tackling sports, the distal aspect of FDP is avulsed from its insertion on the distal phalanx in zone I, with or without a fragment of bone. Because of this classic injury mechanism and pattern, providers may not seek advanced imaging beyond plain radiographs. Although rare, injury to FDP more proximally may occur. More often this injury is associated with a weak underlying tendon because of repetitive microtrauma or anomalous anatomy, for example. We present a case of a closed rupture of the FDP in zone III, and stress the importance of maintaining a high clinical suspicion and the potential use of adjunct ultrasound imaging to localise the site of injury.

Survival and cardiac toxicity in patients with HER2-positive, metastatic breast cancer treated with trastuzumab in routine clinical practice.

AIMS: We sought to describe survival outcomes and toxicities of trastuzumab in real-world patients with HER2-positive, metastatic breast cancer (MBC) and compare these to a recent systematic review of clinical trials. METHODS: We searched the medical records of three Sydney cancer centers for patients with HER2-positive, MBC starting trastuzumab from January 2001 to March 2017. We recorded patient, tumor, and treatment characteristics; survival times from start of palliative trastuzumab; and rates of cardiac toxicity. Survival distribution was summarized using the following percentiles (represented scenario): 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). Survival times were compared to recent review of HER2-positive MBC randomized trials. Factors associated with survival were assessed with Cox models. RESULTS: Characteristics of the 126 patients were: median age 53 years, ER positive cancer (50%), de-novo metastatic disease (23%), prior adjuvant trastuzumab (15%), liver metastases (37%), and brain metastases (23%). The median duration of first-line trastuzumab was 11 months (interquartile range, (IQR) 5-27). Survival times in months (vs the systematic review) were: 90th percentile 8 (9); 75th percentile 16 (19); and median 34 (33). Follow-up duration was insufficient to estimate the 25th and 10th percentiles, similar to the systematic review. Liver metastases were associated with shorter survival (HR = 1.74, 95% CI, 1.1-2.76, P = .02). Seventy percent of patients had a baseline cardiac assessment. Five patients (3.9%) developed symptomatic cardiac toxicity, similar to clinical trials. CONCLUSION: Survival and cardiac toxicity rates for women starting trastuzumab in routine practice were comparable to clinical trials. Oncologists can use clinical trial data as a reference point when explaining survival outcomes to women with HER2-positive MBC.