Learning curve in relation to health-related quality of life in long-term, disease free survivors after McKeown minimally invasive esophagectomy.

BACKGROUND: The potential impact of learning curve on long-term health-related quality of life (QoL) after esophagectomy for cancer has not been investigated. The aim of this article is to investigate the relationship between learning curve for McKeown minimally invasive esophagectomy (MIE) and health-related quality of life (QoL) in long-term, disease free survivors up to 10 years after esophageal cancer resection. METHODS: Esophageal cancer patients who underwent McKeown MIE between 2009 and 2019 were identified in which 280 who were free of disease at the time of survey and completed health-related QoL and symptom questionnaires, including EORTC QLQ-C30, EORTC QLQ-OES18, and Digestive Symptom Questionnaire. Patients were assessed in 3 cohorts according to the learning phases of expertise reported by our previous study: initial phase; plateau phase, and; experienced phase. RESULTS: Median time from operation to survey was 5.8 years (interquartile range 4.6-8.2). The QLQ-C30 mean scores of functional scales, and symptom scales of respiratory and digestive systems including dyspnea (P = 0.006), shortness of breath (P = 0.003), and dysphagia (P = 0.031) were significantly better in experienced phase group. Furthermore, in the subgroup analyses for patients without postoperative major complications, patients in the initial learning phase remained suffering from more symptoms of dyspnea (P = 0.040) and shortness of breath (P = 0.001). CONCLUSION: Esophageal cancer patients undergoing McKeown MIE in initial learning phase tend to suffer from a deterioration in long-term health-related QoL and higher symptomatic burden as compared to experienced learning phase, which did not improved over time and warranted more attention.

HK2 and LDHA upregulation mediate hexavalent chromium-induced carcinogenesis, cancer development and prognosis through miR-218 inhibition.

Hexavalent chromium [Cr(VI)] is one of the most common environmental contaminants due to its tremendous industrial applications, but its effects and mechanism remain to be investigated. Our previous studies showed that Cr(VI) exposure caused malignant transformation and tumorigenesis. This study showed that glycolytic proteins HK2 and LDHA levels were statistically significant changed in blood samples of Cr(VI)-exposed workers and in Cr-T cells compared to the control subjects and parental cells. HK2 and LDHA knockdown inhibited cell proliferation and angiogenesis, and higher HK2 and LDHA expression levels are associated with advanced stages and poor prognosis of lung cancer. We found that miR-218 levels were significantly decreased and miR-218 directly targeted HK2 and LDHA for inhibiting their expression. Overexpression of miR-218 inhibited glucose consumption and lactate production in Cr-T cells. Further study found that miR-218 inhibited tumor growth and angiogenesis by decreasing HK2 and LDHA expression in vivo. MiR-218 levels were negatively correlated with HK2 and LDHA expression levels and cancer development in human lung and other cancers. These results demonstrated that miR-218/HK2/LDHA pathway is vital for regulating Cr(VI)-induced carcinogenesis and human cancer development.

Performance of the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease in a Large Chinese Cohort.

OBJECTIVE: The purpose of this research was to ascertain the effectiveness of the newly established criteria for classifying IgG4-related disease (IgG4-RD), as applied to a large Chinese cohort in real-world clinical settings. METHODS: Patient data were procured from the digital health records of 4 prominent academic hospitals. The criterion standard for identifying IgG4-RD patients was from a seasoned rheumatologist. The control group consisted of individuals with other ailments such as cancer, other forms of pancreatitis, infectious diseases, and illnesses that mimic IgG4-RD. RESULTS: A total of 605 IgG4-RD patients and 760 mimickers were available for analysis. The 2019 EULAR/ACR criteria have a sensitivity of 69.1% and a specificity of 90.9% in this large Chinese cohort. IgG4-RD had a greater proportion of males (55.89% vs 36.25%, p < 0.001), an older average age at diagnosis (54.91 ± 13.44 vs 48.91 ± 15.71, p < 0.001), more pancreatic (29.59% vs 6.12%, p < 0.001) and salivary gland (63.30% vs 27.50%, p < 0.001) involvement, and a larger number of organ involvement (3.431 ± 2.054 vs 2.062 ± 1.748, p < 0.001) compared with mimickers. CONCLUSIONS: The 2019 EULAR/ACR criteria are effective in classifying IgG4-RD in Chinese patients, demonstrating high specificity and moderate sensitivity.

Impact of perioperative decreased serum albumin level on anastomotic leakage in esophageal squamous cell carcinoma patients treated with neoadjuvant chemotherapy followed by minimally invasive esophagectomy.

BACKGROUND: Anastomotic leakage (AL) is a severe complication following esophagectomy with high mortality. Perioperative decreased serum albumin level is considered a predictive of AL, however, its impact on AL incidence in patients treated with neoadjuvant chemotherapy (NCT) followed by minimally invasive esophagectomy (MIE) is not well defined. METHODS: The data of 318 consecutive esophageal cancer patients who underwent MIE were collected retrospectively from January 2021 to December 2021. The perioperative level of albumin was detected and the baseline of altering levels for albumin was established. The incidence of postoperative complications and survival rate were analyzed between groups. RESULTS: After exclusion, 137 patients were enrolled and assigned to more decreased albumin (MA) and less decreased albumin (LA) groups. The levels of albumin descended significantly after MIE (p < 0.0001). There was no significant difference in the clinicopathologic characteristics or surgical outcomes between groups. The incidence of postoperative AL was 10.2% in MA group and 1.4% in LA group (p = 0.033). Three patients died due to AL in MA group, while no mortality was observed in LA group (p = 0.120). The rate of other postoperative complications was similar between groups. Progression-free survival (PFS) in LA group was a little higher than that in MA group, but it was no significant difference (p = 0.853). Similarly, no difference was observed in overall survival (OS) between groups (p = 0.277). CONCLUSIONS: Severely deficient serum albumin after MIE was an indicator of AL in esophageal cancer patients treated with NCT. TRIAL REGISTRATION: Chinese clinical trial registry: ChiCTR2200066694, registered December14th,2022. https://www.chictr.org.cn/edit.aspx?pid=185067&htm=4 .

Preventive effect of LCZ696 on hypoxic pulmonary hypertension in rats via regulating the PI3K/AKT signaling pathway.

Hypoxic pulmonary hypertension (HPH) is a devastating disease worldwide; however, effective therapeutic drugs are lacking. This study investigated the effects and underlying mechanisms of LCZ696 treatment on hypoxia-induced pulmonary hypertension. Male Sprague-Dawley (SD) rats were kept in a hypobaric chamber with an oxygen concentration of 5% for 4 weeks. Rats were treated with either LCZ696 (18 mg/kg, 36 mg/kg, and 72 mg/kg) or sildenafil. The mean pulmonary artery pressure (mPAP), right ventricle hypertrophy index (RVHI), and lung system index were measured. Hematoxylin-eosin (HE) staining, Masson staining, and immunofluorescence staining were used for histological analysis. Enzyme linked immunosorbent assay (ELISA) kits were used to determine the concentrations of inflammatory and hypoxia-related factors. Western blotting was used to examine the expression of apoptotic and PI3K/AKT signaling pathway proteins in rat lung tissue. Hypoxia increased mPAP, RVHI, and lung system index and induced pulmonary vascular remodeling, pulmonary arteriomyosis, and pulmonary artery fibrosis. LCZ696 treatment reduced the increase in mPAP, RVHI, and the lung system index and ameliorated the induced pathological changes. Hypoxia upregulated expression of NF-kB, TNF-α, IL-6, HIF-1α, and Vascular endothelial growth factor (VEGF), decreased the ratio of Bax/Bcl-2, and activated the PI3K/AKT signaling pathway in lung tissue, and these effects were partially reversed by treatment with LCZ696. These results demonstrated that LCZ696 can ameliorate hypoxia-induced HPH by suppressing apoptosis, inhibiting the inflammatory response, and inhibiting the PI3K/AKT signaling pathway. It provides a reference for clinical rational drug use and lays a foundation for the study of HPH therapeutic drugs.

Effect of pleural adhesions on short- and long-term outcomes after minimally invasive esophagectomy: a propensity score matching analysis.

BACKGROUND: The extent to which the presence of pleural adhesions affects the surgical and oncological outcomes of patients undergoing McKeown minimally invasive esophagectomy (MIE) for esophageal cancer (EC) has not previously been studied. METHODS: Data of consecutive EC patients undergoing McKeown MIE by a single surgeon in the Department of Thoracic Surgery at Daping Hospital from November 2015 to December 2020 were collected. Patients were grouped according to the presence or absence of pleural adhesions when entering the chest cavity. Propensity score matching (PSM) was used to reduce selection bias from confounding factors. Kaplan-Meier was used to assess the survival differences. RESULTS: A total of 617 consecutive EC patients underwent McKeown MIE were enrolled. There were 116 patients with pleural adhesions (Group A) and 501 patients without pleural adhesions (Group B). Patients in Group A were more likely to be older than those of patients in Group B: (66.26 vs. 63.27, P = 0.001). In addition, Group A had more patients with chronic obstructive pulmonary disease (COPD) (24.1% vs. 16.8%, P = 0.04). After propensity score matching (102 matched patients in Group A and 185 matched patients in Group B), these findings were no longer statistically significant. Postoperative pulmonary infection occurred in 57 patients in Group A and in 15 patients in Group B (53.9% vs. 13.0%, P < 0.001). In addition, the presence of pleural adhesions was significantly associated with the prolonged operation time (232 min vs. 210 min, P < .001), length of stay (12 days vs. 10 days, P = 0.001), and hydrothorax requiring drainage (12.7% vs. 5.4%, P = 0.04). However, the disease-specific survival and disease-free survival rates were comparable between the two groups (P = 0.40 and 0.13, respectively). CONCLUSIONS: The presence of pleural adhesions predicted an increased operation time, length of stay, postoperative pneumonia, and hydrothorax requiring drainage of EC patients undergoing McKeown MIE, but did not exert unfavourable effect on long-term survival.

Concurrent radiotherapy cannot provide superiority of surgical oncological outcome and long-term survival rate in locally advanced esophageal squamous cell carcinoma patients receiving neoadjuvant chemotherapy followed by minimally invasive esophagectomy.

BACKGROUND: To evaluate effectiveness of concurrent radiotherapy in esophageal cancer patient treated with neoadjuvant therapy. METHODS: The data of 1026 consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent minimally invasive esophagectomy (MIE) were retrospectively collected. The main inclusion criteria were patients with locally advanced (cT2-4N0-3M0) ESCC who underwent neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) followed by MIE, and divided into two groups according to different neoadjuvant strategies. Propensity score matching was performed to improve the comparability between the two groups. RESULTS: After exclusion and matching, 141 patients were enrolled retrospectively: 92 received NCT, and 49 received NCRT. No difference in clinicopathologic characteristics or incidence of adverse events between groups. A shorter operation time (215.7 ± 35.5 min) (p < 0.001), less blood loss (111.2 ± 67.7 ml) (p = 0.0007) and a greater number of lymph nodes retrieved (33.8 ± 11.7) (p = 0.002) were observed in NCT group than in NCRT group. The incidence of postoperative complications was similar between groups. Although patients in NCRT group had better pathological complete response (16, 32.7%) (p = 0.0026) and ypT0N0 (10, 20.4%) (p = 0.0002) rates, there was no significant difference in 5-year progression-free survival (p = 0.1378) or disease-specific survival (p = 0.1258) between groups. CONCLUSIONS: Compared with NCRT, NCT has certain advantages in that it can simplify the surgical procedure and decrease the surgical technique required without compromising the surgical oncological outcomes and long-term survival of patients.

Safety and feasibility of three-dimensional McKeown minimally invasive esophagectomy.

BACKGROUND: To compare the perioperative outcomes from McKeown minimally invasive esophagectomy (MIE) when performed in three-dimensional versus two-dimensional visualization system, and investigate the learning curve of a single surgeon who implemented three-dimensional McKeown MIE. METHODS: A total of 335 consecutive cases (three-dimensional or two-dimensional) were identified. Perioperative clinical parameters were compared and cumulative sum learning curve was plotted. Propensity score matching was used to reduce selection bias from confounding factors. RESULTS: Patients in three-dimensional group were associated with more chronic obstructive pulmonary disease (23.9% vs 3.0%, p < 0.01). After propensity score matching (108 matched patients in each groups), this finding was no longer statistically significant. Comparing to two-dimensional group, significant improvement in total retrieved lymph nodes (28 vs 33, p = 0.003) was observed in three-dimensional group. In addition, more lymph nodes around the right recurrent laryngeal nerve were harvested in three-dimensional group than that in two-dimensional group (p = 0.045). However, there were no significantly differences were found between the two groups in terms of other intraoperative parameters (e.g., operative time) and postoperative relevant outcomes (e.g., lung infection). Furthermore, the change point in the cumulative sum learning curves for intraoperative blood loss and thoracic procedure time was 33 procedures, respectively. CONCLUSION: Three-dimensional visualization system appears to be superior in performing lymphadenectomy during McKeown MIE to that of a two-dimensional technique. For surgeons proficient in performing two-dimensional McKeown MIE, the learning curve for a three-dimensional procedure appears to begin near proficiency after more than 33 cases.

PxRdl2 dsRNA increased the insecticidal activities of GABAR-targeting compounds against Plutella xylostella.

The utilization of RNA interference (RNAi) for pest management has garnered global interest. The bioassay results suggested the knockout of the PxRdl2 gene significantly increased the insecticidal activities of the γ-aminobutyric acid receptor (GABAR)-targeting compounds (fipronil, two pyrazoloquinazolines, and two isoxazolines), thereby presenting a viable target gene for RNAi-mediated pest control. Consequently, we suggest enhancing the insecticidal activities of GABAR-targeting compounds by knockdown the transcript level of PxRdl2. Furthermore, PxRdl2 dsRNA was expressed in HT115 Escherichia coli to reduce costs and protect dsRNA against degradation. In comparison to in vitro synthesized dsRNA, the recombinant bacteria (ds-B) exhibited superior interference efficiency and greater stability when exposed to UV irradiation. Collectively, our results provide a strategy for insecticide spray that combines synergistically with insecticidal activities by suppressing PxRdl2 using ds-B and may be beneficial for reducing the usage of insecticide and slowing pest resistance.

[Hyperspectral imaging technology distinguishes between Puerariae Lobatae Radix and Puerariae Lobatae Caulis].

Puerariae Lobatae Radix, the dried root of Pueraria lobata, is a traditional Chinese medicine with a long history. Puerariae Lobatae Caulis as an adulterant is always mixed into Puerariae Lobatae Radix for sales in the market. This study employed hyperspectral imaging(HSI) to distinguish between the two products. VNIR lens(spectral scope of 410-990 nm) and SWIR lens(spectral scope of 950-2 500 nm) were used for image acquiring. Multi-layer perceptron(MLP), partial least squares discriminant analysis(PLS-DA), and support vector machine(SVM) were employed to establish the full-waveband models and select the effective wavelengths for the distinguishing between Puerariae Lobatae Caulis and Puerariae Lobatae Radix, which provided technical and data support for the development of quick inspection equipment based on HSI. The results showed that MLP model outperformed PLS-DA and SVM models in the accuracy of discrimination with full wavebands in VNIR, SWIR, and VNIR+SWIR lens, which were 95.26%, 99.11%, and 99.05%, respectively. The discriminative band selection(DBS) algorithm was employed to select the effective wavelengths, and the discrimination accuracy was 93.05%, 98.05%, and 98.74% in the three different spectral scopes, respectively. On this basis, the MLP model combined with the effective wavelengths within the range of 2 100-2 400 nm can achieve the accuracy of 97.74%, which was close to that obtained with the full waveband. This waveband can be used to develop quick inspection devices based on HSI for the rapid and non-destructive distinguishing between Puerariae Lobatae Radix and Puerariae Lobatae Caulis.

Novel Polycyclic Fused Amide Derivatives: Properties and Applications for Sky-blue Electroluminescent Devices.

Aromatic imide derivatives play a critical role in boosting the electroluminescent (EL) performance of organic light-emitting diodes (OLEDs). However, the majority of aromatic imide-based materials are limited to long wavelength emission OLEDs rather than blue emissions due to their strong electron-withdrawing characteristics. Herein, two novel polycyclic fused amide units were reported as electron acceptor to be combined with either a tetramethylcarbazole or acridine donor via a phenyl linker to generate four conventional fluorescence blue emitters of BBI-4MeCz, BBI-DMAC, BSQ-4MeCz and BSQ-DMAC for the first time. BSQ-4MeCz and BSQ-DMAC based on a BSQ unit exhibited higher thermal stability and photoluminescence quantum yields than BBI-4MeCz and BBI-DMAC based on a BBI unit due to their more planar acceptor structure. The intermolecular interactions that exist in the BSQ series materials effectively inhibit the molecular rotation and configuration relaxation, and thus allow for blue-shifted emissions. Blue OLED devices were constructed with the developed materials as emitters, and the effects of both the structure of the polycyclic fused amide acceptor and the electron donor on the EL performance were clarified. Consequently, a sky-blue OLED device based on BSQ-DMAC was created, with a high maximum external quantum efficiency of 4.94% and a maximum luminance of 7761 cd m-2.

Multi-tailoring of a modified MOF-derived CuxO electrochemical transducer for enhanced hydrogen peroxide sensing.

Reasonable control of the redox states within the catalytic units together with the interconnection degrees of the substrate is of great significance in the modulation of a well-performing transducer. Herein, a novel carbon black (CB)-modified copper metal-organic framework nanomaterial (CB@Cu-MOF) prepared at room temperature was utilized as a precursor to synthesize mixed-valent copper-oxide composite catalysts (NC/CuxO-T). By tuning the carbonization process of the precursor at different temperatures (T = 100 °C, 200 °C, 300 °C and 400 °C), the different ratio configurations of the redox-alternated CuxO portions were successfully controlled with the simultaneous effective tailoring of the defect abundance in the N-doped carbon substrate. As a result, an optimized NC/CuxO-300 electrochemical H2O2 sensor was able to present a low detection limit (0.26 µM) and decent linear ranges (0.02-1.79 mM and 2.29-9.29 mM). Our strategy using easily available initial materials with mild preparation conditions is expected to promote the practical application of the star materials in laboratories.

Incidence And Risk Factors Of Contrast Nephropathy After Tace In Patients With Liver Cancer And Chronic Kidney Disease.

PURPOSE: Incidence of contrast induced nephropathy (CIN) and related risk factors in patients with liver cancer and chronic kidney disease after trans-catheter arterial chemoembolization (TACE) is higher. The purpose of this study was to investigate the feasibility and safety of TACE therapy in such patients. METHODS: A retrospective analysis was performed on 103 patients with liver cancer and chronic kidney disease who underwent TACE treatments. TACE was performed according to Seldinger's technique of arterial embolization with minor modifications. Based on CIN diagnostic criteria, patients were divided into non-CIN (n=89) and CIN (n=14) groups. Multiple clinical parameters were assessed for the two groups after TACE. Serum creatinine levels were measured 48-72 h after TACE. RESULTS: Tumor size (>5 cm), TACE frequency, contrast agent dosage, solitary kidney, volume of iodized oil used in the TACE (ml) and urea levels were significantly higher in CIN group in comparison with the non-CIN group, while serum albumin and haemoglobin levels were significantly lower. Multivariate logistic regression analysis confirmed that the volume of iodized oil and TACE frequency were significantly positively correlated, and serum albumin level was negatively correlated in the CIN group. CONCLUSION: Volume of iodized oil, TACE frequency and low serum albumin levels were found to be independent risk factors for CIN after TACE. Thus, it is safe and feasible for hepatocellular carcinoma patients with chronic kidney disease to receive TACE treatment, but adverse events management after TACE needs to be addressed.

Effect of surgical start time on short- and long-term outcomes after minimally invasive esophagectomy: a propensity-score matching analysis.

There is growing focus on the relationship between surgical start time and postoperative outcomes. However, the extent to which the operation start time affects the surgical and oncological outcomes of patients undergoing esophagectomy has not previously been studied. The purpose of this retrospective study was to investigate the potential effect of surgical start time on the short- and long-term outcomes for patients who underwent thoracoscopic-laparoscopic McKeown esophagectomy. From September 2009 to June 2019, a total of 700 consecutive patients suffering from esophageal cancer underwent thoracoscopic-laparoscopic McKeown esophagectomy in the Department of Thoracic Surgery at Daping Hospital. Among these patients, 166 esophagectomies were performed on the same day and were classified as the first- or second-start group. Patients in the first-start group were more likely to be older than those in the second-start group: (64.73 vs. 61.28, P = 0.002). In addition, patients with diabetes mellitus were more likely to be first-start cases (8.4 vs. 1.2%). After propensity score matching (52 matched patients in first-start cases and 52 matched patients in second-start cases), these findings were no longer statistically significant. There was no difference in the incidence rate of peri- or postoperative adverse events between the first- and second-start groups. The disease-specific survival rates and disease-free survival rates were comparable between the two groups (P = 0.236 and 0.292, respectively). On the basis of the present results, a later start time does not negatively affect the short- or long-term outcomes of patients undergoing minimally invasive McKeown esophagectomy.

Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway.

Nicotinamide adenine dinucleotide (NADH) has been reported to regulate synaptic plasticity recently, while its role in this process remains unclear. To explore the contribution and the underlying mechanisms of NADH regulating synaptic plasticity, here, we examined NADH's effect on immediate-early response genes (IEGs) expressions, including C-Fos and Arc in primary cultured cortical neurons and the frontal cortex of mouse brain. Our results showed that NADH promoted IEGs expression and that the C-Fos and Arc levels are increased in primary cultured cortical neurons, which is almost completely blocked by N-methyl-D-aspartate receptor (NMDAR) inhibitor, MK-801. Moreover, NADH significantly increased intracellular Ca2+ levels and the phosphorylation of Erk1/2, a downstream molecule of the NMDAR. Furthermore, NADH also significantly increased IEGs expression in vivo, accompanied by the changes of Ca2+ in neurons and activation of excitatory neurons in the mouse frontal cortex. In conclusion, this study indicates that NADH can promote the expression of synaptic plasticity-related IEGs through the NMDAR/Ca2+/Erk1/2 pathway, which provides a new way to understand the regulatory role of NADH in synaptic plasticity.

[The level of the stress biomarker salivary alpha amylase is correlated with semen quality in infertile young men].

Objective: To investigate the relationship between the level of the stress biomarker salivary alpha amylase (SAA) and semen quality in infertile young men. METHODS: Totally, 313 infertile and 96 normal healthy men, aged 20－40 years old, were enrolled in this study. The SAA levels and semen parameters of the subjects were measured and compared between the two groups. RESULTS: Compared with the normal healthy controls, the young infertility patients showed a significantly higher SAA level (ï¼»141.04 ± 44.13ï¼½ vs ï¼»151.48 ± 38.42ï¼½ µmol/L, P < 0.05) and percentage of immotile sperm (IMS) (ï¼»39.98 ± 14.53ï¼½% vs ï¼»64.48 ± 26.32ï¼½%, P < 0.05), but lower sperm concentration (ï¼»44.23 ± 21.63ï¼½ vs ï¼»32.42 ± 23.07ï¼½ ×106/ml, P < 0.05) and percentage of progressively motile sperm (PMS) (ï¼»52.13 ± 15.42ï¼½% vs ï¼»27.91 ± 21.22ï¼½%, P < 0.05). Sperm concentration (ï¼»26.33 ± 31.83ï¼½ vs ï¼»35.28 ± 27.70ï¼½ ×106/ml, P < 0.05) and the percentage of PMS were remarkably lower in the infertile men with a high than in those with a low SAA level (ï¼»19.85 ± 21.55ï¼½% vs ï¼»31.70 ± 20.02ï¼½%, P < 0.05), while the percentage of IMS was higher in the former than in the latter group (ï¼»74.19 ± 26.84ï¼½% vs ï¼»59.92 ± 24.85ï¼½%, P < 0.05). The SAA level in the young infertility patients was correlated positively with the percentage of IMS (r = 0.170, P < 0.01), but negatively with sperm concentration (r = －0.227, P < 0.01) and the percentage of PMS (r = －0.468, P < 0.01). CONCLUSIONS: The stress biomarker salivary alpha amylase level in infertile young men is negatively correlated with semen quality, and therefore semen parameters can be improved by reducing the stress level.

RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination.

RNF6, a RING-type ubiquitin ligase, has been identified as an oncogene in various cancers but its role in multiple myeloma (MM) remains elusive. In the present study we first showed that the expression levels of RNF6 in MM were significantly elevated compared with the bone marrow cells of healthy donors. Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation, whereas knockdown of RNF6 led to apoptosis of MM cells. Furthermore, we revealed that RNF6, as a ubiquitin ligase, interacted with glucocorticoid receptor (GR) and induced its K63-linked polyubiquitination. Different from current knowledge, RNF6 increased GR stability at both endogenous and exogenous contexts. Such an action greatly promoted GR transcriptional activity, which was confirmed by luciferase assays and by the increased expression levels of prosurvival genes including Bcl-xL and Mcl-1, two typical downstream genes of the GR pathway. Consistent with these findings, ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone, a typical anti-myeloma agent. In conclusion, we demonstrate that RNF6 promotes MM cell proliferation and survival by inducing atypical polyubiquitination to GR, and RNF6 could be a promising therapeutic target for the treatment of MM.

Short- and long-term outcomes of prophylactic thoracic duct ligation during thoracoscopic-laparoscopic McKeown esophagectomy for cancer: a propensity score matching analysis.

BACKGROUND: Chylothorax remains a challenging and potentially life-threatening postoperative complication after minimally invasive esophagectomy (MIE). The effect of intraoperative prophylactic thoracic duct ligation on preventing postoperative chylothorax still remains controversial. Moreover, the potential impact of thoracic duct ligation on long-term outcome after MIE has not been well established. METHODS: From September 2009 to July 2018, a total of 600 consecutive patients suffering from thoracic esophageal cancer who underwent thoracoscopic-laparoscopic McKeown esophagectomy in the Department of Thoracic surgery at Daping hospital were eligible. Among them, 559 patients received esophagectomy with preventive thoracic duct ligation and 41 patients did not. Propensity score matching (PSM) was performed to improve comparability between the two groups. Log-rank test was used to assess the survival differences between groups. RESULTS: Postoperative chylothorax occurred in five patients in the preservation group (PG) and in seven patients in the ligation group (LG) (12.2% vs. 1.3%, P = 0.001). The median age of the patients in the preservation group (PG) was 57.78 (range, 37-76) years, while the median age in the ligation group (LG) was 62.75 (range, 39-87) years. The PG had more patients with tumor located in middle thoracic esophagus and stage T3 than LG, 82.9% vs. 55.6%, 70.7% vs. 45.6%, respectively. After PSM (40 matched patients in PG and 134 in LG), there was no significant between-group difference with respect to age, tumor location, and T stage. The median survival times for patients in the PG and LG were 69.5 months (95% interval confidence, CI 54.6-84.3) and 65.2 months (95% CI 56.3-74.1), respectively (P = 0.977). The 5-year survival rates were comparable between PG and LG (54.9% vs. 54.4%, P = 0.977). CONCLUSION: On the basis of the present results, routine thoracic duct ligation during minimally invasive McKeown esophagectomy for cancer is an effective and safe method for prevention of postoperative chylothorax, and does not exert unfavourable effect on long-term survival.

The Postoperative outcomes of thoracoscopic-laparoscopic Ivor-Lewis surgery plus D2 celiac lymphadenectomy for patients with adenocarcinoma of the esophagogastric junction.

OBJECTIVES: Adenocarcinoma of the esophagogastric junction (AEG) is one of the most aggressive and poor prognosis cancers. To date, no standard procedures have been established for the surgical treatment of Siewert type II. In this study, we proposed the approach of thoracoscopic-laparoscopic Ivor-Lewis surgery plus D2 celiac lymphadenectomy (TLILD2) and aimed to investigate the patterns of lymph node metastasis and long-term survival. METHODS: From June 2015 to June 2018, 72 patients accepted TLILD2 and enrolled in this study. Relevant patient characteristics and postoperative variables were collected and evaluated. The disease-free survival (DFS) and disease-specific survival (DSS) were determined by the Kaplan-Meier method and compared by log-rank tests. RESULTS: There was no case of postoperative death in this study, and the most common complication was anastomotic mediastinal fistula (5/72, 6.9%). A total of 2811 lymph nodes were retrieved, and the positivity rate was 11.9% (334/2811). The positivity rate of celiac and mediastinal lymph nodes was 14.4% (314/2186) and 3.2% (20/625), respectively. The percentage of patients who had positive celiac and mediastinal lymph nodes reached up to 58.3% (42/72) and 8.3% (6/72), respectively. The DFS and DSS of these 72 patients were 94% and 93.4% at 1 year after surgery and 59.8% and 62% at 3 years after surgery, respectively. The pTNM stage showed a significant difference between DFS and DSS. CONCLUSIONS: TLILD2 could be a potential way to promote long-term survival of AEG patients. On the basis of the patterns of lymph nodes metastasis, we suggest that lower mediastinal and D2 celiac lymphadenectomy is necessary to improve the oncological outcome.

Heterogeneity of cannabinoid ligand-induced modulations in intracellular Ca2+ signals of mouse pancreatic acinar cells in vitro.

We recently reported that a CB2R agonist, GW405833 (GW), reduced both the ACh-induced Ca2+ oscillations and the L-arginine-induced Ca2+ signal enhancement in mouse pancreatic acinar cells, suggesting that GW-induced inhibition may prevent the pathogenesis of acute pancreatitis. In this study, we aim to evaluate the effects of other cannabinoid ligands on Ca2+ signaling in acinar cells. Patch-clamp whole-cell recordings were applied to measure ACh-induced intracellular Ca2+ oscillations in pancreatic acinar cells acutely dissociated from wild-type (WT), CB1R knockout (KO), and CB2R KO mice, and the pharmacological effects of various cannabinoid ligands on the Ca2+ oscillations were examined. We found that all the 8 CB2R agonists tested inhibited ACh-induced Ca2+ oscillations. Among them, GW, JWH133, and GP1a caused potent inhibition with IC50 values of 5.0, 6.7, and 1.2 µmol/L, respectively. In CB2R KO mice or in the presence of a CB2R antagonist (AM630), the inhibitory effects of these 3 CB2R agonists were abolished, suggesting that they acted through the CB2Rs. The CB1R agonist ACEA also induced inhibition of Ca2+ oscillations that existed in CB1R KO mice and in the presence of a CB1R antagonist (AM251), suggesting a non-CB1R effect. In WT, CB1R KO, and CB2R KO mice, a nonselective CBR agonist, WIN55,212-2, inhibited Ca2+ oscillations, which was not mediated by CB1Rs or CB2Rs. The endogenous cannabinoid substance, 2-arachidonoylglycerol (2-AG), did not show an inhibitory effect on Ca2+ oscillations. In conclusion, CB2R agonists play critical roles in modulating Ca2+ signals in mouse pancreatic acinar cells, while other cannabinoid ligands modulate Ca2+ oscillations in a heterogeneous manner through a CB receptor or non-CB-receptor mechanism.