Empowering pancreatic tumor homing with augmented anti-tumor potency of CXCR2-tethered CAR-NK cells.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising immunotherapy for solid cancers; however, their effectiveness against pancreatic cancer is limited by the immunosuppressive tumor microenvironment. In particular, low NK cell infiltration poses a major obstacle that reduces cytotoxicity. The current study aimed to enhance the tumor-homing capacity of CAR-NK cells by targeting the chemokine-chemokine receptor axis between NK and pancreatic cancer cells. To this end, data from a chemokine array and The Cancer Genome Atlas pan-cancer cohort were analyzed. Pancreatic cancer cells were found to secrete high levels of ligands for C-X-C motif receptor 1 (CXCR1) and CXCR2. Subsequently, we generated anti-mesothelin CAR-NK cells incorporating CXCR1 or CXCR2 and evaluated their tumor-killing abilities in 2D cancer cell co-culture and 3D tumor-mimetic organoid models. CAR-NK cells engineered with CXCR2 demonstrated enhanced tumor killing and strong infiltration of tumor sites. Collectively, these findings highlight the potential of CXCR2-augmented CAR-NK cells as a clinically relevant modality for effective pancreatic cancer treatment. By improving their infiltration and tumor-killing capabilities, these CXCR2-augmented CAR-NK cells have the potential to overcome the challenges posed by the immunosuppressive tumor microenvironment, providing improved therapeutic outcomes.

Efficacy of Adductor Canal Block on Medial Knee Pain in Patients with Knee Osteoarthritis: A Randomized Single-Blind Placebo-Controlled Study.

BACKGROUND: This study aimed to confirm the efficacy of ultrasound-guided adductor canal block (ACB) as a treatment option for medial knee pain caused by knee osteoarthritis (KOA). METHODS: In total, 31 participants with medial knee pain due to KOA were randomized to either the ACB (ultrasound-guided ACB, n = 15) or placebo group (1 mL of 1% lidocaine, n = 16). The primary outcome was a numerical rating scale (NRS) for knee pain intensity comparing before and 4 weeks after injection. The secondary outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), average daily number of analgesics consumed, average daily opioid consumption, and Timed Up and Go (TUG) test results before and 4 weeks after injection. RESULTS: Participants' baseline characteristics were not significantly different between the groups, except for age. At 4 weeks post-injection, the NRS score in the ACB group significantly improved compared to that in the placebo group (p = 0.009). However, the WOMAC, average daily number of analgesics consumed, average daily opioid consumption, and TUG test results did not show significant differences. CONCLUSION: ACB can be an effective treatment for reducing medial knee pain in patients with KOA.

Alverine citrate promotes myogenic differentiation and ameliorates muscle atrophy.

Sarcopenia is the age-related loss of muscle mass and function and no pharmacological medication has been approved for its treatment. We established an atrogin-1/MAFbx promoter assay to find drug candidates that inhibit myotube atrophy. Alverine citrate (AC) was identified using high-throughput screening of an existing drug library. AC is an established medicine for stomach and intestinal spasms. AC treatment increased myotube diameter and inhibited atrophy signals induced by either C26-conditioned medium or dexamethasone in cultured C2C12 myoblasts. AC also enhanced myoblast fusion through the upregulation of fusion-related genes during C2C12 myoblast differentiation. Oral administration of AC improves muscle mass and physical performance in aged mice, as well as hindlimb-disused mice. Taken together, our data suggest that AC may be a novel therapeutic candidate for improving muscle weakness, including sarcopenia.

Receptor-Mediated Muscle Homeostasis as a Target for Sarcopenia Therapeutics.

Sarcopenia is a disease characterized by age-related decline of skeletal muscle mass and function. The molecular mechanisms of the pathophysiology of sarcopenia form a complex network due to the involvement of multiple interconnected signaling pathways. Therefore, signaling receptors are major targets in pharmacological strategies in general. To provide a rationale for pharmacological interventions for sarcopenia, we herein describe several druggable signaling receptors based on their role in skeletal muscle homeostasis and changes in their activity with aging. A brief overview is presented of the efficacy of corresponding drug candidates under clinical trials. Strategies targeting the androgen receptor, vitamin D receptor, Insulin-like growth factor-1 receptor, and ghrelin receptor primarily focus on promoting anabolic action using natural ligands or mimetics. Strategies involving activin receptors and angiotensin receptors focus on inhibiting catabolic action. This review may help to select specific targets or combinations of targets in the future.

Comparative molecular analysis of endurance exercise in vivo with electrically stimulated in vitro myotube contraction.

Exercise has positive effects on health and improves a variety of disease conditions. An in vitro model of exercise has been developed to better understand its molecular mechanisms. While various conditions have been used to mimic in vivo exercise, no specific conditions have matched a specific type of in vivo exercise. Here, we screened various electrical pulse stimulation (EPS) conditions and compared the molecular events under each condition in myotube culture with that obtained under voluntary wheel running (VWR), a mild endurance exercise, in mice. Both EPS and VWR upregulated the mRNA levels of genes involved in the slow-type twitch (Myh7 and Myh2) and myogenesis (Myod and Myog) and increased the protein expression of peroxisome proliferator-activated receptor-γ coactivator-1α, which is involved in mitochondrial biogenesis. These changes were accompanied by activation of p38 and AMPK. However, neither condition induced the expression of muscle-specific E3 ligases such as MAFbx and MuRF1. Both EPS and VWR consistently induced antioxidant genes such as Sod3 and Gpx4 but did not cause similar changes in the expression levels of the calcium channel/pump-related genes Ryr and Serca. Furthermore, both EPS and VWR reduced glycogen levels but not lactate levels as assessed in post-EPS culture medium and post-VWR serum, respectively. Thus we identified an in vitro EPS condition that effectively mimics VWR in mice, which can facilitate further studies of the detailed molecular mechanisms of endurance exercise in the absence of interference from multiple tissues and organs.NEW & NOTEWORTHY This study establishes an optimal condition for electrical pulse stimulation (EPS) in myotubes that shows a similar molecular signature as voluntary wheel running. The specific EPS condition 1) upregulates the mRNA of slow-twitch muscle components and myogenic transcription factors, 2) induces antioxidant genes without any muscle damage, and 3) promotes peroxisome proliferator-activated receptor-γ coactivator-1α and its upstream regulators involved in mitochondrial biogenesis.