OBJECTIVE: To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma. METHODS: We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups. RESULTS: There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI: 0.299-1.213, P=0.156; multivariate analysis: OR=0.693, 95% CI: 0.330-1.458, P=0.334), PFS (univariate analysis: HR=1.230, 95% CI: 0.789-1.916, P=0.361; multivariate analysis: HR=1.151, 95% CI: 0.732-1.810, P=9.544), or OS (univariate analysis: HR=0.552, 95% CI: 0.208-1.463, P=0.232; multivariate analysis: HR=1.085, 95% CI: 0.685-1.717, P=0.729). CONCLUSION Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use* ; Humans ; Immunotherapy/methods* ; Liver Neoplasms/drug therapy* ; Prospective Studies ; Retrospective Studies

Chemokine signal pathways are important for the regulation of tumour metastasis. Chemokine receptors CXCR4 (C-X-C chemokine receptor type 4) and XCR1 (chemokine XC receptor 1) are involved in the metastasis of breast cancer, while the interaction between them remains unclear. Here we first identified the interaction between CXCR4 and XCR1 based on membrane protein yeast two-hybrid assays. Bioluminescence resonance energy transfer (BRET) showed that XCR1 could competitively bind to CXCR4 to form a heterodimer (P < 0.01). Results of wound healing assays via transient transfection of XCR1 and CXCR4 into HEK293 cells showed that 41.55% of the migration area rate in the co-transformation group was lower than 58.75% in the CXCR4-alone group after adding 30 nmol/L S D F-β. The co-expression of XCR1 inhibited the cellular motility, possibly mediated by the SDF-1β (stromal cell-derived factor 1)/CXCR4 signal pathway (P < 0.05). Furthermore, CXCR4 on the cell surface after co-expression of XCR1 in CXCR4-EGFP transgenic HEK293 cells was detected by flow cytometry. And the result suggested that XCR1 could accelerate the internalization of CXCR4 into the heterodimer induced by 30 nmol/L SDF-1β (P<0.05), which increased the internalization rate from 14.38% to 64.10%. Finally, the phosphorylation of Akt and ERK, which were involved in cell proliferation and migration, respectively, were examined. After 10 minutes of SDF-1β stimulation, ERK phosphorylation in the CXCR4-alone group showed a 3.59-fold increase, whereas the increase of ERK phosphorylation in the co-transfected group was only 2.08-fold. Interestingly, heterodimer formation reduced the phosphorylation level of ERK and shortened the activation time, whereas the phosphorylation level of Akt remained unchanged. Collectively, our findings revealed the hetero-dimerization of CXCR4 and XCR1 and its effects on CXCR4-mediated cellular motility, receptor internalization, and ERK pathway phosphorylation. Therefore, XCR1-targeting drugs could be candidates for cross-desensitization of CXCR4 and might represent a possible option for inhibiting breast cancer metastasis.

Collagen α3 (IV) chains are one of the major constituent components of the basement membrane in the mammalian testis. Studies have shown that biologically active fragments, such as noncollagenase domain (NC1)-peptide, can be released from the C-terminal region of collagen α3 (IV) chains, possibly through the proteolytic action of metalloproteinase 9 (MMP9). NC1-peptide was shown to promote blood-testis barrier (BTB) remodeling and fully developed spermatid (e.g., sperm) release from the seminiferous epithelium because this bioactive peptide was capable of perturbing the organization of both actin- and microtubule (MT)-based cytoskeletons at the Sertoli cell-cell and also Sertoli-spermatid interface, the ultrastructure known as the basal ectoplasmic specialization (ES) and apical ES, respectively. More importantly, recent studies have shown that this NC1-peptide-induced effects on cytoskeletal organization in the testis are mediated through an activation of mammalian target of rapamycin complex 1/ribosomal protein S6/transforming retrovirus Akt1/2 protein (mTORC1/rpS6/Akt1/2) signaling cascade, involving an activation of cell division control protein 42 homolog (Cdc42) GTPase, but not Ras homolog family member A GTPase (RhoA), and the participation of end-binding protein 1 (EB1), a microtubule plus (+) end tracking protein (+TIP), downstream. Herein, we critically evaluate these findings, providing a critical discussion by which the basement membrane modulates spermatogenesis through one of its locally generated regulatory peptides in the testis.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER NCT02063100 on ClinicalTrials.gov.

Objective:To compare the clinical efficacy of transperitoneal robot assisted laparoscopic radical prostatectomy (RARP) versus extraperitoneal single port RARP.Methods:A retrospective analysis was perfoumed on 142 cases of RARP from July 2019 to June 2020 in Robotic Minimally Invasive Center of Sichuan Provincial People's Hospital, including 82 cases(Group A) , aged 70.0(65.6-78.0), undergoing transperitoneal RARP and 60 cases(Group B), aged 68.2 years old(60.1-79.2), undergoing extraperitoneal single port RARP. For group A, PSA was 12.9(5.6-64.0) ng/ml, with 26 cases of less than 10 ng/ml(31.7%), 40 cases of 10-20 ng/ml(48.8%), and 16 cases of more than 20 ng/ml(19.5%), the Gleason score was 7.2(6.0-10.0), with 14 cases(17.1%) of ≤6, 56 cases(68.3%) of 7, and 12 cases(14.6%) of ≥8, and the prostate volume was 61.3(29.0-112.0) ml. There were 49 cases with BMI≤25 kg/m 2, accounting for 59.8%, and 33 cases with BMI>25 kg/m 2, accounting for 40.2%. There were 17 cases(20.7%) of T 1, 44 cases(53.7%) of T 2 and 21 cases(25.6%) of T 3. The proportion of lymph node dissection was 17.1%, and 4 cases(4.9%)had a history of operation. For group B, the PSA was 12.2(1.0-42.6)ng/ml, with 20 cases (33.3%) of <10 ng/ml, 31 cases(51.7%)of 10-20 ng/ml, and 9 cases (15%) of >20 ng/ml. Gleason score was 7.1(6.0-9.0), with 12 cases (20.0%) of ≤6, 42 cases (70.0%) of 7, and 6 cases (10.0%)of ≥8. Prostate volume was 42.4(31.2-72.8)ml on average. There were 37 cases (61.7%) with BMI≤25 kg/m 2, and 23 cases (38.3%)with BMI >25 kg/m 2 . There were 17 cases(28.3%)of T 1, 32 cases(53.3%)of T 2 and 11 cases(18.3%)of T 3.The proportion of lymph node dissection was 11.7% and 4 cases (6.7%) had a history of operation.There was no statistically significant difference in term of age, PSA level, Gleason score, BMI, clinical stage, proportion of lymph node dissection or history of operation between the two groups( P>0.05), but there was statistically significant difference for prostate volume( P<0.05). All operations were performed by the same operator. Four different ways of bladder neck and urethral dissociation was selected according to the intraoperative conditions in Group A, include VIP style, T-shape incision style, VIP plus T-shape incision style or the style along the lateral side of the bladder neck. Small and single anterograde incision stripping of bladder neck was routinely performed in the Group B. Postoperative follow-up was performed to compare the operation time, intraoperative blood loss, bladder neck and urethral anastomosis time, postoperative hospital stay, postoperative exhaust time, postoperative complications, positive rate of surgical margin, indwelling time of urinary catheter, urinary continence satisfaction rate of immediately after operation, 3 months and 6 months after operation, wound healing and aesthetics. Results:All of the operations were successfully completed under robot-assisted laparoscopy, and there was no conversion to open surgery. The operation time was 56.0(45.0-112.0) min in the Group A and 65.4(55.5-96.8) min in the Group B, and there was no statistically significant difference( P>0.05). The intraoperative blood loss was 76.2(30.0-120.5) ml and 55.6(45.5-114.6) ml, respectively, and the difference was not statistically significant( P>0.05). The time of bladder neck urethral anastomosis was 18.9(12.6-25.6) min and 16.2(10.7-19.3) min, respectively, and the difference was not statistically significant( P>0.05). The postoperative hospital stay days were 9.3(8.0-16.0) d and 8.4(7.0-13.0) d, respectively, and the difference was not statistically significant( P>0.05). The postoperative exhaust time was 1.3(0.7-3.0) d and 3.4(2.0-7.0) d, respectively, and the difference was statistically significant( P<0.05). There was 1 case of anastomotic fistula with ureteral injury in Group A, and no serious complication in Group B, and the difference was not statistically significant( P>0.05). The number of positive surgical margin in the two groups was 13(15.9%)and 9(15.0%)respectively, and the difference was not statistically significant( P>0.05). The indwelling time of urinary catheter after operation was 9(7-21) d and 6(4-8) d, respectively, and the difference was statistically significant( P<0.05). The number of patients with satisfactory urinary continence immediately after surgery, 3 months and 6 months after surgery in the two groups were 8(9.8%), 51(62.2%), 62(75.6%) and 17(28.3%), 43(71.7%) and 54(90.0%), respectively. The differences were statistically significant( P<0.05). The total incision lengths in the two groups were 12.1(10.4-13.4) cm and 5.6(5.0-6.0) cm, respectively, and the difference was statistically significant( P<0.05). Conclusions:The extraperitoneal single port RARP is safe and feasible, and the postoperative effect is similar to that of transperitoneal RARP. It has the advantages of shorter recovery time, higher urinary continence satisfaction rate, neater and more beautiful incision. The long-term therapeutic effect needs further confirming by prospective study.

Objective:To evaluate the oncologic outcomes of different laparoscopic radical hysterectomy.Methods:From January 2011 to December 2014, the laparoscopic operation cases of cervical cancer at stage Ⅰb1, Ⅰb2, Ⅱa1 and Ⅱa2, including the histologic subtypes of squamous-cell carcinoma, adenocarcinoma and adenosquamous carcinoma, were collected in five clinical centers. The data were divided into two groups according to the surgical procedures, that is, modified laparoscopic-vaginal radical hysterectomy (mLVRH) and total laparoscopic radical hysterectomy (TLRH). The overall survival rate (OS), disease-free survival rate (DFS) at 5 years were retrospectively analyzed in this study.Results:There were 674 cases in total, including 377 cases of mLVRH, 297 cases of TLRH. (1) The OS at 5 years: the mLVRH was 96.1% and the TLRH was 92.0%, and the mLVRH was higher than that of TLRH （ P=0.010）. Stratify analysis， including stage of disease （Ⅰb1 and Ⅱa1）， histologic subtypes （squamous-cell carcinoma, adenocarcinoma）， lymph node metastasis， revealed that, ① Stage of disease: in stage Ⅰb1, the OS at five years of mLVRH was higher than that in TLRH group （98.6% vs 93.6%, P=0.012）. In stage Ⅱa1, there was significant difference between the two groups, the OS at five years of mLVRH and TLRH were 93.6% and 77.6% （ P=0.007）. ② Histologic subtypes: for the OS at five years of squamous-cell carcinoma, mLVRH and TLRH were 96.1% and 92.3%, and there was significant difference （ P=0.046）； for adenocarcinoma, the OS at five years were 91.0% and 88.6%， and there was no difference between two groups （ P=0.230）. ③ Lymph node metastasis： the mLVRH and TLRH with lymph node metastasis, the OS at five years were 98.6% and 96.4%; the mLVRH and TLRH without lymph node metastasis, the OS at five years were 89.3% and 80.8%. There were no significant differences between the two groups,respectively ( P=0.156， P=0.093）. (2) The DFS at 5 years: there was no significant difference between mLVRH and TLRH (94.1% vs 90.9%, P=0.220). Stratify analysis for stage of disease, the mLVRH group was higher than that in the TLRH group in stage Ⅰb1 (97.0% vs 92.8%, P=0.039). However, for stage Ⅱa1, there was no significant difference between mLVRH and TLRH group （88.2% vs 75.8%, P=0.074）. Conclusions:The results of this retrospective study indicated that different laparoscopy surgical procedures had diverse oncologic outcomes. The OS at 5 years of the mLVRH is superior to the TLRH. The DFS at 5 years in Ⅰb1 stage, the mLVRH is higher than the TLRH. Therefore, the modified laparoscopy is still an alternative surgery for early cervical cancer patients when following the principle of no-tumor-exposure.

OBJECTIVE: To identify the chaperone of polypyrimidine tractor-binding protein-associated splicing factor (PSF) in myeloid leukemia cells, and to explore the mechanism and redistributive pattern to cell surface of PSF in chemo-sensitive HL60 cells and resistant HL60/DOX cells. METHODS: The eukaryotic expression vector of PSF was transfected with liposomes transiently, then flow cytometry was used to detect the expression level of PSF on the cell surface 24 h, 48 h and 72 h after vector transfections. We constructed a chimeric expression vector, streptavidin binding peptide (SBP)-PSF, meanwhile this vector was transfected and made SBP-PSF fusion protein overexpress. In addition, we used streptavidin magnetic beads to precipitate the cellular chaperonin of PSF and then identified its chaperonin by mass spectrometry (MS). Lentiviral vectors containing cytokeratin18 (K18) interference sequences were transfected into 293T cells to prepare lentivirus. HL60 and HL60/DOX cells were infected with lentivirus to obtain stable interfering K18 cell lines. Next, flow cytometry was used to test the membrane relocation level of PSF. Together, these methods confirmed the similar or different mechanisms of the PSF redistributing to membrane synergistically mediated by K18 in HL60 and HL60/DOX cells. RESULTS: The expression of membrane relocated PSF was detected every day for three days (at the end of 24 h, 48 h and 72 h) after transient overexpression. The expressing rate of PSF on the cell surface was 22.4%±3.5%, 37.9%±6.0%, 58.3%±8.8%, respectively in sensitive HL60 cells, while that was 4.7%±0.5%, 3.9%±0.6%, 2.9%±0.6% , respectively in resistant HL60/DOX cells. The difference of expressing rate on each day was significant, P<0.01. We identified K18 detected by co-immunoprecipitation and mass spectrum assay which was the cellular chaperone of PSF. We found that K18 knockdown decreased the PSF expression level which redistributed on cell surface from 48.9%±5.4% to 6.2%±1.0% in sensitive HL60 cells, and from 9.11%±1.2% to 2.21%±0.51% in resistant HL60/DOX cells, respectively. CONCLUSION K18 is the intracellular chaperonin of PSF. The interaction of PSF and K18 mediates its redistribution to cell membrane in sensitive cells. While in resistant cells, PSF failed to relocate at the cell surface and accumulated in cells, which mediated resistance to chemotherapeutics.
Cell Membrane ; Doxorubicin ; Drug Resistance, Multiple ; Humans ; Keratin-18/metabolism* ; Leukemia, Myeloid

Prostate cancer (PCa) risk calculators (RCs) with prostate-specific antigen (PSA) and other risk factors can greatly improve the accurate prediction of potential risk of PCa compared to PSA. The European Randomized Study of Screening for PCa Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) are developed on the Western population. However, the Western RCs showed limited diagnostic efficacy in the Eastern Asian population, mainly due to racial differences between the two populations. We aimed to review the application of Western RCs and Eastern Asian RCs in Eastern Asian cohorts and to identify the characteristics and efficacy of these RCs.
Aged ; Early Detection of Cancer ; Asia, Eastern ; Humans ; Male ; Middle Aged ; Models, Theoretical ; Prostate-Specific Antigen/blood* ; Prostatic Neoplasms/diagnosis* ; Risk Assessment ; Risk Factors

OBJECTIVE: To investigate the effect of augmented renal clearance (ARC) on plasma concentration of vancomycin, bacteriological outcome, and clinical outcome in children with methicillin-resistant Staphylococcus aureus (MRSA) infection treated by vancomycin. METHODS: A retrospective analysis was performed for the clinical data of 60 critically ill children who were treated with vancomycin due to MRSA infection from January 2013 to July 2017 and underwent plasma concentration monitoring. According to estimated glomerular filtration rate, these children were divided into an ARC group with 19 children and a normal renal function group with 41 children. The two groups were compared in terms of the use of vancomycin, plasma concentration of vancomycin, and treatment outcome. RESULTS: The children in the ARC group had an age of 1-12 years, and the ARC group had significantly higher body weight and body surface area than the normal renal function group (P<0.05). Compared with the normal renal function group, the ARC group had a significantly lower initial trough concentration of vancomycin and a significantly lower proportion of children who achieved the effective trough concentration of vancomycin (10-20 mg/L) (P<0.05). There were no significant differences in bacteriological outcome and clinical outcome between the two groups (P>0.05), but the ARC group had significantly longer length of stay in the pediatric intensive care unit (PICU) and length of hospital stay than the normal renal function group (P<0.05). CONCLUSIONS ARC can significantly reduce the trough concentration of vancomycin and prolong the length of PICU stay and the length of hospital stay in children with MRSA infection. Idividualized medication should be administered to children with ARC.
Anti-Bacterial Agents ; Child ; Child, Preschool ; Humans ; Infant ; Methicillin ; Methicillin-Resistant Staphylococcus aureus ; Retrospective Studies ; Staphylococcal Infections ; drug therapy ; Treatment Outcome ; Vancomycin ; therapeutic use

During spermatogenesis, developing germ cells that lack the cellular ultrastructures of filopodia and lamellipodia generally found in migrating cells, such as macrophages and fibroblasts, rely on Sertoli cells to support their transport across the seminiferous epithelium. These include the transport of preleptotene spermatocytes across the blood-testis barrier (BTB), but also the transport of germ cells, in particular developing haploid spermatids, across the seminiferous epithelium, that is to and away from the tubule lumen, depending on the stages of the epithelial cycle. On the other hand, cell junctions at the Sertoli cell-cell and Sertoli-germ cell interface also undergo rapid remodeling, involving disassembly and reassembly of cell junctions, which, in turn, are supported by actin- and microtubule-based cytoskeletal remodeling. Interestingly, the underlying mechanism(s) and the involving biomolecule(s) that regulate or support cytoskeletal remodeling remain largely unknown. Herein, we used an in vitro model of primary Sertoli cell cultures that mimicked the Sertoli BTB in vivo overexpressed with the ribosomal protein S6 (rpS6, the downstream signaling protein of mammalian target of rapamycin complex 1 [mTORC1]) cloned into the mammalian expression vector pCI-neo, namely, quadruple phosphomimetic and constitutively active mutant of rpS6 (pCI-neo/p-rpS6-MT) versus pCI-neo/rpS6-WT (wild-type) and empty vector (pCI-neo/Ctrl) for studies. These findings provide compelling evidence that the mTORC1/rpS6 signal pathway exerted its effects to promote Sertoli cell BTB remodeling. This was mediated through changes in the organization of actin- and microtubule-based cytoskeletons, involving changes in the distribution and/or spatial expression of actin- and microtubule-regulatory proteins.
Actins/metabolism* ; Animals ; Blood-Testis Barrier/metabolism* ; Cells, Cultured ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism* ; Permeability ; Rats ; Ribosomal Protein S6/metabolism* ; Seminiferous Epithelium/metabolism* ; Sertoli Cells/metabolism* ; Signal Transduction/physiology*