Endothelin-1-mediated Brainstem Glial Activation Produces Asthmatic Airway Vagal Hypertonia Via Enhanced ATP-P2X4 Receptor Signaling in Sprague-Dawley Rats.

The occurrence of major asthma symptoms is largely attributed to airway vagal hypertonia, of which the central mechanisms remain unclear. This study tests the hypotheses that endothelin-1-mediated brainstem glial activation produces asthmatic airway vagal hypertonia via enhanced action of adenosine 5'-triphosphate on neuronal purinergic P2X4 receptors. A rat model of asthma was prepared using ovalbumin. Airway vagal tone was evaluated by the recurrent laryngeal discharge and plethysmographic measurement of pulmonary function. The changes in the brainstem were examined using ELISA, Western blot, luciferin-luciferase, quantitative reverse transcription-polymerase chain reaction, enzyme activity assay and immunofluorescent staining, respectively. The results showed that in the medulla of rats, endothelin receptor type B and P2X4 receptors were primarily expressed in astrocytes and neurons, respectively, and both of which, along with endothelin-1 content, were significantly increased after ovalbumin sensitization. Ovalbumin sensitization significantly increased recurrent laryngeal discharge, which was blocked by acute intracisternal injection of P2X4 receptor antagonist 5-BDBD, knockdown of brainstem P2X4 receptors, and chronic intraperitoneal injection of endothelin receptor type B antagonist BQ788, respectively. Ovalbumin sensitization activated microglia and astrocytes and significantly decreased ecto-5'-nucleotidase activity in the medulla, and all of which, together with the increase of medullary P2X4 receptor expression and decrease of pulmonary function, were reversed by chronic BQ788 treatment. These results demonstrated that in rats, allergic airway challenge activates both microglia and astrocytes in the medulla via enhanced endothelin-1/endothelin receptor type B signaling, which subsequently causes airway vagal hypertonia via augmented adenosine 5'-triphosphate/P2X4 receptor signaling in central neurons of airway vagal reflex.

Prognostic significance of systemic immune-inflammation index in patients with nonfunction pancreatic neuroendocrine tumor undergoing surgical resection.

PURPOSE: The purpose of our study was to investigate the clinical significance and prognostic role of the systemic immune-inflammation index (SII) in patients who underwent surgical resection for nonfunctioning pancreatic neuroendocrine tumors (pNETs). METHODS: We conducted a retrospective analysis of 364 patients with nonfunctioning pNETs. The association between the SII level and clinical parameters was investigated. The receiver operating characteristic (ROC) curve was used to calculate the optimal SII value. Cox proportional hazard analysis was performed to evaluate the prognostic factors. RESULTS: Our study included 364 patients with nonfunctioning pNETs who underwent surgery. The median age was 51.0 (43.0, 59.3), and 164 (45.1%) were male. The optimal threshold of SII determined by ROC analysis was 523.95. Higher SII levels were significantly associated with older age (p = 0.001), sex (p = 0.011), tumor size (p = 0.032), and tumor grade (p = 0.002). Recurrence was observed in 70 (19.2%) patients following a median follow-up of 98 months. Univariate analysis showed that higher SII (p < 0.0001), tumor size >4 cm (p = 0.015), and G2/G3 grade (p = 0.002) were significantly associated with disease-free survival (DFS). Multivariate analysis revealed that higher SII (HR: 7.35; 95% CI: 3.44, 15.70; p < 0.0001) and G2/G3 grade (HR: 3.11; 95% CI: 1.42, 6.82; p = 0.005) remained significantly associated with tumor recurrence. Furthermore, 46 (12.6%) patients died during the follow-up. Higher SII (HR: 8.43; 95% CI: 3.19, 22.72; p < 0.0001) and G2/G3 grade (HR: 3.16; 95% CI: 1.01, 9.86; p = 0.048) were independent predictors of overall survival (OS) by multivariate analysis. CONCLUSION: In conclusion, our study revealed that a higher SII level was associated with tumor-related features (larger tumor size and advanced grade) and subsequent shorter DFS and OS in patients with nonfunctioning pNETs. These results indicated that the SII could serve as an efficient prognostic biomarker for nonfunctioning pNETs.

A nomogram to preoperatively predict the aggressiveness of non-functional pancreatic neuroendocrine tumors based on CT features.

OBJECTIVES: To develop a nomogram to predict the aggressiveness of non-functional pancreatic neuroendocrine tumors (NF-pNETs) based on preoperative computed tomography (CT) features. METHODS: This study included 176 patients undergoing radical resection for NF-pNETs. These patients were randomly divided into the training (n = 123) and validation sets (n = 53). A nomogram was developed based on preoperative predictors of aggressiveness of the NF-pNETs which were identified by univariable and multivariable logistic regression analysis. The aggressiveness of NF-pNETs was defined as a composite measure including G3 grading, N+, distant metastases, and/ or disease recurrence. RESULTS: Altogether, the number of patients with highly aggressive NF-pNETs was 37 (30.08 %) and 15 (28.30 %) in the training and validation sets, respectively. Multivariable logistic regression analysis identified that tumor size, biliopancreatic duct dilatation, lymphadenopathy, and enhancement pattern were preoperative predictors of aggressiveness. Those variables were used to develop a nomogram with good concordance statistics of 0.89 and 0.86 for predicting aggressiveness in the training and validation sets, respectively. With a nomogram score of 59, patients with NF-pNETs were divided into low-aggressive and high-aggressive groups. The high-aggressive group had decreased overall survival (OS) and disease-free survival (DFS). Moreover, the nomogram showed good performance in predicting OS and DFS at 3, 5, and 10 years. CONCLUSION: The nomogram integrating CT features helped preoperatively predict the aggressiveness of NF-pNETs and could potentially facilitate clinical decision-making.

Clusterin is upregulated by erastin, a ferroptosis inducer and exerts cytoprotective effects in pancreatic adenocarcinoma cells.

Ferroptosis is a novel form of cell death, which is distinguished from apoptosis and necrosis, and characterized by accumulation of lipid-based reactive oxygen species (ROS) in an iron-dependent manner. Erastin, a small molecule, was widely reported to trigger ferroptosis in various kinds of cancer cells, including pancreatic cancer cells by inducing ROS accumulation. However, how erastin treatment exerts cytotoxicity is not still fully understood. In this study, the effects of erastin in causing pancreatic cancer cell death via inducing ferroptosis and apoptosis are investigated. As expected, erastin treatment caused ROS accumulation, increase in iron concentration and non-apoptotic cell death, which is different from that of induced by apoptosis inducer, staurosporine. Interestingly, erastin treatment caused the upregulation of clusterin, which contributes to the regulation of malignant behaviors of pancreatic cancer, including preventing apoptosis and inducing chemoresistance. Without erastin treatment, overexpressed clusterin significantly promoted cell proliferation, which is consistent with its cytoprotective roles. After erastin treatment, overexpressed clusterin decreased erastin-induced ROS accumulation and cell death. By measuring iron concentration, reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4), it is revealed that clusterin caused resistance to erastin-induced ferroptosis potentially via maintaining the enzymatic activity of GPX4, without disturbing GSH amount. Thus, ferroptosis inducer, erastin, may crosstalk with apoptotic cell death via regulating clusterin, indicating a more complex regulatory network between ferroptosis and apoptosis.

Decoding surgical skill: an objective and efficient algorithm for surgical skill classification based on surgical gesture features -experimental studies.

BACKGROUND: Various surgical skills lead to differences in patient outcomes and identifying poorly skilled surgeons with constructive feedback contributes to surgical quality improvement. The aim of the study was to develop an algorithm for evaluating surgical skills in laparoscopic cholecystectomy based on the features of elementary functional surgical gestures (Surgestures). MATERIALS AND METHODS: Seventy-five laparoscopic cholecystectomy videos were collected from 33 surgeons in five hospitals. The phase of mobilization hepatocystic triangle and gallbladder dissection from the liver bed of each video were annotated with 14 Surgestures. The videos were grouped into competent and incompetent based on the quantiles of modified global operative assessment of laparoscopic skills (mGOALS). Surgeon-related information, clinical data, and intraoperative events were analyzed. Sixty-three Surgesture features were extracted to develop the surgical skill classification algorithm. The area under the receiver operating characteristic curve of the classification and the top features were evaluated. RESULTS: Correlation analysis revealed that most perioperative factors had no significant correlation with mGOALS scores. The incompetent group has a higher probability of cholecystic vascular injury compared to the competent group (30.8 vs 6.1%, P =0.004). The competent group demonstrated fewer inefficient Surgestures, lower shift frequency, and a larger dissection-exposure ratio of Surgestures during the procedure. The area under the receiver operating characteristic curve of the classification algorithm achieved 0.866. Different Surgesture features contributed variably to overall performance and specific skill items. CONCLUSION: The computer algorithm accurately classified surgeons with different skill levels using objective Surgesture features, adding insight into designing automatic laparoscopic surgical skill assessment tools with technical feedback.

Dinaciclib exerts a tumor-suppressing effect via ß-catenin/YAP axis in pancreatic ductal adenocarcinoma.

Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing ß-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating ß-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.

TSPO is a novel biomarker for prognosis that regulates cell proliferation through influencing mitochondrial functions in HCC.

The disorder of mitochondrial functions plays a key role in oncogenesis. It is known that TSPO (18-kDa translocator protein) lies in a peculiar location at the interface between the mitochondria and the cytosol. TSPO is found in many types of tissues and is associated with multiple cellular processes, including apoptosis, cell proliferation and the regulation of mitochondria. However, the involvement of TSPO in hepatocellular carcinoma (HCC) remains unclear. In this study, we found that TSPO is upregulated in HCC tissue and is associated with poor differentiation and poor survival. Multivariate analyses showed that TSPO was an independent predictive factor for poor prognosis in HCC patients. For the first time, we provided evidence that TSPO knockdown suppressed HCC cell proliferation in vitro. Hence, TSPO knockdown-induced apoptosis by disturbing mitochondrial function by enhancing the formation of reactive oxygen species (ROS) and decreasing the mitochondrial membrane potential (ΔΨm). An assay exploring the underlying mechanism revealed that TSPO knockdown modulated apoptotic regulatory proteins by regulating the ERK signaling pathway. Through a functional assay and an in vivo mouse model, the anti-cancer effect of PK11195, a specific ligand of TSPO, on HCC was revealed. In summary, TSPO may potentially serve as a prognostic biomarker, and TSPO might be a potential therapeutic target for HCC.

Improved Results From Medium and Long-Term Outcomes of Autogenous Osteoperiosteal Grafting for Large Cystic Lesions of the Talus.

PURPOSE: To investigate the medium and long-term follow-up outcomes of large cystic medial osteochondral lesions of the talus (OLTs) treated with autologous tibial osteoperiosteal grafts from the medial tibia, and to explore the risk factors influencing the treatment outcomes. METHODS: The retrospective study included 75 patients with large cystic medial OLTs who underwent autologous osteoperiosteal cylinder graft taken from the medial tibia between January 2004 and August 2018. They were assessed preoperatively and postoperatively using a visual analog scale (VAS), the Orthopedic Foot & Ankle Society Ankle-Hindfoot Scale (AOFAS) and short-form 36-item questionnaire score (SF-36). Magnetic resonance observation of cartilage repair tissue (MOCART), second-look arthroscopy, and biopsy were used to evaluate the grafting areas. RESULTS: After a follow-up period of 6.3 years, the VAS score decreased to 1.47 ± 1.32, while the AOFAS and SF-36 scores increased to 82.78 ± 11.65 and 83.26 ± 8.49, respectively, all of which showed significant improvement over preoperative scores (P < .001), and the average MOCART score was 82.6 ± 8.4 (56.0-91.6). Eight patients underwent a second-look arthroscopic examination and were rated by the International Cartilage Repair Society scale; of them, 2 patients were rated grade Ⅰ, 4 were rated grade Ⅱ, and 2 were rated grade Ⅲ. Three patients underwent grafting area biopsy during the second-look arthroscopy, and the results showed that the grafting areas were rich in chondrocytes. Large-size OLTs (≥200 mm2) and obesity (BMI ≥ 25 kg/m2) were responsible for the poor improvement of AOFAS, according to multivariate Cox regression analysis. CONCLUSIONS: Autologous osteoperiosteal grafting was an effective treatment for large cystic medial OLTs, with effective cartilage regeneration in the grafted areas in the medium and long term. However, the large-size OLTs and obesity may reduce the treatment outcomes. LEVEL OF EVIDENCE: Level IV, case series.

Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma.

BACKGROUND: Islet amyloid deposition and reduced ß-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects. To date, the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma (PDAC) have not been specifically addressed. AIM: To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences (proximal vs distal residual pancreas) are associated with islet amyloid deposition. METHODS: We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients, including 14 patients with normal glucose tolerance (NGT), 16 patients with prediabetes and 15 new-onset diabetes (NOD) patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020. Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans. Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows: (1) Hematoxylin and eosin for general histological appearance; (2) hematoxylin and insulin for the determination of fractional ß-cell area (immunohistochemistry); and (3) quadruple insulin, glucagon, thioflavin T and DAPI staining for the determination of ß-cell area, α-cell area and amyloid deposits. RESULTS: Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition, fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions, especially in the prediabetes and NOD groups. Consistent with this finding, the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group (37.35 ± 12.16 cm3 vs 69.79 ± 18.17 cm3, P < 0.001). As expected, islets that stained positive for amyloid (islet amyloid density) were found in the majority of PDAC cases. The proportion of amyloid/islet area (severity of amyloid deposition) was significantly higher in both prediabetes and NOD patients than in NGT patients (P = 0.002; P < 0.0001, respectively). We further examined the regional differences in islet amyloid deposits. Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups (3.98% ± 3.39% vs 0.50% ± 0.72%, P = 0.01; 12.03% vs 1.51%, P = 0.001, respectively). CONCLUSION: In conclusion, these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation, which may be associated with the pathogenesis of NOD secondary to PDAC.

A double-cannula pancreatic gastrostomy method for pancreatic duct stenosis due to disconnected pancreatic duct syndrome: A surgical case report.

INTRODUCTION AND IMPORTANCE: Disconnected Pancreatic Duct Syndrome (DPDS) without peripancreatic fluid collections are relatively difficult for endoscopists to manage and usually treated with distal pancreatectomy or pancreaticojejunostomy. However, these procedures are risky for patients with severe edema of pancreatic tissue. We report an original one-stage surgical approach for these patients, namely, the "double-cannula pancreatic gastrostomy method". CASE PRESENTATION: A 38-year-old man was admitted with recurrent acute pancreatitis. ct images suggest pancreatic duct discontinuity syndrome. Intraoperative exploration revealed that pancreas inflammation was severe and distal pancreatectomy or pancreaticojejunostomy were risky. Therefore, we decided to perform a double-cannula pancreatic gastrostomy. A 16F type catheter penetrated the front and back walls of the stomach for gastrostomy, and a 6F catheter was inserted into the pancreatic duct for drainage. We placed the drainage tube of pancreatic duct into the gastrostomy tube to ensure the drainage tube of pancreatic duct could reach the gastric cavity. The gastrostomy tube is led out of the body through the abdominal wall. CLINICAL DISCUSSION: Both endoscopic and surgical approaches have been reported in treating DPDS patients. Internal drainage and excision are common surgical methods. CONCLUSIONS: The double-cannula pancreatic gastrostomy was a safe and effective method in this patient. CORE TIP: In this case, the patient suffered recurrent acute pancreatitis due to disconnected pancreatic duct syndrome. This patient without peripancreatic fluid collections was relatively difficult for endoscopists to manage. However, intraoperative exploration revealed a high risk of distal pancreatectomy or pancreaticojejunostomy. Therefore, we used A double-cannula pancreatic gastrostomy method and successfully treated the complications of pancreatic duct stenosis.

The differential effects of sarcopenia and cachexia on overall survival for pancreatic ductal adenocarcinoma patients following pancreatectomy: A retrospective study based on a large population.

OBJECTIVES: Both cachexia and sarcopenia have been considered adverse predictors for prognosis in patients with pancreatic cancer; although sarcopenia and cachexia share some similarities, they are still defined as distinct nutritional conditions. We aimed to explore the differential impacts of sarcopenia and cachexia on prognosis for pancreatic ductal adenocarcinoma (PDAC) patients following radical excision. METHODS: From January 2015 to May 2022, 614 patients undergoing surgery for PDAC were retrospectively included. Sarcopenia was defined as the L3 total skeletal muscle index below 52.4 cm2 /m2 (men) and 38.5 cm2 /m2 (women). Cachexia was classified according to the following criteria: involuntary weight loss >5% over the past 6 months, or weight loss >2% and BMI <20 kg/m2 , or weight loss >2% and sarcopenia. RESULTS: Of the 614 patients included in the analysis, 62% and 48% were diagnosed with sarcopenia and cachexia, respectively. Kaplan-Meier analysis showed that sarcopenia and/or cachexia were significantly associated with worse overall survival (OS) rather than worse recurrence-free survival (RFS). Moreover, Cox regression analysis revealed that cachexia rather than sarcopenia was an adverse factor for OS in all PDAC patients. For poorly differentiated PDAC, both cachexia and sarcopenia were significantly associated with shorter OS. However, for moderately/well-differentiated PADC, cachexia was an independent factor for adverse OS, but not sarcopenia. CONCLUSIONS: Sarcopenia and cachexia have different effects on OS for PDAC patients undergoing radical excision. This difference may provide some important information for preoperative management.

Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance.

BACKGROUND: Patients after pancreaticoduodenectomy (PD) showed improved glucose tolerance. Evidence for the effect of extrahepatic cholestasis on impaired glucose homeostasis secondary to ductal adenocarcinoma of the pancreatic head is limited. METHODS: In this prospective cross-sectional study, 50 patients with ductal adenocarcinoma of the pancreatic head were included to assess the effect of extrahepatic cholestasis on glucose tolerance status based on the oral glucose tolerance test (OGTT) before pancreatic surgery. RESULTS: Patients with extrahepatic cholestasis more frequently suffered from worsened impaired glucose homeostasis (prediabetes and new-onset diabetes, 95.2% vs. 58.6%, p = 0.004). Elevated bile acid level was recognized as an independent risk factor for impaired glucose homeostasis (p = 0.024, OR = 6.85). Hepatic insulin clearance (HIC) was significantly higher in patients with elevated bile acid levels (p = 0.001). A strong positive correlation was found between bile acid levels and HIC (r = 0.45, p = 0.001). CONCLUSIONS: This study suggested a connection between elevated bile acid levels and worsened impaired glucose homeostasis through increased insulin clearance function in ductal adenocarcinoma of pancreatic head patients.

Preoperative acute pancreatitis and hyperenzymemia are associated with poor prognosis in patients with nonfunctional pancreatic neuroendocrine tumors.

BACKGROUND: We aimed to investigate the prevalence of acute pancreatitis (AP) and hyperenzymemia as well as their clinical impact on postoperative survival outcomes in patients with pancreatic neuroendocrine tumors (PNETs). METHODS: A retrospective cohort study of 218 patients who underwent radical surgical resection for nonfunctional PNETs (NF-PNETs) was conducted. Multivariate survival analysis was performed by the Cox proportional hazard model, with results expressed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Of the 151 patients who met the inclusion criteria, the incidences of preoperative AP and hyperenzymemia were 7.9% (12/152) and 23.2% (35/151), respectively. The mean recurrence-free survival (RFS, 95% CI) for patients in control, AP, and hyperenzymemia groups was 136 (127-144), 88 (74-103), and 90 (61-122) months, with a 5-year RFS rate of 86.5%, 58.3%, and 68.9%, respectively. In the multivariable-adjusted Cox hazard model that included tumor grade and lymph node status, the adjusted HR of AP and hyperenzymemia for recurrence was 2.58 (95% CI: 1.47-7.86, p = 0.008) and 2.43 (95% CI: 1.08-7.06, p = 0.040). CONCLUSION: Preoperative AP and hyperenzymemia are associated with poor RFS following radical surgical resection in NF-PNETs patients.

Associations between Systemic Immune-Inflammation Index and Diabetes Mellitus Secondary to Pancreatic Ductal Adenocarcinoma.

BACKGROUND: There is a high prevalence of diabetes mellitus (DM) in patients with pancreatic ductal adenocarcinoma (PDAC). An inflammatory response is considered as a potential mechanism involved in the process. The systemic immune-inflammation (SII) index is an integrated and novel inflammatory indicator developed in recent years. The purpose of this study was to determine the relationship between the SII and DM secondary to PDAC. METHOD: Patients with a confirmed diagnosis of PDAC were analyzed in this cross-sectional study. Anthropometric measures, glucose-related data (including fasting glucose, 2 h OGTT, glycated hemoglobin, fasting insulin, and fasting c-peptide), tumor characteristics (tumor volumes, location and stages), and the periphery blood inflammatory index (white blood cell count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and SII) were recorded. The inflammation index was analyzed for its association with glucose-related parameters. Multivariable logistic regression analysis was used to analyze the association between SII levels and DM secondary to PDAC. RESULTS: Blood cell results showed that the white blood cell count, neutrophils, lymphocytes, monocytes, platelets, the neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were higher in patients with diabetes. It was worth noting that SII significantly increased in patients with diabetes secondary to PDAC (4.41 vs. 3.19, p < 0.0001). Multivariable logistic regression analysis showed that SII (OR: 2.024, 95%CI: 1.297, 3.157, p = 0.002) and age (OR: 1.043, 95%CI: 1.01, 1.077, p = 0.011) were the risk factors for DM secondary to PDAC after adjusting for covariates. According to Spearmen correlation analysis, SII was positively correlated with fasting glucose (r = 0.345, p < 0.0001), 2 h OGTT (r = 0.383, p < 0.0001), HbA1c (r = 0.211, p = 0.005), fasting insulin (r = 0.435, p < 0.0001), fasting C-peptide (r = 0.420, p < 0.0001), and HOMA2-IR (r = 0.491, p < 0.0001). CONCLUSIONS: In conclusion, SII is significantly increased among patients with DM secondary to PDAC and is associated with the DM in patients with PDAC (OR: 2.382, 95% CI: 1.157, 4.903, p = 0.019). Additionally, SII is significantly correlated with insulin resistance. We are the first to investigate the relationship between SII and diabetes secondary to PDAC and further confirm the role of an inflammatory response in this process. More studies need to be designed to clarify how inflammatory responses participate.

Double-bundle reconstruction of the anterior talofibular ligament by partial peroneal brevis tendon.

BACKGROUND: Anatomic anterior talofibular ligament (ATFL) reconstruction with autologous single-bundle tendon has been widely used in the treatment of ATFL injury. However, there are few clinical reports of using the peroneus brevis tendon (PBT) for double-bundle ATFL reconstruction. The aim of this study was to investigate the clinical effect of double-bundle ATFL reconstruction with PBT. METHODS: This was a retrospective review of all patients diagnosed with ATFL injury presenting from August 2019 to December 2021. Fifty-three patients were selected after screening based on the inclusion and exclusion criteria. The following data were compared before and after surgery: Visual Analogue Scale (VAS) score, American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), the pain interference (PI) and physical function (PF) scores of the Patient-Reported Outcomes Measurement Information System (PROMIS), the diameter and width of PBT in ultrasound and muscle strength. RESULTS: All functional scores (VAS, PI/PF, AO-FAS, KAFS) and muscle strength were significantly improved at the last follow-up (P < 0.05). The diameter and width of the PBT on ultrasound postoperation were smaller than those preoperatively. CONCLUSION: Double-bundle ATFL reconstruction with the partial PBT technique is a feasible, anatomic reconstruction technique for chronic lateral instability of the ankle, which meets the anatomical characteristics of the double bundle of the ligament, and the absence of partial PBT does not affect the peroneal muscle strength. LEVEL OF EVIDENCE: Level IV, retrospective case series.

AURKA, as a potential prognostic biomarker, regulates autophagy and immune infiltration in nasopharyngeal carcinoma.

BACKGROUND: Dysfunction of Aurora A (AURKA) plays crucial role in tumorigenesis and development of many types of cancer. However, the role of AURKA in nasopharyngeal carcinoma (NPC) has not been investigated yet. MATERIALS AND METHODS: Two independent NPC cohorts (GSE61218 and GSE102349) were enrolled from public database to investigate the expression level of AURKA between NPC and nasopharyngitis samples, the association of AURKA expression level with prognosis in NPC, and the potential mechanism of AURKA in NPC by using bioinformatics analyses. The expression level of AURKA protein in 62 paired NPC and nasopharyngitis tissues was evaluated by immunohistochemistry (IHC). Two NPC cell lines (SUNE-1 and CNE-2) were enrolled and the expression levels of AURKA in the NPC cells were inhibited by RNA interference. The expression levels of mRNAs were tested by qPCR and western-blotting. CCK-8 assay was applied to measure the cell growth. Cell migration was measured by using wound healing assays. RESULTS: AURKA was highly expressed in NPC samples compared to nasopharyngitis samples in GSE61218, which was confirmed by IHC. High expression of AURKA was associated with worse prognosis in GSE102349. Notably, silencing of AURKA was associated with significantly decreased cell growth and migration in NPC. Moreover, we found that the differentially expressed genes between high and low AURKA expression groups in GSE102349 were majorly enriched in both autophagy-related and immune-related pathways. Additionally, the expression level of AURKA was associated with the expression levels of autophagy-related genes and the infiltration of immune cells. CONCLUSION: AURKA overexpressed in NPC, which was associated with poor prognosis. Silencing of AURKA inhibited the proliferation and migration of NPC cells. Besides, AURKA might participate in the regulation of both autophagy and immunity in NPC.

Induction chemotherapy with sequential nimotuzumab plus concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma: A retrospective real-world study.

Many locally advanced nasopharyngeal carcinoma patients develop local recurrence or distant metastasis. Our retrospective real-world study aims to evaluate the efficacy and safety of curative sequential approach with induction chemotherapy followed by concurrent chemoradiation + nimotuzumab as first-line therapy in advanced nasopharyngeal carcinoma. From 2015 to 2021, the clinic data of 117 patients with advanced nasopharyngeal carcinoma (stage III-IV a) who were treated in the Affiliated Hospital of Guangdong Medical University were retrospectively reviewed. Fifty-four patients in observation group received taxanes, cisplatin, and 5-fluorouracil/taxanes and cisplatin induction chemotherapy and nimotuzumab (200 mg, weekly) combined with concurrent chemo-radiotherapy (cisplatin: 40 mg/m2 weekly; intensity-modulated radiation therapy); 63 patients in control group received same therapy without nimotuzumab. There was no significant difference in patients' characteristic baseline between 2 groups (P > .05). The complete response rate and objective response rate of the observational group was significantly higher than control group (46.30% vs 17.64%, P = .01; 96.30% vs 82.54%, P = .02). The median follow-up time was 24.77 (3.53-65.97) months. Both of the median progress free survival time and overall survival time were not reached. The 5-year progression-free survival rate of observation group was greater than control group (84.40% vs 63.70%, hazard ratios 0.365, 95% confidence intervals 0.147-0.909, P = .03). The 5-year overall survival rate of observation group and control group were 91.70% and 84.60%, respectively (P = .20). None of the patients withdrew from the study due to adverse events. Nimotuzumab combined with concurrent chemoradiotherapy as first-line therapy in advanced nasopharyngeal carcinoma can improve objective response rate and 5-year progress free survival rate with good safety profile.

Knockdown of CALM2 increases the sensitivity to afatinib in HER2-amplified gastric cancer cells by regulating the Akt/FoxO3a/Puma axis.

Gastric cancer (GC) is a global health issue that lacks effective treatment options. Afatinib is a tyrosine kinase inhibitor (TKI) that has shown promising results in the treatment of GC. However, resistance to afatinib is inevitable and hampers its clinical application. To date, there is limited knowledge regarding the mechanisms underlying the resistance of GC cells to afatinib. This study aimed to identify novel factors that may contribute to the resistance of GC cells to afatinib. We found that upregulation of calmodulin 2 (CALM2), a member of the CALM family, confers resistance to afatinib in GC cells. Knockdown of CALM2 can overcome the resistance to afatinib by promoting mitochondrial apoptosis in a caspase-dependent manner. Mechanistically, it was found that the downregulation of CALM2 led to the upregulation of the FoxO3a/Puma axis. Inhibition of either FoxO3a or Puma abrogated the effects of CALM2 downregulation in GC cells. In addition, we revealed that CALM2 knockdown inhibited Akt signaling, which is responsible for blocking the FoxO3a/Puma axis. Altogether, our results indicated that CALM2 could be considered a potential target to overcome the resistance of GC cells to afatinib.