A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds

Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image analysis (HCI). This study describes the development of a scalable human iPSC-neuromuscular disease model, whereby suspended elastomer nanofibers support long-term stability, alignment, maturation, and repeated contractions of iPSC-myofibers, innervated by iPSC-motor neurons in 96-well assay plates. In this platform, optogenetic stimulation of the motor neurons elicits robust myofiber-contractions, providing a functional readout of neuromuscular transmission. Additionally, HCI provides rapid and automated quantification of axonal outgrowth, myofiber morphology, and neuromuscular synapse number and morphology. By incorporating amyotrophic lateral sclerosis (ALS)-related TDP-43G298S mutant motor neurons and CRISPR-corrected controls, key neuromuscular disease phenotypes are recapitulated, including weaker myofiber contractions, reduced axonal outgrowth, and reduced number of neuromuscular synapses. Treatment with a candidate ALS drug, the receptor-interacting protein kinase-1 (RIPK1)-inhibitor necrostatin-1, rescues these phenotypes in a dose-dependent manner, highlighting the potential of this platform to screen novel treatments for neuromuscular diseases

Thrust enhancement of DTMB 5415 with elastic flapping foil in regular head waves

Recent studies indicate that bow foil biomimetic systems can significantly improve ship propulsion in waves. In this paper, the DTMB 5415 ship model is taken as the object and a semi-active elastic flapping foil is proposed to install at its bow underwater position. When a ship sails in head wave, heave and pitch motion will occur, which will drive the bow foil to form heave motion. According to the working characteristics of elastic foil, bow foil can generate forward thrust under drive of given heave motion. At first, co-simulation of the ship with self-pitching bow foil in head waves is realized by ISIS-CFD solver and preliminarily realizes drag reduction and thrust increase effect of the bow foil. At the same time, it is found that the effect of bow foil on hull drag reduction is reflected in two aspects, one is the additional thrust generated by the bow foil and the other is that suppression of the bow foil on hull motion also reduces hull resistance in waves. Then, in order to optimize the working characteristics of elastic bow foil, the influence of spring stiffness and span length of the bow foil on drag reduction and thrust increase effect is discussed. A preliminary spring optimization result is obtained, as well as the influence of the span length of the bow foil on the system

Novel Implications of Exosomes and lncRNAs in the Diagnosis and Treatment of Pancreatic Cancer

Pancreatic cancer remains a leading cause of cancer-related deaths. Most patients are present with advanced stages of the disease at the time of diagnosis; thus, surgery, which is the best curative option for this malignancy, is no longer an effective treatment modality for affected individuals. As a likely source of “liquid biopsies,” exosomes, which are secreted by fusing intracellular multivesicular bodies with cell membranes, have relative stability and composition, allowing them to cover the entire range of cancer-related biomarkers, including cellular proteins, lipids, DNA, RNA, miRNA, and long non-coding RNAs (lncRNAs). To explore the early detection biomarkers of pancreatic cancer and to develop successful therapeutic intervention for this disease, assessing the implications of exosomes in pancreatic cancer patients is essential. In this chapter, we wish to focus on the possibility of using exosomes and lncRNAs in the clinical management of patients with pancreatic cancer. We will discuss the mechanisms of tumor formation under the exosomal action, demonstrate how circulating exosomes and lncRNAs have come into the research spotlight as likely biomarkers of pancreatic cancer, and discuss the applications of exosomes as transfer vectors in tumor therapeutics

Upadacitinib sustained-release tablets for the treatment of chronic refractory gouty arthritis: a case report and literature review

BackgroundGouty arthritis (GA) is a crystal-related joint disease caused by the deposition of monosodium urate (MSU) crystals, directly associated with hyperuricemia resulting from purine metabolism disorder and/or reduced uric acid excretion. Acute attacks of typical gouty arthritis are generally relieved through the clinical use of NSAIDs, colchicine, or glucocorticoids. However, managing patients with chronic refractory gout poses challenges due to complications such as multiple tophi, gouty nephropathy, diabetes, and gastrointestinal bleeding. While there have been numerous studies on gout in recent years, research specifically regarding chronic refractory gout remains limited. The management of such cases still faces several unresolved issues, including recurrent disease flare-ups and poor patient compliance leading to inadequate drug utilization and increased risk of side effects. In this report, we present a case of successful improvement in chronic refractory gouty arthritis using the biologic agent upadacitinib sustained-release tablets.Case presentationOur case report involves a 53 years-old Asian patient with recurrent gouty arthritis who had a history of over 20 years without regular treatment, presenting with tophi and an increasing number of painful episodes. During hospitalization, various analgesics and anti-inflammatory drugs provided inadequate relief, requiring the use of steroids to alleviate symptoms. However, tapering off steroids proved challenging. We decided to add upadacitinib sustained-release tablets to the treatment regimen, which ultimately improved the patient’s condition. After 6 months of follow-up, the patient has not experienced any further acute pain episodes.ConclusionThis case highlights the potential therapeutic effect of upadacitinib sustained-release tablets during the acute phase of chronic refractory gouty arthritis

Blocking Wnt Secretion Reduces Growth of Hepatocellular Carcinoma Cell Lines Mostly Independent of β-Catenin Signaling

AbstractAberrant activation of Wnt/β-catenin signaling plays a key role in the onset and development of hepatocellular carcinomas (HCC), with about half of them acquiring mutations in either CTNNB1 or AXIN1. However, it remains unclear whether these mutations impose sufficient β-catenin signaling or require upstream Wnt ligand activation for sustaining optimal growth, as previously suggested for colorectal cancers. Using a panel of nine HCC cell lines, we show that siRNA-mediated knockdown of β-catenin impairs growth of all these lines. Blocking Wnt secretion, by either treatment with the IWP12 porcupine inhibitor or knockdown of WLS, reduces growth of most of the lines. Unexpectedly, interfering with Wnt secretion does not clearly affect the level of β-catenin signaling in the majority of lines, suggesting that other mechanisms underlie the growth-suppressive effect. However, IWP12 treatment did not induce autophagy or endoplasmic reticulum (ER) stress, which may have resulted from the accumulation of Wnt ligands within the ER. Similar results were observed for colorectal cancer cell lines used for comparison in various assays. These results suggest that most colorectal and liver cancers with mutations in components of the β-catenin degradation complex do not strongly rely on extracellular Wnt ligand exposure to support optimal growth. In addition, our results also suggest that blocking Wnt secretion may aid in tumor suppression through alternative routes currently unappreciated