Background: Several studies have shown that excessive protein degradation is a major cause of skeletal muscle atrophy induced by sepsis, and autophagy is the main pathway participating in protein degradation. However, the role of autophagy in sepsis is still controversial. Previously, we found that neuregulin-1β (NRG-1β) alleviated sepsis-induced diaphragm atrophy through the phosphatidylinositol-3 kinase signaling pathway. Akt/mechanistic target of rapamycin (mTOR) is a classic signaling pathway to regulate autophagy, which maintains intracellular homeostasis. This study aimed to investigate whether NRG-1β could alleviate sepsis-induced skeletal muscle atrophy by regulating autophagy. Methods: L6 rat myoblast cells were differentiated using 2% fetal bovine serum into myotubes, which were divided into four groups: Con group treated with normal serum; Sep group treated with septic serum to form a sepsis cell model; septic serum + NRG-1β (SN) group treated with septic serum for 24 h followed by injection with NRG-1β and incubation for another 48 h; and serum+NRG-1β+LY294002 group, in which the PI3K inhibitor LY294002 was added 30 min before NRG-1β, and other treatments were similar to those in SN group. Effects of NRG-1β were also evaluated in vivo using Sprague–Dawley (SD) rats, in which sepsis was induced by cecal ligation and puncture (CLP). Results: In L6 myotubes treated with septic serum, the expression of autophagy-related proteins UNC-51 like kinase 1, p-Beclin-1, and Beclin-1, and the ratio of LC3B II/I were highly increased, while protein p62 expression was decreased, indicating that autophagy was excessively activated. Moreover, NRG-1 expression was decreased, as detected by confocal immunofluorescence and western blotting. Upon exogenous addition of NRG-1β, autophagy was inhibited by the activation of Akt/mTOR signaling pathway, and cell viability was also increased. These effects disappeared in the presence of LY294002. In SD rats, sepsis was induced by CLP. NRG-1β was shown to inhibit autophagy in these rats via the Akt/mTOR pathway, leading to increased body weight of the septic SD rats and alleviation of atrophy of the tibialis anterior muscle. Conclusion: NRG-1β could alleviate sepsis-induced skeletal muscle atrophy by inhibiting autophagy via the AKT/mTOR signaling pathway.

Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.

Since its introduction in 2013, the anterior quadratus lumborum (QL) block (QLB) has been widely used for analgesia in abdominal, pelvic, and hip surgeries, based on the assumption that it has analgesic effects on both incisional and visceral pain. However, the mechanism of the anterior QLB remains unclear, and the results of relevant studies are contradictory. This review aimed to summarize the dispersion patterns of injectates in anterior QLB. We conducted literature searches using PubMed, Cochrane, and Embase databases. A total of 10 cadaveric or radiological studies meeting the inclusion and exclusion criteria were summarized. The dye or contrast agent spread to the thoracic paravertebral space in only 5 of the studies reviewed. Variability in the selection of injection sites relative to the anterior layer of the thoracolumbar fascia during anterior QLB implementation may explain the dispersion difference. The correct injection site of an anterior QLB is anterior to the QL muscle and between the QL muscle and the anterior layer of the thoracolumbar fascia. Further studies are needed to verify the injectate dispersion pattern during anterior QLB.

Article: Comparison of the analgesic effect of quadratus lumborum block and epidural block in open uterine surgery: a randomized controlled trial - Minerva Anestesiologica 2021 April;87(4):414-22 - Minerva Medica - Journals

Objectives: This study aimed to investigate the perioperative analgesic effects of anterior quadratus lumborum block (QLB) for total laparoscopic hysterectomy (TLH). Materials and Methods: One hundred patients undergoing TLH were randomized to receive an anterior QLB or placebo before general anesthesia. The primary and secondary outcomes were postoperative sufentanil consumption, intraoperative remifentanil demand, time to first opioid demand, numeric rating scale (NRS) pain scores, heart rate, mean arterial pressure, and complications within 24 hours after surgery. Results: No significant intergroup differences were observed in sufentanil consumption within 24 hours after surgery. Remifentanil consumption during surgery was lower in the QLB group than in the placebo group. At 1 hour after surgery, the NRS scores of abdominal visceral pain at rest and during activity were 1.26 and 1.41 points lower than those in the placebo group. In other time points, the differences in abdominal visceral pain were neither statistically significant nor clinically significant (pain difference <1) or both. No significant differences in NRS scores of shoulder pain, abdominal incisional pain, and perineal pain were observed between the 2 groups, at rest or during activity. There were no significant differences in other secondary outcome variables between the 2 groups. Discussion: Preoperative bilateral anterior QLB only reduced intraoperative opioid demand and postoperative abdominal visceral pain scores at 1 hour after surgery. Thus, the clinical significance of anterior QLB in TLH may be limited.

Purpose: Multiple regional nerve blocks proved no additional benefit in total laparoscopic hysterectomy in multimodal analgesia, as postoperative pain may mainly originate from the vaginal cuff. Theoretically, caudal block can relieve pain from the vaginal cuff by a sacral spinal nerve block. We aimed to verify whether a caudal block with ropivacaine and morphine can achieve an analgesic effect without additional adverse effects after a total laparoscopic hysterectomy. Patients and Methods: Forty-eight patients undergoing total laparoscopic hysterectomy were randomly allocated to receive preoperative caudal block with 20 mL of mixture including 0.25% ropivacaine and 2 mg morphine (caudal block group) or sham block (sham group). The primary outcome was the postoperative 24 h cumulative sufentanil consumption. Results: Median (IQR) sufentanil consumption in the first 24 postoperative hours of the caudal block group and the sham group was 0.00 (0.00 to 0.05) μg/kg vs 0.13 (0.04 to 0.21) μg/kg, respectively, p < 0.001. The majority of patients felt that visceral pain was more intense than incisional pain at 1, 6, 12, and 24 h post-surgery in the sham group (95.8% at 1 h, 95.8% at 6 h, 95.8% at 12 h, and 75% at 24 h post-surgery). Compared to the sham group, the caudal block reduced visceral pain scores at rest and during movement at 1 h (p < 0.001), 6 h (p < 0.001), 12 h (p < 0.001), and 24 h (p < 0.001) post-surgery. Intraoperative remifentanil consumption was significantly lower in the caudal block group than in the sham group (p = 0.004). There were no significant differences in other secondary outcomes between the two groups. Conclusion: A caudal block with ropivacaine and morphine could provide a satisfactory analgesic effect for 24 h postoperatively without additional adverse effects after total laparoscopic hysterectomy.