Objective To investigate the toxic effects of combined yttrium and lead exposure on liver and kidney functions in male Sprague-Dawley (SD) rats. Methods Adult male specific pathogen-free SD rats were randomly divided into four groups. Rats in the low-, medium-, and high-dose groups were co-administered with yttrium acetate (10.0, 50.0, and 100.0 mg/kg body weight, respectively) and lead acetate (4.0, 20.0, and 40.0 mg/kg body weight, respectively) by intragastric gavage, once per day for 28 consecutive days. Rats in the control group received an equal volume of deionized water. Yttrium and lead levels in whole blood, liver, and kidney tissues of the rats were measured using inductively coupled plasma mass spectrometry. Serum index of liver and kidney function were measured by a double reagent method, and histopathological changes in the liver and kidney were observed. Results The body weights of rats in all the three exposure groups were lower than those in the control group from day 14 of exposure until the end of exposure (all P<0.05). Body weight gain of rats was observed only in the low-dose group at day 28, whereas no body weight gain was observed throughout the exposure period in the medium- and high-dose groups. Histopathological examination showed dose-dependent liver and kidney injuries in rats of the three exposure groups compared with the control group. Specifically, the liver exhibited widening of intercellular spaces and increased inflammatory cell infiltration, while the kidney showed increased tissue hemorrhage and increased damage to glomeruli and renal tubules. Lead levels in whole blood, liver, and kidney tissues of the rats were higher than yttrium levels in all the three exposure groups (all P<0.05). Blood yttrium levels in rats of the high-dose group were higher than those in the other three groups (all P<0.05), and yttrium levels in the liver and kidney tissues of the three exposure groups were higher than those in the control group (all P<0.05). Lead levels in whole blood, liver, and kidney tissues of the rats increased with increasing exposure dose (all P<0.05). At the end of exposure, the kidney organ coefficient of rats in the high-dose group was higher than those in the other three groups (all P<0.05). The serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio of rats in the high‑dose group was lower than that in the control group (P<0.05). The serum urea and uric acid levels in the medium‑ and high‑dose groups were lower than those in the control group (both P<0.05). The serum cystatin C level in the high‑dose group was higher than that in the control group (P<0.05). Blood yttrium and blood lead levels were each negatively correlated with serum ALT/AST ratio, serum urea nitrogen, and uric acid levels (both P<0.05). Both yttrium and lead levels in liver tissue were each negatively correlated with serum ALT/AST ratio (all P<0.05). Both yttrium and lead levels in kidney tissue were each negatively correlated with both serum urea nitrogen and uric acid levels (all P<0.05), and each positively correlated with serum cystatin C levels (both P<0.05). Conclusion Co-exposure to yttrium and lead induces dose‑dependent hepatotoxicity and nephrotoxicity in male SD rats. Lead exhibits a more pronounced accumulation effect and contributes more substantially to the observed toxicity.

Objective:To investigate whether neoadjuvant therapy can improve the prognosis of patients with pancreatic cancer.Methods:A retrospective case-control study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on 12, 103 patients who underwent surgical treatment between January 1, 2010, and December 31, 2021. Patients were divided into the neoadjuvant therapy group ( n=3 276) and the upfront surgery group ( n=8 827) based on whether they received neoadjuvant treatment. The neoadjuvant therapy group included 2 342 patients receiving neoadjuvant chemotherapy and 934 patients receiving neoadjuvant chemoradiotherapy. The upfront surgery group consisted of 4 335 patients receiving adjuvant chemotherapy, 1 987 patients receiving adjuvant chemoradiotherapy, 63 patients receiving adjuvant radiotherapy, and 2 442 patients undergoing surgery alone. Propensity score matching was used to eliminate group differences and create a cohort with no statistical differences in other clinicopathological features except for the grouping variable. Variables such as age, gender, tumor location, race, population of residence, tumor diameter, household income, TNM stage, and information on radiotherapy and chemotherapy were used for 1∶1 case matching. T stage, N stage, and the use of radiotherapy or chemotherapy were matched exactly. After matching, 1 182 patients were included in each group: the neoadjuvant therapy group contained 1 155 patients receiving neoadjuvant chemoradiotherapy and 27 receiving neoadjuvant chemotherapy, while the upfront surgery group comprised 848 patients receiving adjuvant chemotherapy and 334 receiving adjuvant chemoradiotherapy. TNM staging was reported according to the 7th edition of the AJCC guidelines. The primary outcome was overall survival. Measurement data with skewed distributions were expressed as M( Q1, Q3), and intergroup comparisons were conducted using the Wilcoxon rank-sum test. Categorical data were compared using the chi-square test or the Fisher′s exact test. The Log-rank test and subgroup analyses to assess interactions between neoadjuvant therapy and subgroup in COX regression models were used to compare survival benefits across variables. Landmark analysis was performed to create segmented survival curves, studying the impact of neoadjuvant therapy on prognosis during different follow-up periods. Results:The neoadjuvant therapy group had a higher proportion of T 4 tumor involving celiac axis, superior mesenteric artery, and/or common hepatic artery compared to the upfront surgery group (14.7% vs 2.8%, P<0.001). Additionally, significant differences were observed between groups in terms of race, location, population of residence, age, tumor diameter, tumor stage, and adjuvant therapy regimen ( P<0.05). The median overall survival time in the neoadjuvant therapy group was 30 months, compared to 22 months in the upfront surgery group ( P<0.001). In the neoadjuvant therapy group, the median survival was 30 months for both neoadjuvant chemotherapy and chemoradiotherapy patients; in the upfront surgery group, it was 26 months for both adjuvant chemotherapy and chemoradiotherapy patients, 17 months for adjuvant radiotherapy patients, and 12 months for surgery-only patients. After propensity score matching, there were no differences in the distribution of clinical characteristics between groups ( P>0.05), and all patients in the matched cohort had received chemotherapy. The matched neoadjuvant therapy group had a longer median overall survival compared to the upfront surgery group (30 months vs 27 months, P<0.001). Subgroup interaction analysis revealed that T stage had a significant interaction with neoadjuvant therapy, both before (T 4 stage: HR=0.382, 95% CI: 0.319-0.458; T 2-T 3 stages: HR=0.696, 95% CI: 0.656-0.738; T 1 stage: HR=1.199, 95% CI: 0.867-1.657; interaction P<0.001) and after matching (T 4 stage: HR=0.581, 95% CI: 0.414-0.814; T 2-T 3 stages: HR=0.827, 95% CI: 0.734-0.931; T 1 stage: HR=1.320, 95% CI: 0.716-2.433; interaction P=0.043). Subgroup interaction analysis indicated that T 1 patients did not benefit from neoadjuvant therapy; survival curves plotted for matched T 1 patients showed no difference in survival between the neoadjuvant therapy group and the upfront surgery group ( P=0.323). Conversely, non-T 1 (T 2-T 4) stage patients showed significant survival benefits in both unmatched and matched cohorts ( P<0.001). Landmark analysis showing that the survival benefits occurred mainly in the early postoperative period of up to 3 years ( P<0.001), but there was no difference in overall survival between the neoadjuvant therapy group and the upfront surgery group of >3 years ( P>0.05). Patients with Arterial invasion (T 4 stage compared to T 1-T 3 stages) showed a similarly significant interaction with the benefit of neoadjuvant therapy in both the pre-matching cohort (interaction P<0.001) and the post-matching cohort (interaction P=0.037). Patients with T 4 stage disease in the neoadjuvant therapy group had longer overall survival compared to the upfront surgery group (median overall survival in pre-matching cohort: 30 months vs 13 months, P<0.001; median overall survival in post-matching cohort: 28 months vs 18 months, P=0.001). Among T 4 stage patients in the post-matching cohort, neoadjuvant therapy provided significant survival benefits during the early postoperative period of up to 3 years ( P=0.001). However, there was no difference in overall survival between the neoadjuvant therapy group and the direct surgery group beyond 3 years( P=0.729). Conclusions:The prognosis in the neoadjuvant therapy group was better than in the upfront surgery group. Propensity score matching and subgroup interaction analysis showed that non-T 1 and T 4 stage patients benefited more from neoadjuvant therapy, with benefits mainly seen in the early postoperative period (≤3 years).

Objective To screen key differentially expressed genes in head and neck squamous cell carcinoma(HNSCC)and analyze their prognostic value,based on biological information from gene expression omnibus(GEO)and the cancer genome atlas(TCGA)databases.Methods HNSCC mRNA expression data(GSE74530)were downloaded from the GEO database as a test dataset,and differentially expressed genes(DEGs)were identified.The biological function of DEGs in HNSCC was investigated by gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.HNSCC mRNA expression data were obtained from the TCGA database as a validation dataset to preliminarily verify the expression of DEGs in HNSCC tissues and normal tissues.Seven up-regulated DEGs variants were analyzed using the cBioPortal database,and their effects on the survival of HNSCC patients were evaluated by the Kaplan-meier method and COX regression analysis.The co-expressed genes of ATP6V1C1 were analyzed by the cBioPortal database.Results A total of 1 432 differential genes were screened from HNSCC tissue and paracancerous tissue in the GSE74530 test dataset,among which 7 of the 10 most significant genes were up-regulated,respectively:MMP1,WDR66,PTPRZ1,TEAD4,RBM38,ATP6V1C1 and CBLB were downregulated by CGNL1,LOC100506990 and ADH1B.GO and KEGG enrichment analysis showed that HNSCC tissue differential genes were mainly enriched in lymphocyte migration and extracellular matrix regulation pathways.The TCGA dataset confirmed that 7 upregulated DEGs were highly expressed in HNSCC.cBioPortal analysis showed that the proportion of ATP6V1C1 gene changes was the highest among the 7 up-regulated genes,and the overall survival rate of patients with high expression of ATP6V1C1 gene decreased significantly.Correlation analysis showed that BIRC5 was the most closely related gene to ATP6V1C1.Conclusion MMP1,WDR66,PTPRZ1,TEAD4,RBM38,ATP6V1C1 and CBLB were highly expressed in HNSCC patients,among which ATP6V1C1 was the most significant,and its expression level was associated with poor prognosis in HNSCC patients.ATP6V1C1 is expected to be a biomarker for early diagnosis and prognosis of HNSCC,providing a new idea for clinical diagnosis and treatment.

Objective To screen key differentially expressed genes in head and neck squamous cell carcinoma(HNSCC)and analyze their prognostic value,based on biological information from gene expression omnibus(GEO)and the cancer genome atlas(TCGA)databases.Methods HNSCC mRNA expression data(GSE74530)were downloaded from the GEO database as a test dataset,and differentially expressed genes(DEGs)were identified.The biological function of DEGs in HNSCC was investigated by gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.HNSCC mRNA expression data were obtained from the TCGA database as a validation dataset to preliminarily verify the expression of DEGs in HNSCC tissues and normal tissues.Seven up-regulated DEGs variants were analyzed using the cBioPortal database,and their effects on the survival of HNSCC patients were evaluated by the Kaplan-meier method and COX regression analysis.The co-expressed genes of ATP6V1C1 were analyzed by the cBioPortal database.Results A total of 1 432 differential genes were screened from HNSCC tissue and paracancerous tissue in the GSE74530 test dataset,among which 7 of the 10 most significant genes were up-regulated,respectively:MMP1,WDR66,PTPRZ1,TEAD4,RBM38,ATP6V1C1 and CBLB were downregulated by CGNL1,LOC100506990 and ADH1B.GO and KEGG enrichment analysis showed that HNSCC tissue differential genes were mainly enriched in lymphocyte migration and extracellular matrix regulation pathways.The TCGA dataset confirmed that 7 upregulated DEGs were highly expressed in HNSCC.cBioPortal analysis showed that the proportion of ATP6V1C1 gene changes was the highest among the 7 up-regulated genes,and the overall survival rate of patients with high expression of ATP6V1C1 gene decreased significantly.Correlation analysis showed that BIRC5 was the most closely related gene to ATP6V1C1.Conclusion MMP1,WDR66,PTPRZ1,TEAD4,RBM38,ATP6V1C1 and CBLB were highly expressed in HNSCC patients,among which ATP6V1C1 was the most significant,and its expression level was associated with poor prognosis in HNSCC patients.ATP6V1C1 is expected to be a biomarker for early diagnosis and prognosis of HNSCC,providing a new idea for clinical diagnosis and treatment.

Objective:To investigate the correlation between serum proprotein convertase subtilisin/Kexin type 9 (PCSK9) level and white matter hyperintensities (WMHs) in healthy population.Methods:Consecutive healthy individuals underwent routine physical examinations at the Department of Neurology, Jinling Hospital Affiliated to Medical School of Nanjing University (April 2023 to December 2023) and Hexi Branch of Nanjing First Hospital (March 2024 to April 2024) were included prospectively. Enzyme-linked immunosorbent assay was used to detect serum PCSK9 level. The Fazekas scale was used to assess the severity of WMHs (total score 0-6) and they were divided into no or mild WMHs group (0-2) and moderate to severe WMHs group (3-6). Multivariate logistic regression analysis was used to determine the independent correlation between the serum PCSK9 level and the severity of WMHs. Results:A total of 177 subjects were enrolled, including 110 males (62.1%), aged 66.7±10.1 years. The median serum PCSK9 level was 203.9 ng/L. According to the Fazekas score, there were 102 patients (51.6%) in the no or mild WMHs group, and 75 (42.4%) in the moderate to severe WMHs group. One way analysis of variance showed that serum PCSK9 level significantly increased with the increase of WMHs total score ( P=0.001). The serum PCSK9 level in the moderate to severe WMHs group was significantly higher than that in the no or mild WMHs group (437.2±260.4 ng/L vs. 217.9±141.7 ng/L; P=0.001). Multivariate logistic regression analysis showed that after adjusting for age, gender, and other confounding factors, there was a significant independent correlation between higher serum PCSK9 level and moderate to severe WMHs (odds ratio 3.201, 95% confidence interval 2.107-5.082; P=0.001). Conclusion:Higher serum PCSK9 level is an independent risk factor for moderate to severe WMHs in healthy individuals.

Objective:To preliminarily investigate the risk factors for distant metastasis and prognosis, and construct a prognostic nomogram in T 4 stage pancreatic cancer. Methods:A retrospective case-control study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database for pancreatic patients from January 1, 2010, to December 31, 2021. Based on whether the tumor invaded the celiac axis, superior mesenteric artery, and/or common hepatic artery, 38 759 patients were divided into an arterial invasion group (T 4 stage, n=7 471) and a non-arterial invasion group (non-T 4 stage, n=31 288). Clinical and pathological data, including demographic characteristics, treatment information, and tumor data were collected. The primary outcome was overall survival. Categorical data were expressed as numbers (percentages), and intergroup comparisons were made using the chi-square test. Survival benefits were measured using the Log-Rank test. A multivariate logistic model was used to identify high-risk factors for metastasis in T 4 stage pancreatic cancer. Patients were randomly divided into training ( n=5 232) and validation ( n=2 239) sets at a 7∶3 ratio. A nomogram model was created based on independent prognostic factors from the multivariate Cox regression analysis, and the model′s predictive ability was evaluated using the C-index and calibration curves. Results:The overall metastasis rate in the arterial invasion group was higher than that in the non-arterial invasion group (32.8% vs 29.0%, P<0.001), with fewer patients showing no metastasis or single-organ metastasis (86.3% vs 89.7%, P<0.001) and higher rates of lung metastasis ( P<0.001), distant lymph node metastasis ( P<0.001), and other metastases excluding liver, lung, brain, bone, and distant lymph node metastases ( P<0.001). However, no significant difference was found between groups for liver, brain, or bone metastasis rates ( P>0.05). Surgical rates for T 4 stage patients were significantly lower than for non-T 4 stage patients (all patients: 10.7% vs 38.4%, P<0.001; M 0 stage patients: 15.0% vs 52.4%, P<0.001; M 1 stage patients: 2.1% vs 4.1%, P<0.001). Additionally, significant differences were observed in age, race, radiotherapy, chemotherapy, tumor location, tumor size, and tumor stage ( P<0.05). The median survival for patients with arterial invasion was 8 months, significantly lower than the 10-month median survival for non-arterial invasion patients ( P<0.001). The median survival for surgical patients with arterial invasion was 22 months, lower than the 24-month median for non-T 4 stage patients underwent surgery ( P<0.001) but significantly higher than for patients without surgery (T 4 stage patients without surgery: 8 months, P<0.001; non-T 4 stage patients without surgery: 6 months, P<0.001). For lymph node metastasis, patients with or without positive local lymph node metastasis had similar overall survival ( P>0.05). However, Patients with distant lymph node metastasis had significantly lower overall survival than that in patients without distant lymph node metastasis ( P<0.001). The multivariate logistic model indicated that tumor location in the body and tail ( OR=2.591, 95% CI: 2.343-2.867), positive regional lymph nodes ( OR=2.033, 95% CI: 1.836-2.252), and age <70 years old ( OR=1.183, 95% CI: 1.067-1.312) were risk factors for distant metastasis in arterial invasion patients. The multivariate Cox model showed that surgery ( HR=0.451, 95% CI: 0.405-0.503), radiotherapy ( HR=0.729, 95% CI: 0.677-0.784), chemotherapy ( HR=0.277, 95% CI: 0.258-0.297), tumor location in the body and tail ( HR=0.928, 95% CI: 0.874-0.985), and household income ≥$80, 000 ( HR=0.908, 95% CI: 0.853-0.968) were independent protective factors for prognosis in arterial invasion patients. Living in areas with a population ≤1 million ( HR=1.109, 95% CI: 1.044-1.178), age ≥70 years old ( HR=1.220, 95% CI: 1.150-1.296), larger tumor size (>2 cm but ≤4 cm: HR=1.124, 95% CI: 0.954-1.323; >4 cm: HR=1.310, 95% CI: 1.114-1.541), and having a metastatic burden (lung metastasis: HR=1.049, 95% CI: 0.869-1.267; distant lymph node metastasis: HR=1.179, 95% CI: 0.910-1.527; bone metastasis: HR=1.419, 95% CI: 0.854-2.359; brain or other metastasis: HR=1.519, 95% CI: 1.350-1.709; liver metastasis: HR=1.737, 95% CI: 1.600-1.886; two types of metastasis: HR=1.913, 95% CI: 1.689-2.168; three or more types: HR=2.436, 95% CI: 1.947-3.048) were independent risk factors for prognosis. The nomogram based on these prognostic factors had a C-index of 0.749 in the training set and 0.745 in the validation set; calibration curves in both sets were near the 45° line. Conclusions:High metastasis rates and low surgery rates are characteristic of pancreatic cancer with arterial invasion. Investigating the risk factors for distant metastasis and developing a prognostic nomogram incorporating metastatic burden hold significant clinical value for T 4 stage pancreatic cancer.

Gingival recessions (GRs) result in root hypersensitivity, root surface caries, and esthetic problems. Various root coverage surgeries are being developed for periodontal plastic therapy. The tunnel technique (TUN) is one of the most widely applied surgeries due to its features of being minimally invasive, practical, excellent outcomes and long-term stability; however, there are still some limitations of this technique. The history and evolution from the envelope flap to TUN, including its efficiency when compared with coronally advanced flaps with a connective tissue graft (CTG), are reviewed in this paper. The limitations of TUN are discussed in consideration of our clinical experience; for example, there is high technique sensitivity when TUN is applied in GR>5 mm because of the great difficulty in covering the grafts. The advantages of surgical access, including vertical incisions in the vestibule, “W” type and pinhole access, are discussed for different situations. Mattress sutures and sling sutures in a single tooth or multiple teeth are applied in TUN. The different types of grafts, such as CTG, platelet-rich plasma, articular dermal matrix and xenogeneic collagen matrix, are described. Mechanical, chemical and biological conditioning of the root surface are recommended during surgery. Protecting the surgical area and taking antibiotics postoperatively are also very important. Finally, the modifications when TUN is applied with other kinds of techniques are discussed, including lateral closed TUN, laterally positioned flaps, double papilla flaps and frenuloplasty. Minimally invasive, esthetic, long-term stability and simplified techniques are the development trends of TUN in the future.

Pancreatic cancer, notorious for its late diagnosis and aggressive progression, poses a substantial challenge owing to scarce treatment alternatives. This review endeavors to furnish a holistic insight into pancreatic cancer, encompassing its epidemiology, genomic characterization, risk factors, diagnosis, therapeutic strategies, and treatment resistance mechanisms. We delve into identifying risk factors, including genetic predisposition and environmental exposures, and explore recent research advancements in precursor lesions and molecular subtypes of pancreatic cancer. Additionally, we highlight the development and application of multi-omics approaches in pancreatic cancer research and discuss the latest combinations of pancreatic cancer biomarkers and their efficacy. We also dissect the primary mechanisms underlying treatment resistance in this malignancy, illustrating the latest therapeutic options and advancements in the field. Conclusively, we accentuate the urgent demand for more extensive research to enhance the prognosis for pancreatic cancer patients.
Humans ; Pancreatic Neoplasms/therapy* ; Prognosis ; Pancreas/pathology* ; Genetic Predisposition to Disease ; Genomics

Primary adrenal small cell neuroendocrine carcinoma is clinically rare. This article reported a patient, who was diagnosed as primary adrenal small cell neuroendocrine carcinoma complicated with renal vein cancer thrombus, and underwent laparoscopic left adrenal + left kidney + left renal vein tumor embolectomy.The carcinoma relapsed after 19 months of follow-up after surgery. The patient and his family refused further treatment.

Objective:To investigate the correlation between the lipocalin-2 (LCN-2) level and white matter hyperintensities (WMHs) in patients with ischemic stroke.Methods:Consecutive patients with ischemic stroke admitted to the Department of Neurology, Jinling Hospital, Medical School of Nanjing University from September 2021 to November 2021 and whose duration from onset to hospitalization <14 d were prospectively enrolled. Enzyme-linked immunosorbent assay was used to detect the serum LCN-2. Fazekas scale was used to assess the severity of periventricular and subcortical WMHs. A total WMHs score ≥3 was defined as severe WMHs. Multivariate logistic regression analysis was used to determine the correlation between serum LCN-2 level and WMHs. Results:A total of 179 patients were enrolled, including 122 males (68.2%), aged 64.7±11.6 years. The median serum LCN-2 level was 387.1 g/L, and 86 patients (48.0%) had severe WMHs. Serum LCN-2 in the severe WMH group was significantly higher than that in the non-severe WMH group (505.3±342.4 g/L vs. 367.8±224.5 g/L; t=3.110, P=0.002). Multivariable logistic regression analysis showed that after adjusting for the relevant confounding factors, there was a significant correlation between higher serum LCN-2 and severe WMHs (odds ratio 2.32, 95% confidence interval 1.17-4.63; P=0.017) and higher total WMHs score (odds ratio 1.62, 95% confidence interval 1.12-2.35; P=0.011). Conclusion:Higher serum LCN-2 level is associated with severe WMHs in patients with ischemic stroke.