Pan-cancer analysis reveals that TK1 promotes tumor progression by mediating cell proliferation and Th2 cell polarization.

BACKGROUND: TK1 (Thymidine kinase 1) is a member of the thymidine kinase family and has been observed to be significantly upregulated in a variety of cancer types. However, the exact roles of TK1 in tumor progression and the tumor immune microenvironment are not fully understood. This study aims to investigate the comprehensive involvement of TK1 in pan-cancer through the utilization of bioinformatics analysis, validation of pathological tissue samples, and in vitro experimental investigations. METHODS: The expression profiles together with diagnostic and prognostic role of TK1 in pan-cancer were investigated though TCGA, TARGET, GTEx, and CPTAC databases. The single-sample gene set enrichment analysis (ssGSEA) and single-cell sequencing datasets were used to examine the relationship between TK1 and immune infiltration. The expression of TK1 were verified in hepatocellular carcinoma (HCC) through qPCR, western blotting and immunohistochemical assays. The proliferative capacity of HCC cell lines was assessed through CCK-8 and colony formation assays, while cytokine levels were measured via ELISA. Furthermore, flow cytometry was utilized to analyze cell cycle distribution and the proportions of Th2 cells. RESULTS: TK1 was overexpressed in most cancers and demonstrated significant diagnostic and prognostic value. Among the various immune cells in pan-cancer, Th2 cells exhibited the closest association with TK1. Furthermore, the single-cell atlas provided insights into the distribution and proportion of TK1 in immune cells of HCC. In vitro experiments revealed an elevated expression of TK1 in HCC tissue and cell lines, and its role in influencing HCC cell proliferation by regulating G0/G1 phase arrest. Additionally, TK1 in cancer cells was found to potentially modulate Th2 cell polarization through the chemokine CCL5. CONCLUSION: TK1 holds immense potential as a biomarker for pan-cancer diagnosis and prognosis. Additionally, targeting the expression of TK1 represents a promising therapeutic approach that can enhance the efficacy of current anti-tumor immunotherapy by modulating Th2 cell polarization and multiple mechanisms.

Association of thyroid autoantibodies with aggressive characteristics of papillary thyroid cancer: a case-control study.

PURPOSE: Although the potential association between autoimmune thyroiditis and papillary thyroid cancer (PTC) has been acknowledged, whether the clinicopathological features of PTC will be affected by thyroid autoantibodies remains unknown. PATIENTS AND METHODS: We conducted a case-control study to investigate the association of thyroid autoantibodies with clinicopathological characteristics of PTC in 15,305 patients (including 11,465 females and 3,840 males) from 3 medical centers in the central province of China. Logistic regression and restricted cubic spline models were performed to analyze the association of thyroid autoantibodies with clinicopathological features of PTC. RESULTS: In total, out of the 15,305 patients enrolled in this study, 10,087 (65.9%) had negative thyroid autoantibodies, while 5,218(34.1%) tested positive thyroid autoantibodies. Among these individuals, 1,530(10.0%) showed positivity for TPOAb only, 1,247(8.2%) for TGAb only and a further 2,441(15.9%) exhibited dual positivity for both TPOAb and TGAb combined. Thyroid autoantibodies level demonstrated significant correlations with certain aggressive features in PTC. Specifically, TGAb level displayed a direct correlation to an increased likelihood of multifocality, bilateral tumor, extrathyroidal extension, lymph node metastasis, as well as more than five affected lymph nodes. However, TPOAb level exhibited an inverse association with the risk associated with extrathyroidal extension, lymph node metastasis, and more than five affected lymph nodes. CONCLUSION: Elevated level of TGAb were positively correlated with the risk of aggressive features in PTC, while high level of TPOAb were inversely associated with the risk of extrathyroidal extension and lymph node metastasis.

Nanoclay Drug-Delivery System Loading Potassium Iodide Promotes Endocytosis and Targeted Therapy in Anaplastic Thyroid Cancer.

The rapid proliferative biological behavior of primary foci of anaplastic thyroid cancer (ATC) makes it a lethal tumor. According to the specific iodine uptake capacity of thyroid cells and enhanced endocytosis of ATC cells, we designed a kind of nanoclay drug-loading system and showed a promising treatment strategy for ATC. Introducing potassium iodide (KI) improves the homoaggregation of clay nanoparticles and then affects the distribution of nanoparticles in vivo, which makes KI@DOX-KaolinMeOH enriched almost exclusively in thyroid tissue. Simultaneously, the improvement of dispersibility of KI@DOX-KaolinMeOH changes the target uptake of ATC cells by improving the endocytosis and nanoparticle-induced autophagy, which regulate the production of autolysosomes and autophagy-enhanced chemotherapy, eventually contributing to a tumor inhibition rate of more than 90% in the primary foci of ATC. Therefore, this facile strategy to improve the homoaggregation of nanoclay by introducing KI has the potential to become an advanced drug delivery vehicle in ATC treatment.

Postoperative complications and short-term prognosis of laparoscopic pancreaticoduodenectomy vs. open pancreaticoduodenectomy for treating pancreatic ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Although laparoscopic pancreaticoduodenectomy (LPD) has been accepted worldwide for treating pancreatic ductal adenocarcinoma (PDA), it is a very technical and challenging procedure. Also, it is unclear whether LPD is superior to open pancreaticoduodenectomy (OPD). This study summarized the experience and efficacy of LPD for treating PDA in our medical center. METHODS: This retrospective cohort study included patients with PDA admitted at the Affiliated Hospital of Jiangnan University from October 2019 and January 2021. Patients received either LPD or OPD. Clinical outcomes (operation time, duration of anesthesia, intraoperative hemorrhage), postoperative complications, and short-term outcomes were compared. Cox proportional hazard model and Kaplan-Meier method were used to analyze overall survival (OS) and progression-free survival (PFS). RESULTS: Among the PDA patients, 101 patients underwent surgical treatment, 4 patients converted from LPD to OPD, and 7 of them received conservative treatment. Forty-six patients were cured of LPD, and 1 of them died shortly after the operation. Moreover, 44 patients received OPD, and there were 2 postoperative deaths. There were significant differences in the location of the operation time, duration of anesthesia, postoperative hemorrhage, abdominal infections, and postoperative pneumonia between the two groups (all p < 0.05). Multivariate analysis showed that LPD was an independent factor negatively correlated with the incidence of pneumonia (relative risk (RR) = 0.072, 95%CI: 0.016-0.326, p = 0.001) and abdominal infection (RR = 0.182, 95%CI: 0.047-0.709, p = 0.014). Also, there were no differences in OS (hazard ratio (HR) = 1.46, 95%CI: 0.60-3.53, p = 0.40) and PFS (HR = 1.46, 95%CI: 0.64-3.32, p = 0.37) at 12 months between the two groups. CONCLUSIONS: LPD could be efficacy and feasible for managing selected PDA patients. Also, LPD has a better effect in reducing postoperative pneumonia and abdominal infection compared to OPD.

Association of Ozone Exposures with the risk of thyroid nodules in Hunan Province: a population-based cohort study.

BACKGROUND: Increasing evidence associates air pollution with thyroid dysfunction, whereas the potential relationship between exposure to ozone (O3) and Thyroid Nodules (TNs) is unclear. METHODS: This retrospective cohort study investigated the association between O3 exposure and TNs in Hunan province, enrolling 191,357 Chinese adults who lived in Hunan province from January 2009 to December 2019 and received voluntary medical examinations. Individual exposure levels to O3 from 2010 to 2019 were measured on account of participants' residential addresses at the district level. Associations of O3 exposure with the risk of incidental TNs were assessed by restricted cubic splines and surveyed as odds ratios after adjusting for demographic factors. RESULTS: In total, 81,900 adults were newly diagnosed with TNs during the study period. Age-standardized TNs detection rate in Hunan province increased from 25.9 to 46.3% between 2010 and 2019, with the greatest annual percent change being 8.1 [95% CI, 7.3-8.8]. A similar trend has been found in all tumor sizes, ages, and both sexes. O3 exposure presented a statistically significant dose-dependent positive correlation (greater than 0.036 ppm) with TNs. Similarly, long-term exposure to high levels of O3 (1-year average O3 concentrations exceeding 0.0417 ppm) was found positively associated with increased TSH levels. CONCLUSIONS: High-level O3 exposure in the long term was associated with an increase in TSH. Consequently, increased TSH was related to the increased risk of TNs. Being exposed to high-level O3 in the long term was related to the increased detection rates of TNs in Hunan province, which could be mediated by TSH.

Pan-cancer analysis of the oncogenic role of discs large homolog associated protein 5 (DLGAP5) in human tumors.

BACKGROUND: In recent years, there have been many studies on the relationship between DLGAP5 and different types of cancers, yet there is no pan-cancer analysis of DLGAP5. Therefore, this study aims to analyze the roles of DLGAP5 in human tumors. METHODS: Firstly, we evaluated the expression level of DLGAP5 in 33 types of tumors throughout the datasets of TCGA (Cancer Genome Atlas) and GEO (Gene Expression Synthesis). Secondly, we used the GEPIA2 and Kaplan-Meier plotter to conduct Survival prognosis analysis. Additionally, cBioPortal web was utilized to analyze the genetic alteration of DLGAP5, after which we selected hepatocellular carcinoma (HCC) cell lines to define the function of DLGAP5. Last but not least, we performed immune infiltration analysis and DLGAP5-related gene enrichment analysis. RESULTS: DLGAP5 is highly expressed in most type of cancers, and there is a significant correlation between the expression of DLGAP5 and the prognosis of cancer patients. We have observed that DLGAP5 promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cell lines. We also found that DLGAP5 expression was related with the CD8+ T-cell infiltration status in kidney renal clear cell carcinoma, uveal melanoma, and thymoma, and cancer-associated fibroblast infiltration was observed in breast invasive carcinoma, kidney renal papillary cell carcinoma and testicular germ cell tumors. In addition, enrichment analysis revealed that cell cycle- and oocyte meiosis-associated functions were involved in the functional mechanism of DLGAP5. CONCLUSIONS: Taken together, our unpresented pan-cancer analysis of DLGAP5 provides a relatively integrative understanding of the oncogenic role of DLGAP5 in various tumors. DLGAP5 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of DLGAP5 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

Global Phosphoproteomic Analysis Reveals Significant Metabolic Reprogramming in the Termination of Liver Regeneration in Mice.

Phosphorylation is crucial in regulating various biological processes. However, comprehensive phosphoproteomic profiling in the termination of liver regeneration (LR) is still missing. Here, we used Tandem Mass Tag (TMT) labeling coupled with phosphopeptide enrichment and two-dimensional (2D) liquid chromatography-mass spectrometry (LC-MS)/MS analysis to establish a global phosphoproteomic map in the liver of mice at day 5 after partial hepatectomy (PH). Altogether, 9731 phosphosites from 3443 proteins were identified and 7802 phosphosites from 2980 proteins were quantified. Motif analysis of the identified phosphosites revealed a diverse array of consensus sequences, suggesting that multiple kinase families including ERK/MAPK, PKA/PKC, CaMK-II, CKII, and CDK may be involved in the termination of LR. Functional clustering analysis of proteins with dysregulated phosphosites showed that they mainly participate in metabolic pathways, DNA replication, and tight junction. More importantly, the deletion of PP2Acα in the liver remarkably changes the overall phosphorylation profile, indicating its critical role in regulating the termination of LR. Finally, several differentially phosphorylated sites were validated by co-immunoprecipitation and Western blot. Taken together, our data unravel the first comprehensive phosphoproteomic map in the termination of LR in mice, which greatly expands our knowledge in the complicated regulation of this process and provides new directions for the treatment of liver cancer using liver resection.

PP2Acα inhibits PFKFB2-induced glycolysis to promote termination of liver regeneration.

The mechanisms underlying the initiation and proliferation of liver regeneration (LR) has been extensively studied using the partial hepatectomy (PHx) model, while little is known about the termination of LR. PP2Acα (protein phosphatase 2 A catalytic subunit α isoform) is the catalytic subunit of protein phosphatase 2 A (PP2A), accounting for most of intracellular serine/threonine phosphatase activity. We have previously observed that termination of LR delayed in PP2Acα liver-specific knockout (LKO) mice after PHx. In our study, we used phospho explorer antibody array analysis to screen the potential phosphorylation targets of PP2Acα, and PP2Acα had a great influence on the hepatic phosphoproteomic signaling in the termination of LR after PHx. We then tested the phosphorylation changes and metabolic function of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2 (PFKFB2), an isoform of the key glycolytic enzyme PFKFB, which was significantly regulated by PP2Acα knockout. PP2Acα knockout enhanced glycolysis in vivo and in vitro, while adenoviral-mediated RNAi of PFKFB2 reversed the extension of postoperative liver regeneration in KO mice along with the downregulation of glycolysis. Therefore, we demonstrated that PP2Acα liver-specific knockout regulated the hepatocytes glycolysis via activating PFKFB2, thus enhancing liver regeneration during the termination stage.

Age-stratified risk factors of re-intervention for uterine fibroids treated with high-intensity focused ultrasound.

OBJECTIVE: To estimate the rate and risk factors of re-intervention for patients with uterine fibroids (UFs) undergoing high-intensity focused ultrasound (HIFU) at different age distributions. METHOD: A retrospective cohort study was conducted in Nanchong Central Hospital, recruiting a total of 672 patients with UFs undergoing HIFU from June 2017 to December 2019. Using univariate and multivariate logistic regression, risk factors for re-intervention were assessed. RESULTS: Among 401 patients with UFs who completed the follow-up visits (median 47 months, range 34-61), 50 (12.46%) patients underwent re-intervention (such as high-intensity focused ultrasound, uterine artery embolization, myomectomy and hysterectomy). In the different age distributions, the re-intervention rate was 17.5% (34/194) in patients aged <45 years and 7.7% (16/207) in those aged ≥45 years. Regarding the younger patient group (aged <45 years), hypo- or iso-intensive fibroids in T2-weighted magnetic resonance imaging (T2WI) intensity may elevate the risk of re-intervention for UFs (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.37-6.62; P = 0.007). Among the older patient group (aged ≥45 years), preoperative anemic patients had an increased risk of re-intervention compared with those without anemia (OR 3.30, 95% CI 1.01-10.37; P = 0.041). CONCLUSION: The re-intervention rate of HIFU decreased with increasing age. Among those aged <45 years, T2WI intensity was the independent risk factor for re-intervention, and among those aged ≥45 years, preoperative anemic status may be related to re-intervention outcome.

Loss of Claudin-1 incurred by DNMT aberration promotes pancreatic cancer progression.

Pancreatic cancer (PC) is one of the most malignant and deadly tumors of digestive system with complex etiology and pathogenesis. Dysregulations of oncogenes and tumor suppressors due to epigenetic modifications causally affect tumorogenesis; however the key tumor suppressors and their regulations in PC are only partially defined. In this study, we found that Claudin-1 (encoded by CLDN1 gene) was significantly suppressed in PC that correlated with a poor clinical prognosis. Claudin-1 knockdown enhanced PC cell proliferation, migration, and stemness. Pancreatic specific Cldn1 knockout in KPC (LSLKrasG12D/Pdx1-Cre/Trp53R172H+) and KC (LSLKrasG12D/Pdx1-Cre) mice reduced mouse survival, promoted acinar-to-ductal metaplasia (ADM) process, and accelerated the development of pancreatic intraepithelial neoplasia (PanIN) and PC. Further investigation revealed that Claudin-1 suppression was mainly caused by aberrant DNA methylatransferase 1 (DNMT1) and DNMT3A elevations and the resultant CLDN1 promoter hypermethylation, as a DNMT specific inhibitor SGI-1027 effectively reversed the Claudin-1 suppression and inhibited PC progression both in vitro and in vivo in a Claudin-1 preservation-dependent manner. Together, our data suggest that Claudin-1 functions as a tumor suppressor in PC and its epigenetic suppression due to DNMT aberrations is a crucial event that promotes PC development and progression.

DNA Methylation-Mediated GPX4 Transcriptional Repression and Osteoblast Ferroptosis Promote Titanium Particle-Induced Osteolysis.

Metal wear particles generated by the movement of joint prostheses inevitably lead to aseptic osteolytic damage and ultimately prosthesis loosening, which are aggravated by various types of regulated cell death of bone. Nevertheless, the exact cellular nature and regulatory network underlying osteoferroptosis are poorly understood. Here, we report that titanium particles (TP) induced severe peri-implant osteolysis and ferroptotic changes with concomitant transcriptional repression of a key anti-ferroptosis factor, GPX4, in a mouse model of calvarial osteolysis. GPX4 repression was accompanied by an increase in DNA methyltransferases (DNMTs) 1/3a/3b and hypermethylation of the Gpx4 promoter, which were partly mediated by the transcriptional regulator/co-repressor KLF5 and NCoR. Conversely, treatment with SGI-1027, a DNMT-specific inhibitor, resulted in marked reversal of Gpx4 promoter hypermethylation and GPX4 repression, as well as improvement in ferroptotic osteolysis to a similar extent as with a ferroptosis inhibitor, liproxstatin-1. This suggests that epigenetic GPX4 repression and ferroptosis caused by the increase of DNMT1/3a/3b have a causal influence on TP-induced osteolysis. In cultured primary osteoblasts and osteoclasts, GPX4 repression and ferroptotic changes were observed primarily in osteoblasts that were alleviated by SGI-1027 in a GPX4 inactivation-sensitive manner. Furthermore, we developed a mouse strain with Gpx4 haplodeficiency in osteoblasts (Gpx4 Ob+/-) that exhibited worsened ferroptotic osteolysis in control and TP-treated calvaria and largely abolished the anti-ferroptosis and osteoprotective effects of SGI-1027. Taken together, our results demonstrate that DNMT1/3a/3b elevation, resulting GPX4 repression, and osteoblastic ferroptosis form a critical epigenetic pathway that significantly contributes to TP-induced osteolysis, and that targeting DNMT aberration and the associated osteoferroptosis could be a potential strategy to prevent or slow down prosthesis-related osteolytic complications.

The impact of laparoscopic versus open inguinal hernia repair for inguinal hernia treatment: A retrospective cohort study.

Objectives: Although laparoscopic inguinal hernia repair (LIHR) has been widely accepted for treating inguinal hernia, the procedure remains very technical and challenging. The present study aimed to assess the effect of LIHR in relation to operation time, intraoperative hemorrhage and postoperative hospitalization. Methods: A total of 503 patients with inguinal hernia admitted at the Wuxi Rehabilitation Hospital between June 2019 and July 2021 were included in this retrospective cohort study. Binary logistic and linear regressions were used for categorical and continuous outcomes, respectively. The learning curve was drawn by cumulative sum analysis. Results: Multivariate logistic regression analysis identified LIHR as an independent factor associated with prolonging operation time (odd ratio [OR] = 1.750, 95% confidence interval [CI]: 1.215-2.520, p = 0.003) and decreasing intraoperative hemorrhage levels (OR = 0.079, 95 CI: 0.044-0.142, p < 0.001). Multivariate linear regression identified LIHR (Coefficient = -0.702, 95% CI: [-1.050] to [-0.354], p < 0.001) as an independent factor for shortening postoperative hospitalization time. After learning curve, LIHR (OR = 1.409, 95% CI: 0.948 to 2.094, p = 0.090) no longer resulted as a risk factor prolonging operation time. Conclusions: LIHR is an important independent predictive factor for decreasing intraoperative hemorrhage levels and shortening postoperative hospitalization time. Additionally, LIHR does not prolong operation time after the learning curve.

The role of preoperative biliary drainage on postoperative outcome after pancreaticoduodenectomy in patients with obstructive jaundice.

Background: The role of preoperative biliary drainage (PBD) on obstructive jaundice patients is still controversial. The aim of this retrospective study is to clarify the effect of PBD on postoperative outcomes of pancreaticoduodenectomy (PD) and explore a reasonable PBD strategy for periampullary carcinomas (PAC) patients with obstructive jaundice before surgery. Methods: A total of 148 patients with obstructive jaundice who underwent PD were enrolled in this research and divided into drainage group and no-drainage group according to whether they received PBD. Patients who received PBD were classified into long-term group (>2 weeks) and short-term group (≤2 weeks) according to PBD duration. The clinical data of patients were statistically compared between groups to explore the influence of PBD and its duration. Analysis of pathogens in bile and peritoneal fluid was performed to probe the role of bile pathogens in opportunistic pathogenic bacterial infection after PD. Results: Of all, 98 patients underwent PBD. The mean duration between drainage and surgery was 13 days. Regarding postoperative outcomes, the incidence of postoperative intra-abdominal infection was significantly higher in the drainage group than the no-drainage group (P=0.026). In patients with total bilirubin (TB) less than 250 µmol/L, postoperative intra-abdominal infection was more frequently observed in the drainage group compared to the no-drainage group (P=0.022). Compared to the short-term drainage group, the proportion of positive ascites culture was significantly higher in the long-term drainage group (P=0.022). There were no statistically significant differences in postoperative complications between short-term group and no-drainage group. The most frequent pathogens detected in bile were Klebsiella pneumoniae, hemolytic Streptococcus and Enterococcus faecalis. The most commonly detected pathogens in peritoneal fluid were Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus epidermidis which appeared to have a high agreement with pathogens in preoperative bile cultures. Conclusions: Routine PBD should not be performed in obstructive jaundice PAC patients with TB less than 250 µmol/L. For patients with indications for PBD, the drainage duration should be controlled within 2 weeks. Bile bacteria may represent a major source of opportunistic pathogenic bacteria infection after PD.

A Retrospective Study on the Three-Port Technique of Laparoscopic Common Bile Duct Exploration for the Management of Cholelithiasis and Choledocholithiasis.

Background: Laparoscopic cholecystectomy (LC) with laparoscopic common bile duct exploration (LCBDE) is convenient in treating cholelithiasis and choledocholithiasis due to its advantage of accelerated recovery. This retrospective study aimed to summarize the experience of cholelithiasis and choledocholithiasis treatment via three-port approach of LCBDE in Eastern China. Methods: Patients diagnosed with cholelithiasis and choledocholithiasis between July 2019 and October 2021 were included. Patients who received LC+LCBDE+primary suturing of the common bile duct (CBD) via a three-port approach were assigned to the LCBDE-P group, and those who received LC+LCBDE+T-tube drainage of CBD comprised the LCBDE-T group. The measurement data were compared between the two groups. P-values <0.05 indicated statistical significance. Results: A total of 88 patients were divided into two groups: LCBDE-P (n=50) and LCBDE-T (n=38). Multiple logistic regression analysis showed that LCBDE-P is associated with a shorter length of stay (OR=0.115, 95% CI: 0.040-0.329, P<0.001) and lower hospitalization costs (OR=0.120, 95% CI: 0.041-0.357, P<0.001). No significant differences between the two groups were detected in the operation time, intraoperative hemorrhage, clearance rate of CBD stones, postoperative liver function, and postoperative complications (P>0.05). Conclusion: The three-port approach of LCBDE is a safe and feasible strategy for managing cholelithiasis and choledocholithiasis. Compared to LCBDE-T, LCBDE-P reduces the length of hospital stay and medical costs during hospitalization.

Age-based factors modulating the required thyroxine dose to achieve thyrotropin suppression in intermediate-and high-risk papillary thyroid cancer.

Background: Guidelines widely recommend thyrotropin suppression to reduce the risk of recurrence in intermediate- and high-risk papillary thyroid cancer (PTC) after total thyroidectomy. However, an insufficient or excessive dosage may result in a number of symptoms/complications especially in older patients. Patients and methods: We constructed a retrospective cohort including 551 PTC patient encounters. Using propensity score matching and logistic regression models, we determined the independent risk factors affecting levothyroxine therapy at different ages. Our outcomes included: expected TSH level and an unexpected TSH level, which was based on the initial thyroid-stimulating hormone (TSH) goal< 0.1 mIU/L with usual dosage of L-T4 (1.6 µg/kg/day). Results: From our analysis, more than 70% of patients undergoing total thyroidectomy did not achieve the expected TSH level using an empirical medication regimen, and the effect of the drug was affected by age (odds ratio [OR], 1.063; 95% CI, 1.032-1.094), preoperative TSH level (OR, 0.554; 95% CI, 0.436-0.704) and preoperative fT3 level (OR, 0.820; 95% CI, 0.727-0.925). In patients with age < 55 years old, preoperative TSH level (OR, 0.588; 95% CI, 0.459-0.753), and preoperative fT3 level (OR, 0.859; 95% CI, 0.746-0.990) were two independent protective factors, while, in patients with age ≥ 55 years old, only preoperative TSH level (OR, 0.490; 95% CI, 0.278-0.861) was the independent protective factors to achieve expected TSH level. Conclusion: Our retrospective analysis suggested the following significant risk factors of getting TSH suppression in PTC patients: age (≥55 years), lower preoperative TSH and fT3 levels.

[Significance of lipopolysaccharide binding protein in serum and ascites of patients with hepatic cirrhosis complicated with spontaneous bacterial peritonitis].

OBJECTIVE: To investigate the levels of lipopolysaccharide binding protein (LBP) in serum and ascites of cirrhotic patients, and determine their diagnostic value for spontaneous bacterial peritonitis (SBP). METHODS: Cirrhotic patients were divided into groups according to diagnosis of SBP, ascites without SBP, no ascites. To explore the significance of LBP in clinically suspect SBP cases, the ascites without SBP group was sub-divided into two groups according to the symptoms of abdominal pain or elevated white blood cell (WBC) count, and abdominal pain combined with elevated WBC count. Two control groups were composed of patients with intraperitoneal pus and a group of healthy, non-cirrhotic individuals. The LBP levels in serum and ascites were determined by enzyme-linked immunosorbent assay (ELISA). The ascites routine, ascites culture and albumin assay were carried out in the Second Affiliated Hospital of Chongqing Medical University. Data between the two groups were compared using the t-test or nonparametric test of independent samples, and the areas under the curve were compared using the Z test. Results The levels of LBP in serum and pus were significantly higher in the intraperitoneal pus group than in the cirrhosis group with ascites (P less than 0.01). RESULTS: The level of serum LBP was significantly higher in the cirrhosis group with SBP than in the cirrhosis group without SBP but with ascites and the cirrhosis group with no ascites (P less than 0.01). There was no significant difference in the level of ascites LBP in the cirrhosis group with SBP and the cirrhosis group without SBP but with ascites (P more than 0.05). In the clinically suspect cases with SBP, the levels of LBP in serum and ascites were significantly higher than those in the cirrhosis group without SBP but with ascites (228.00 mug/ml vs. 80.95 mug/ml and 22.50 mug/ml vs. 11.45 mug/ml, P less than 0.05). Determination of serum LBP had a higher sensitivity than the determination of ascites LBP or ascites WBC. CONCLUSION: Gram-negative bacteria infection in the intra-abdominal cavity causes serum and body fluid levels of LBP to increase significantly. Patients with cirrhosis complicated with SBP have significantly elevated levels of serum LBP. The serum and ascites LBP levels are significantly elevated in SBP patients with suspected clinical diagnosis. Measurements of both the serum LBP and ascites LBP may have diagnostic value for SBP.

Pressure increases PD-L1 expression in A549 lung adenocarcinoma cells and causes resistance to anti-ROR1 CAR T cell-mediated cytotoxicity.

Due to the abnormal vasculation and proliferation, the tumor microenvironment is hypoxic, lacking nutrients, and under high interstitial pressure. Compared to oxygen and nutrients, the effect of pressure on cancer biology remains poorly studied. Here we constructed αROR1-CAR T cells and co-cultured with A549 cells with and without elevated pressure. We then measured apoptosis and cell death by flow cytometry and luciferase activity. We also measured cytokine (IL-2, IFN-γ, and TNF-α) release by ELISA. The results show that pressure-preconditioned A549 cells are much resistant to αROR1-CAR T cell-mediated cytotoxicity. Pressure preconditioning does not appear to affect the expression of αROR1-CAR or cytokine production. However, pressure preconditioning upregulates PD-L1 expression in A549 cells and decreases cytokine release from αROR1-CAR T cells. In addition, Pembrolizumab and Cemiplimab that block PD-1::PD-L1 interaction increase the cytokine production in αROR1-CAR T cells, increase the apoptotic cell death in A549 cells, and improve the αROR1-CAR T-mediated cytotoxicity. In xenograft mice, pressure preconditioning increases tumorigenesis of A549 cells, which can be blocked by a combined therapy using Pembrolizumab and αROR1-CAR T cells. Together, our studies suggest that elevated pressure in the tumor microenvironment could blunt the T cell therapy by upregulating PD-L1 expression, which could be overcome by combining CAR T therapy with immune checkpoint inhibitors.

Development and validation of a nomogram for predicting post-operative abdominal infection in patients undergoing pancreaticoduodenectomy.

AIM: The aim of this retrospective study is to develop and validate a predictive nomogram for predicting the risk of post-operative abdominal infection (PAI) in patients undergoing pancreaticoduodenectomy (PD). METHODS: A total of 360 patients who underwent PD were enrolled into this research and randomly divided into the development and validation group. The clinical data of patients were statistically compared and the nomogram was constructed based on the results of multivariate logistic regression analysis and stepwise (stepAIC) selection. The nomogram was internally and crossly validated by the development and validation cohort. The discriminatory ability of the nomogram was estimated by AUC (Area Under the receiver operating characteristic Curve), calibration curve and decision curve analysis. RESULTS: After PD, post-operative abdominal infection occurred in 33.89% (n = 122) of patients. The nomogram showed that preoperative biliary drainage and C-reactive protein (CRP), direct bilirubin (DB), alkaline phosphatase (AKP) levels on the 3rd postoperative day (POD3) were independent prognostic factors for abdominal infection after PD. The internal and cross validation of Receiver Operating Characteristic (ROC) curve was statistically significant (AUC = 0.723 and 0.786, respectively). The calibration curves showed good agreement between nomogram predictions and actual observations. The decision curves showed that the nomogram was of great clinical value. CONCLUSION: A nomogram based on perioperative risk factors such as preoperative biliary drainage, CRP, DB and AKP could simply and accurately predict the risk degree of PAI in patients undergoing PD.

Zinc finger protein 91 accelerates tumour progression by activating ß-catenin signalling in pancreatic cancer.

OBJECTIVES: ZFP91, an E3 ligase, has been reported to possess cancer-promoting functions. This study aimed to elucidate the exact role of ZFP91 in tumour progression of pancreatic cancer and underlying mechanisms. MATERIALS AND METHODS: We analysed the correlation between ZFP91 expression and pancreatic cancer through TCGA and GEO data sets. Growth curve, colony formation, wound healing and transwell invasion assays were conducted to evaluate proliferation, migration and invasion of lentivirus transfected pancreatic cancer cells. GSEA and Western blot analysis were performed to validate the regulatory effect of ZFP91 on ß-catenin. Drug response curve and orthotopic implantation model reflected the sensitivity of chemotherapies. RESULTS: ZFP91 overexpression is prevalent in pancreatic cancer and negatively correlated with overall survival. ZFP91 knock-down attenuated proliferation, migration and invasion of pancreatic cancer cells. ß-catenin was a downstream gene of ZFP91, and its agonist could reverse the phenotype. ZFP91 promoted EMT and chemoresistance in pancreatic cancer. CONCLUSIONS: We demonstrated that ZFP91 promoted pancreatic cancer proliferation, migration and invasion through activating ß-catenin signalling. EMT and chemoresistance were also regulated by ZFP91. ZFP91 might be a potential therapeutic target for pancreatic cancer.