Laparoscopic radical surgery for locally advanced T4 transverse colon cancer and prognostic factors analysis: Evidence from multi-center databases.

The safety and efficacies of laparoscopic radical procedures are still controversial for locally advanced pathological T4 (pT4) TCC (transverse colon cancer). Therefore, the aim of this study is to evaluate the oncologic and perioperative outcomes and to recognize the prognostic factors in radical resection for pT4 TCC derived from multi-center databases. 314 patients with TCC who underwent radical resection between January 2004 and May 2017, including 139 laparoscopic resections and 175 open resections, were extracted from multicenter databases. Oncological as well as perioperative outcomes were investigated. The baseline characteristics of the 2 groups did not differ significantly. Nevertheless, the laparoscopic technique was found to be linked with a significantly longer duration of surgery (208.96 vs 172.89 minutes, P = .044) and a significantly shorter postoperative hospital stay (12.23 vs 14.48 days, P = .014) when compared to the conventional open approach. In terms of oncological outcomes, lymph node resection (16.10 vs 13.66, P = .886), 5-year overall survival (84.7% vs 82.7%, P = .393), and disease-free survival (82.7% vs 83.9%, P = .803) were similar between the 2 approaches. Based on multivariate analysis, it was determined that differentiation and N classification were both independent prognostic factors for overall survival. However, it was found that only N classification was an independent prognostic factor for disease-free survival. These findings underscore the significance of differentiation and N classification as key determinants of patient outcomes in this context. Overall, the laparoscopic approach may offer advantages in terms of shorter hospital stays, while maintaining comparable oncological outcomes. Laparoscopic radical procedure can gain a couple of short-term benefits without reducing long-term oncological survival for patients with pT4 TCC.

Clinical and survival outcomes of colectomy for transverse colon cancer in elderly patients.

It remains controversial whether elderly patients with transverse colon cancer present worse prognoses. Our study utilized evidence from multi-center databases to evaluate the perioperative and oncology outcomes of radical resection of colon cancer in elderly and nonelderly patients. In this study, we analyzed 416 patients with transverse colon cancer who underwent radical surgery from January 2004 to May 2017, including 151 elderly (aged ≥ 65 years) and 265 nonelderly (aged < 65 years) patients. We retrospectively compared the perioperative and oncological outcomes between these 2 groups. The median follow-up in the elderly and nonelderly groups was 52 and 64 months, respectively. There were no significant differences in the overall survival (OS) (P = .300) and disease-free survival (DFS) (P = .380) between the elderly and nonelderly groups. However, the elderly group had longer hospital stays (P < .001), a higher complication rate (P = .027), and fewer lymph nodes harvested (P = .002). The N classification and differentiation were significantly associated with OS based on univariate analysis, and the N classification was an independent prognostic factor for OS based on multivariate analysis (P < .05). Similarly, the N classification and differentiation were significantly correlated with the DFS based on univariate analysis. However, multivariate analysis indicated that the N classification was an independent prognostic factor for DFS (P < .05). In conclusion, the survival and surgical outcomes in elderly patients were similar to nonelderly patients. The N classification was an independent factor for OS and DFS. Even though elderly patients with transverse colon cancer present a higher surgical risk than nonelderly patients, performing radical resection in elderly patients can be an appropriate choice for treatment.

Clinical and Pathological Implications of Increases in Tonsillar CD19+CD5+ B Cells, CD208+ Dendritic Cells, and IgA1-positive Cells of Immunoglobulin A Nephropathy.

OBJECTIVE: Several studies indicated that tonsillectomy can improve the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, the relationship between tonsillar immunity and IgAN is still unclear. METHODS: A total of 14 IgAN patients were recruited in the current study from May 2015 to April 2016 in Tongji Hospital. B cells, dendritic cells (DCs), and IgA1 positive cells in human tonsils were detected using immunofluorescence and immunohistochemistry. Correlations between these cells and clinicopathologic features were evaluated. RESULTS: CD19+CD5+ B cells were predominantly located in germinal centers and mantle zones of lymphoid follicles, the CD208+ DCs were distributed in the interfollicular and subepithelial area, and IgA1-positive cells were predominantly detected in mantle zones of lymphoid follicles and subepithelial tissues. The numbers of CD19+CD5+ B cells, CD208+ DCs, and IgA1-positive cells in tonsillar tissues from IgAN patients were significantly higher than those in the normal controls (P<0.01, respectively). CD19+CD5+ B cells, CD208+ DCs, and IgA1-positive cells in tonsillar tissues were significantly associated with 24-h proteinuria levels and tubular atrophy/interstitial fibrosis of IgAN. CONCLUSION: CD19+CD5+ B cells, CD208+ DCs, and IgA1-positive cells in tonsillar tissues might be involved in the pathogenesis of IgAN.

Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients.

OBJECTIVE: Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients. METHODS: Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria. RESULTS: In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008). CONCLUSION: Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.

Interleukin-7 Is Associated with Clinical and Pathological Activities in Immunoglobulin A Nephropathy and Protects the Renal Proximal Tubule Epithelium from Cellular Fibrosis.

OBJECTIVE: Diagnosis of immunoglobulin A nephropathy (IgAN) requires the evaluation of renal biopsy specimens. However, renal biopsy is an invasive procedure and is not frequently performed for various reasons. Thus, recognized noninvasive biomarkers for predicting IgAN progression are urgently needed. METHODS: In the present study, we included 86 IgAN patients with renal biopsy from June 2015 to May 2016 and had their plasma interleukin-7 (IL-7) level measured with ELISA. The association between the plasma IL-7 level and clinico-pathological characteristics was analyzed. Immunohistochemical staining was used to assay the in situ expression of IL-7 in vivo. Western blotting was performed to examine the production of extracellular matrix, p-mTOR and the markers of autophagy under the treatment of IL-7 after TGF-ß1 stimulation in renal tubular epithelial cells. RESULTS: IL-7 was significantly decreased in patients with IgAN compared to healthy subjects (2.3077 vs. 8.6294 pg/mL, P<0.0001). There was a significant difference in the plasma IL-7 level between tubular atrophy/interstitial fibrosis T0 and T2 classes (P=0.0064). A lower plasma IL-7 value in patients at the time of biopsy indicated a poor renal outcome. In addition, IL-7 was over-expressed in renal tubular epithelial cells and significantly attenuated transforming growth factor ßl-induced extracellular matrix production by suppression of cellular autophagy via activation of mTOR1 signaling. CONCLUSION: These results suggested that IL-7 might be a noninvasive biomarker for predicating IgAN. It protected renal proximal tubular epithelial cells from cellular fibrosis by inhibiting autophagy via mTORl signaling.

Exploring the determinants that influence hospital costs of induction therapy for acute myeloid leukemia.

The financial burden of acute myeloid leukemia (AML) patients is substantial. We retrospectively analyzed the hospital costs of the first induction therapy for 353 newly diagnosed AML patients who were admitted to our hospital from January 2013 to December 2018. We found the median hospital costs were estimated at 110,291.8 RMB. Multivariate analysis showed that length of hospital stay was the leading determinant affecting hospital costs (p < 0.0001), followed by length of agranulocytosis days (p < 0.01), but for the patients who failed to achieve complete remission (CR), length of hospital stay was the independent factor contributing to hospital costs. Besides, patients achieving CR had similar hospital costs to the patients failing to achieve CR. The hospital costs of low-intensity chemotherapy might not be lower than that of intensive chemotherapy.

Trends in disease burden of chronic myeloid leukemia at the global, regional, and national levels: a population-based epidemiologic study.

BACKGROUND: Outcomes of chronic myeloid leukemia (CML) has been improved dramatically in the past two decades, but survival levels of CML patients varied in regions. Comprehensive epidemiological research is necessary to evaluate the global burden of CML. METHODS: All data used in our study came from the Global Burden of Disease (GBD) study 2017. Incidence cases, death cases, disability-adjusted life-years (DALYs), and its corresponding age-standardized rate between 1990 to 2017 were used to describe the distribution of CML burden, according to age, sex, social-demographic index (SDI), and countries. Data about attributable risk factors contributing to CML deaths and DALYs were also extracted and analyzed. RESULTS: Globally, the disease burden of CML gradually decreased from 1990 to 2017. Higher SDI countries achieved a remarkable effect on diminishing the CML burden. Conversely, due to population growth, the incidence cases, death cases, and DALYs of CML in lower SDI quintiles showed an upward trend. India had the most incidence cases and death cases of CML in the world. Additionally, smoking was the most significant attributable risk factor contributing to CML deaths and DALYs, followed by high body mass index. CONCLUSION: The disease burden of CML decreased globally, especially in higher SDI countries in the past 28 years. The increasing incidence cases and death cases were mainly observed in lower SDI countries. Additionally, strategies to control modifiable risk factors such as smoking and high body mass index might be useful in diminishing mortality and DALYs.

Chidamide Inhibits Acute Myeloid Leukemia Cell Proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK Signaling Pathway.

Irregular histone modification and aberrant lncRNAs expression are closely related to the occurrence of tumors including acute myeloid leukemia (AML). However, the effects and specific underlying molecular mechanism of histone deacetylase inhibitors on lncRNA expression in AML cells are unclear. Here, we reported the effects of a novel histone deacetylase inhibitor Chidamide on proliferation and lncRNA expression in AML cells. Chidamide inhibited cell proliferation, blocked G1/S phase transition, and induced cell apoptosis through the caspase-dependent apoptotic pathway in AML cells. Chidamide also inhibited the formation of subcutaneous tumors. Transcriptome sequencing results showed that 1,195 lncRNAs were co-upregulated and 780 lncRNAs were co-downregulated after Chidamide treatment of SKM-1 cells and THP-1 cells. Combined with transcriptome sequencing data and the gene expression profiling interactive analysis dataset, we found that VPS9D1-AS1 expression was negatively correlated with the survival of AML patients. VPS9D1-AS1 knockdown inhibited cell proliferation, arrested cell cycle, as well as inhibited the formation of subcutaneous tumors in vivo. VPS9D1-AS1 overexpression had the reverse effect. Furthermore, VPS9D1-AS1 knockdown inhibited the MEK/ERK signaling pathway, and thus enhanced the inhibitory effect of Chidamide on AML cell proliferation. These findings suggested that targeted regulation of VPS9D1-AS1 might overcome the limitations of Chidamide in the treatment of AML.

Serum uric acid level is correlated with the clinical, pathological progression and prognosis of IgA nephropathy: an observational retrospective pilot-study.

OBJECTIVES: This study was aimed to assess the relationship between serum uric acid (SUA) level and the clinical, pathological phenotype of IgA nephropathy (IgAN), and to determine the role of SUA level in the progression and prognosis of IgAN. METHODS: A total of 208 patients with IgAN were included in this study, and were classified into the normo-uricemia group and hyperuricemia group according to the SUA level. The clinical data at baseline, IgAN Oxford classification scores (MEST-C scoring system), and other pathological features were collected and further analyzed. All patients were followed up and the prognosis was assessed using Kaplan-Meier survival curves. GraphPad Prism 7.0 and SPSS 23.0 were used for statistical analyses. RESULTS: In clinical indicators, patients with hyperuricemia had the significantly higher proportion of males to females, mean arterial pressure, the levels of total cholesterol, triglyceride, Scr, BUN, 24 hour-urine protein, C3, and C4, the lower levels of high-density lipoprotein cholesterol and eGFR than those without (p < 0.05). In terms of pathological characteristics, the tubular atrophy/interstitial fibrosis scores, vascular injury scores, and glomerular sclerosis percentage were significantly higher in patients with hyperuricemia compared with those without (p < 0.01). There was no significant difference in the scores of mesangial hypercellularity, endocapillary hypercellularity, focal segmental glomerulosclerosis, as well as crescents between the two groups (p > 0.05). As for the depositions of immune complexes deposition in IgAN, the hyperuricemia group had less deposition of immunoglobulin G and FRA than the normo-uricemia group (p < 0.05), while the deposition of immunoglobulin A, immunoglobulin M, and complement C3 in the two groups showed no statistical difference. The survival curve suggested that patients in the hyperuricemia group have significantly poorer renal outcome than those in the normo-uricemia group (p = 0.0147). Results also revealed that the SUA level is a valuable predictor of renal outcome in patients with IgAN. The optimal cutoff value was 361.1 µmol/L (AUC = 0.76 ± 0.08167) and 614 µmol/L (AUC = 0.5728 ± 0.2029) for female and male, respectively. CONCLUSIONS: The level of SUA is associated with renal function level and pathological severity of IgAN, and maybe a prognostic indicator of IgAN.

Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E.

Acute kidney injury has a high global morbidity associated with an increased risk of death and chronic kidney disease. Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of acute kidney injury to chronic kidney disease, but the underlying mechanism of abnormal renal tubular repair remains unclear. In the present study, we investigated the role of heterotrimeric G stimulatory protein α-subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (GsaKspKO) mice to show the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid nephropathy (AAN) and unilateral ischemia-reperfusion injury (UIRI). GsaKspKO mice developed more severe renal impairment after AAN and UIRI, higher serum creatinine levels, and more substantial tubular necrosis than wild-type mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing bromodeoxyuridine+ cell numbers in the AAN model and inhibiting cyclin-dependent kinase 2/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro with Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited cyclin-dependent kinase 2/cyclin E1 expression, which was dependent on the Raf-MEK-ERK signaling pathway. In conclusion, Gsa is required for tubular epithelial cell regeneration during kidney repair after AKI. Loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.

Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels.

Protein tyrosine (Tyr) nitration, the covalent addition of a nitro group (•NO2) to Tyr residues, is emerging as a candidate mechanism of endothelial dysfunction. Previous studies have shown that Tyr nitration is primarily induced by nitrosative stress, a process characterized by the production of reactive nitrogen species, especially peroxynitrite anion (ONOO-), which is considered a secondary product of NO in the presence of superoxide radicals (O2•-). However, the impact of nitrosative stress-induced Tyr nitration on endothelial dysfunction has not been thoroughly elucidated to date. We developed an endothelial dysfunction model, a process called "endothelial-to-mesenchymal transition (EndMT)," and evaluated the production of NO, O2•-, and protein nitration during EndMT. The results showed that TGF-ß1 stimulation induced EndMT and elevated endothelial NO and O2•- production as well as nitration of the catalytic subunit of protein phosphatase (PP)2A. Mass spectrometry analysis showed that Tyr265 was the nitration site in the catalytic subunit of protein phosphatase (PP)2A, and this Tyr nitration increased PP2A activity and disrupted endothelial integrity. To devise an endothelial-targeted anti-PP2Ac nitration strategy, a mimic peptide, tyrosine 265 wild type (Y265WT), conjugated with the cell-penetrating peptide HIV-1 TAT protein (TAT) was synthesized. PP2Ac nitration and PP2A activity were significantly inhibited by pretreatment with TAT-265WT, and the integrity of endothelial cells was maintained. Furthermore, injection of TAT-265WT attenuated renal nitration formation and caused anticapillary rarefaction in a unilateral urethral obstructive nephropathy model. Taken together, these results offer preclinical proof of concept for TAT-265WT as a tractable agent to protect against nitrosative stress-induced endothelial dysfunction in renal microvessels.-Deng,Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., Han, M., Xu, G. Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels.