High-dose remifentanil exacerbates myocardial ischemia-reperfusion injury through activation of calcium-sensing receptor-mediated pyroptosis.

Background: The aim of this study was to investigate whether calcium-sensing receptor (CaSR) was involved in HRF-mediated exacerbation of MI/R injury through NLRP3 inflammasome activation and pyroptosis. Methods: In vivo, a rat MI/R model was established by ligating the left coronary artery, and short-term HRF exposure was induced during reoxygenation. Then, TUNEL, H&E, Masson staining, immunohistochemical (IHC) and serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK), as well as the expression levels of CaSR and pyroptosis-related proteins in heart tissues, were measured. H9c2 cells were cultured to create a hypoxia/reoxygenation (H/R) model and exposed to different concentrations of RF. After pretreatment with the CaSR activator gadolinium chloride (GdCl3) and inhibitor NPS2143 in the H/R model and treatment with HRF, we compared cellular viability, TUNEL, cytosolic [Ca2+]i, the levels of LDH and CK, pyroptosis-related proteins and CaSR in H9c2 cells. We further researched the mechanisms of CaSR-mediated pyroptosis in the H/R+HRF model by CaSR-shRNA, Ac-YVAD-CMK, MCC950 and NAC. Results: We found that HRF significantly increased CaSR expression, rate of cell death, levels of CK and LDH, and exacerbated pyroptosis in MI/R model. In vitro, HRF increased CaSR expression, decreased viability, enhanced cytosolic [Ca2+]i and exacerbated pyroptosis in H/R cells. Pretreated with GdCl3 worsen these changes, and NPS2143, MCC950, Ac-YVAD-CMK, NAC and sh-CaSR can reversed these effects. Conclusion: Exposure to HRF for a short time exacerbates MI/R-induced injury by targeting CaSR to increase cytosolic [Ca2+]i and ROS levels, which mediate the NLRP3 inflammasome and pyroptosis.

Loss of MLL Induces Epigenetic Dysregulation of Rasgrf1 to Attenuate Kras-Driven Lung Tumorigenesis.

Menin is necessary for the formation of the menin/mixed lineage leukemia (MLL) complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small-molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations. SIGNIFICANCE: Activation of mutant Kras is dependent on MLL-mediated epigenetic regulation of Rasgrf1, conferring sensitivity to small-molecule inhibition of MLL in Kras-driven lung cancer.

Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease associated with myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine (Dex), an α2-adrenoceptor agonist, has been reported to protect against I/R injury. We examined the cardioprotective effects of Dex on cardiomyocytes under hypoxia/reoxygenation (H/R) conditions and explored the underlying mechanisms. MATERIALS AND METHODS: A H/R model was established to mimic the MI injury. The CCK-8 assay was performed to measure cell viability. Cellular apoptosis was measured using the Annexin V fluorescein isothiocyanate (FITC)-propidium iodide (PI) staining. The levels of interleukin (IL)-1α and tumor necrosis factor (TNF)-α, and the activity of lactate dehydrogenase (LDH) were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Reactive oxygen species (ROS) were measured using the 2'-7' dichlorofluorescein diacetate (DCFH-DA) staining assay. In addition, the levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT), and caspase-3 were measured using a commercial kit. siRNA was used to silence Bcl-2, catalase, or STAT3. Western blotting was used to measure the change in the levels of proteins. RESULTS: Dex improved the cell viability and inhibited the inflammatory response in H9c2 cells exposed to H/R treatment. In addition, Dex inhibited apoptosis and alleviated the endoplasmic reticulum (ER) stress and oxidative stress in H9c2 cells under the H/R treatment. Mechanism investigation showed that Dex inhibited the intrinsic pathway of apoptosis. Moreover, Dex enhanced the activation of the JAK2/STAT3 signaling pathway in H/R-treated H9c2 cells. CONCLUSION: Altogether, our findings suggested Dex as a promising therapeutic agent for myocardial I/R.

Smoking is a risk factor for postoperative ileus after radical resection in male patients.

ABSTRACT: Most smokers are males, and smoking has been indicated as a risk factor for many cancers as well as postoperative complications after cancer surgery. However, little is known about whether smoking is a risk factor for postoperative ileus (POI) after radical rectal cancer resection in males. The aim of this study was to assess whether smoking is a risk factor for POI after radical resection in male rectal cancer patients.Data of 1486 patients who underwent radical resection for rectal cancer were extracted from the clinical medical system in our hospital and were statistically analyzed. POI was defined as nausea, vomiting or pain, failure to have bowel function for more than 4 days postoperatively, and absence of a mechanical bowel obstruction.The rate of POI was 12.79%. Univariate analysis showed that patients in the POI group were more likely to have a history of smoking and drinking and receive intraperitoneal chemotherapy and had a larger intraperitoneal chemotherapy dosage. In the multivariable analysis, smoking remained significantly associated with a higher incidence of POI (OR 2.238, 95% CI [1.545-3.240], P = .000). The results also showed that patients who received postoperative patient-controlled intravenous analgesia had a lower incidence of POI.Male patients with a history of smoking who undergo elective radical resection for rectal cancer have an increased risk for POI complications.

Effect of Deep Versus Moderate Neuromuscular Block on Pain After Laparoscopic Colorectal Surgery: A Randomized Clinical Trial.

BACKGROUND: Anesthesia with deep neuromuscular block for laparoscopic surgery may result in less postoperative pain with lower intra-abdominal pressure. However, results in the existing literature are controversial. OBJECTIVE: The study aimed to evaluate the effect of deep neuromuscular block on postoperative pain at rest and during coughing after laparoscopic colorectal surgery. DESIGN: The design is a parallel-group, randomized clinical trial. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Patients undergoing laparoscopic resection of colorectal tumors were included. INTERVENTIONS: Patients were randomly assigned to either a deep (posttetanic count 1 to 2) or moderate (train-of-four 1 to 2) neuromuscular group. MAIN OUTCOME MEASURES: The coprimary efficacy outcomes were numeric rating scale scores of the postoperative pain at rest and during coughing after surgery. RESULTS: Pain was lower in the deep neuromuscular block group at rest and during coughing at 1, 6, 24, and 48 hours after surgery (median difference of 2 points and 1 point at 1 h; p < 0.001 at each time point). The deep neuromuscular block group displayed a significantly lower number of bolus attempts by the patient (4 in the deep group vs 9 in the moderate group; p < 0.001) and boluses delivered (4 in the deep group vs 9 in the moderate group; p < 0.001) on postoperative day 1. The number of rescue analgesics was lower in the deep group on postoperative day 2 (p < 0.001). The deep neuromuscular block group showed a lower frequency of postoperative nausea and vomiting (p = 0.02) and lower intraoperative intra-abdominal pressure (p < 0.001). LIMITATIONS: This was a single-center study. CONCLUSIONS: Deep neuromuscular block resulted in better pain relief and lower opioid consumption and use of rescue analgesics after laparoscopic colorectal surgery. Deep neuromuscular block was associated with less postoperative nausea and vomiting and facilitated the use of lower intra-abdominal pressure in laparoscopic surgery. See Video Abstract at http://links.lww.com/DCR/B458. EFECTO DEL BLOQUEO NEUROMUSCULAR PROFUNDO VERSUS MODERADO EN EL DOLOR, DESPUS DE LA CIRUGA COLORRECTAL LAPAROSCPICA UN ENSAYO CLNICO ALEATORIZADO: ANTECEDENTES:La anestesia con bloqueo neuromuscular profunda para cirugía laparoscópica, puede resultar con menor dolor postoperatorio y con menos presión intraabdominal. Sin embargo, los resultados en la literatura existente son controvertidos.OBJETIVO:El objetivo del estudio, fue evaluar el efecto del bloqueo neuromuscular profundo en dolor postoperatorio de reposo y con la tos, después de cirugía colorrectal laparoscópica.DISEÑO:Ensayo clínico aleatorizado de grupos paralelos.AJUSTE:El estudio se realizó en un centro de atención terciaria.PACIENTES:Se incluyeron pacientes sometidos a resección laparoscópica de tumores colorrectales.INTERVENCIONES:Los pacientes fueron aleatorizados a un grupo neuromuscular profundo (recuento posttetánico 1 a 2) o moderado (tren de cuatro 1 a 2).PRINCIPALES MEDIDAS DE RESULTADO:Los resultados coprimarios de eficacia, fueron las puntuaciones numéricas en la escala de calificación del dolor postoperatorio en reposo y durante la tos, después de la cirugía.RESULTADOS:El dolor fue menor en el grupo de bloqueo neuromuscular profundo en reposo y durante la tos, en 1, 6, 24, 48 horas después de la cirugía, (diferencia de mediana de 2 puntos y 1 punto respectivamente en 1 hora; p <0,001 en cada punto de tiempo). El grupo de bloqueo neuromuscular profundo, mostró un número significativamente menor de intentos de bolo por parte del paciente, (4 en el grupo profundo versus 9 del grupo moderado, p <0,001) y de bolos administrados (4 en el grupo profundo versus 9 en el grupo moderado, p <0,001) en el primer día postoperatorio. El número de analgésicos de rescate, fue menor en el grupo profundo en el segundo día postoperatorio (p <0,001). El grupo de bloqueo neuromuscular profundo, mostró una menor frecuencia de náuseas y vómitos postoperatorios (p = 0,02) y una menor presión intraoperatoria e intraabdominal (p <0,001).LIMITACIONES:Este estudio fue un estudio de un solo centro.CONCLUSIONES:El bloqueo neuromuscular profundo, resultó en mayor alivio del dolor y menor consumo de opioides y uso de analgésicos de rescate, después de la cirugía colorrectal laparoscópica. El bloqueo neuromuscular profundo, se asoció con menos náuseas y vómitos posoperatorios y facilitó el uso de una presión intraabdominal más baja, en la cirugía laparoscópica. Consulte Video Resumen en http://links.lww.com/DCR/B458.

MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response.

The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Here, we established an ATII-specific KrasG12D/+/Men1-/- driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival.

Efficacy of oxycodone in intravenous patient-controlled analgesia with different infusion modes after laparoscopic radical surgery of cervical cancer a prospective, randomized, double-blind study.

BACKGROUD: The aim of this study was to compare the analgesic and adverse effects of oxycodone with 3 different infusion modes on postoperative pain after laparoscopic radical surgery of cervical cancer. METHODS: Ninety patients undergoing laparoscopic radical surgery of cervical cancer were randomly divided into 3 groups: Group A (continuous infusion with 0.01 mg/kg/h and a bolus dose with 0.03 mg/kg), Group B (a bolus dose with 0.03 mg/kg) and Group C (PCA was administered as a time-scheduled decremental continuous infusion based on lean body mass). A blinded observer recorded Visual Analogue Scale (VAS), Ramsay sedation score (RSS), infused cumulative dose of oxycodone and side effects at 1, 6, 12, 24, and 48 hours postoperatively, and satisfaction during the postoperative 48 hours. RESULTS: There were significant differences in the VAS pain score when resting or coughing among 3 groups at 1, 6 and 48 hours postoperatively (P <.05). VAS was significantly higher in Group B than in Group A and C until postoperative 1, 6, and 48 hours (P <.05). There were significant differences in cumulative PCA dose among the 3 groups at 1 and 48 hours postoperatively (P <.05). Group C showed significantly less amount of cumulative PCA dose compared to other 2 groups at 1 hour, whereas cumulative PCA dose of Group A at 48 hours was significantly more than other 2 groups (P <.05). There were no significant differences in postoperative nausea and vomiting, FAS, muscle chilling score and RSS among 3 groups at 1, 6, 12, 24 and 48 hours postoperatively. In addition, there was no difference in overall satisfaction during 48 hours postoperatively among 3 groups. CONCLUSIONS: Oxycodone provides significant analgesic effect in 3 different infusion modes over 48 hours after laparoscopic radical surgery of cervical cancer, and a time-scheduled decremental continuous infusion of oxycodone can become a better choice for patients after surgery of cervical cancer.