Can surgery boost the survival benefit of chemoradiotherapy in T1b1-T2a1 stage cervical cancer with lymph node metastasis? A population-based study.

OBJECTIVE: This study aimed to determine whether surgery followed by adjuvant chemoradiotherapy has superior survival outcomes for node-positive patients with T1b1-T2a1 stage cervical cancer compared with those who undergo chemoradiation. METHODS: We investigated the Surveillance, Epidemiology, and End Results database for 12,701 patients diagnosed between 2000 and 2018. Patients were stratified according to different T stages and different treatment strategies. Surgery included radical hysterectomy (RH) or total hysterectomy (TH). Radiotherapy (RT) included adjuvant chemoradiation or chemoradiation alone. Cox analyses were performed to select the clinically important factors of survival outcomes. Survival analysis was used to compare those who received different treatment methods. RESULTS: A total of 12,701 International Federation of Gynecology and Obstetrics 2018 stage IIIC cervical cancer patients were identified. The risk of overall survival (OS) was significantly different between patients who received and did not receive chemoradiotherapy in the T categories. In the propensity-score matched dataset, early-T stage (T1b1 and T1b2) and node-positive patients in the "RH+RT" and "TH+RT" groups had better disease-specific survival (DSS) than those in the RT group. No difference in DSS was observed between the "surgery following RT" group and the RT group in locally advanced stage (T1b3 and T2a1, node positive) patients. Regarding T1b1-T2a1 node-positive patients, the RH+RT group had a similar survival outcome to that in the TH+RT group. CONCLUSION: We showed that surgery following RT benefits early-T stage (T1b1 and T1b2) cervical cancer patients with lymph node metastasis. For locally advanced stages (T1b3 and T2a1), surgery and RT had similar survival outcomes.

Comparison of the diagnostic value of [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT in patients with T stage ≤ 2a2 uterine cervical cancer: a prospective study.

PURPOSE: To compare the diagnostic value of [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT in patients with T stage ≤ 2a2 uterine cervical cancer patients. METHODS: Patients pathologically diagnosed with cervical cancer and with a T stage ≤ T2a2 were prospectively enrolled. All patients underwent whole-body [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT within 2 weeks, and surgical treatment was performed within 10 days after PET. RESULTS: Twenty-five patients were enrolled. Twenty patients underwent radical hysterectomy, among which all of them underwent pelvic lymphadenectomy, and 10 patients underwent para-aortic lymphadenectomy. Three patients received merely laparoscopic lymphadenectomy without hysterectomy. Two patients with both [18F]FDG and [68 Ga]Ga-FAPI-04 lymph node high metabolism were staged as FIGO IIIC1r, and concurrent chemoradiation therapy (CCRT) was performed. [18F]FDG and [68 Ga]Ga-FAPI-04 had equivalent detection ability on primary tumors, with a positive detection rate of 96.0%. The accuracy of T staging using [18F]FDG and [68 Ga]Ga-FAPI-04 was relatively 50% and 55.0%. Elevated and underrated staging was due to misdiagnosis of either vaginal infiltration or tumor size. In terms of lymph node metastasis detection, the specificity of [68 Ga]Ga-FAPI-04 was 100% (95% CI, 84.6% ~ 100.0%), which was significantly higher than [18F]FDG (59.1% (95% CI, 36.4% ~ 79.3%)) (p = 0.004). CONCLUSION: [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT demonstrated an equivalent detection ability on cervical cancer primary tumors. However, [68 Ga]Ga-FAPI-04 PET/MR's diagnostic value in lymph node metastasis was significantly higher than [18F]FDG PET/CT. [68 Ga]Ga-FAPI-04 PET/MR has the potential for more accurate treatment planning, thus clarifying fertility preservation indications for early-stage young patients.

[O-arm real-time guidance in cervical pedicle screw fixation].

OBJECTIVE: To explore the technical aspects of the accuracy of cervical pedicle screw placement with O-arm guidance. METHODS: The clinical data of 21 patients who underwent cervical pedicle screw fixation by O-arm real-time guidance from December 2015 to January 2020 were analyzed retrospectively. There were 15 males and 6 females, aged from 29 to 76 years old with an average of (45.3±11.5) years. The postoperative CT scan was utilized to evaluate the placement of the pedicle screw and classified according to the Gertzbein and Robbins classification. RESULTS: A total of 132 pedicle screws were implanted in 21 patients, 116 at C3-C6 and 16 at C1 and C2. According to Gertzbein & Robbins classification, the overall breach rates were found to be 11.36% (15/132) with 73.33% (11 screws) Grade B, 26.67% (4 screws) Grade C, and no Grade D or E screw breaches. There were no pedicle screw placement related complications at final follow-up. CONCLUSION: The application of O-arm real-time guidance technology can make cervical pedicle screw placement reliable. High accuracy and better intra-operative control can increase surgeon's confidence in using cervical pedicle instrumentation. Considering the high-risk nature of anatomical area around cervical pedicle and the possibility of catastrophic complications, the spine surgeon should have sufficient surgical skills, experience, ensures stringent verification of the system, and never relies solely on the navigation system.

[Causes of asymptomatic side limb pain after minimally invasive transforaminal lumbar interbody fusion].

OBJECTIVE: To investigate possible causes and preventive measures for asymptomatic pain in the limbs after minimally invasive transforaminal lumbar interbody fusion(MIS-TLIF). METHODS: Clinical data from 50 patients with lumbar degenerative disease who underwent MIS-TLIF between January 2019 and September 2020 were retrospectively analyzed. The group included 29 males and 21 females aged from 33 to 72 years old, with an average age of (65.3±7.13) years. Twenty-two patients underwent unilateral decompression, and 28 underwent bilateral decompression. The side(ipsilateral or contralateral) and site(low back, hip, or leg) of the pain were recorded before surgery, 3 days after surgery, and 3 months after surgery. The pain degree was evaluated using the visual analogue scale(VAS) at each time point. The patients were further grouped based on whether contralateral pain occurred postoperatively (8 cases in the contralateral pain group and 42 in the no contralateral pain group), and the causes and preventive measures of pain were analyzed. RESULTS: All surgeries were successful, and the patients were followed up for at least 3 months. Preoperative pain on the symptomatic side improved significantly, with the VAS score decreasing from (7.00±1.79) points preoperatively to (3.38±1.32) points at 3 days postoperatively and (3.98±1.17) points at 3 months postoperatively. Postoperative asymptomatic side pain (contralateral pain) occurred in 8 patients within 3 days after surgery, accounting for 16% (8/50) of the group. The sites of contralateral pain included the lumbar area (1 case), hip(6 cases), and leg (1 case). The contralateral pain was significantly relieved 3 months after surgery. CONCLUSION: More cases of contralateral limb pain occur after unilateral decompression MIS-TLIF, and the reason may include contralateral foramen stenosis, compression of medial branches, and other factors. To reduce this complication, the following procedures are recommended: restoring intervertebral height, inserting a transverse cage, and withdrawing screws minimally.

[Cordycepin inhibits the proliferation and migration of human gastric cancer cells by suppressing lipid metabolism via AMPK and MAPK activation].

Objective To explore the inhibitory effect of cordycepin on the proliferation and migration of gastric cancer cells and its molecular mechanism. Methods MGC-803 cells were treated with 0, 25, 50, 100 µmol/L of cordycepin and HGC-27 cells with 0, 5, 25, 50 µmol/L of cordycepin for 48 hours. The proliferation ability of MGC-803 and HGC-27 cells was detected by MTT assay and EdU assay; the colony formation ability of cells was detected by colony formation assay; both wound healing assay and cell migration assay were applied to detect the cell migration ability of MGC-803 and HGC-27 cells; the chromatin agglutination was detected by Hoechst 33342 staining; the apoptosis of gastric cancer cells was detected by annexin V-FITC/PI double labeling combined with flow cytometry; Western blot was used to measure the protein expression levels of lipid metabolism-related proteins including sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), and acetyl coA carboxylase 1 (ACC1), epithelial-mesenchymal transition (EMT)-related proteins including E-cadherin, vimentin, Snail, Slug, matrix metalloproteinase 2 (MMP2), MMP9, AMPK, and phosphorylated AMPK (p-AMPK), MAPK signaling pathway-related proteins including JNK, phosphorylated JNK (p-JNK), p38 MAPK, and p-p38 MAPK, and apoptosis-related proteins including cleaved caspase-9 (c-caspase-9), c-caspase-3, and cleaved poly (ADP-ribose) polymerase (c-PARP). Results Cordycepin significantly inhibited the proliferation, colony formation, and migration of gastric cancer cells. After cordycepin treatment, the karyopycnosis, karyorrhexis, and apoptosis rate of cancer cells increased, and the expressions of apoptosis-related proteins c-caspase-3, c-caspase-9, and c-PARP increased. The expression of E-cadherin increased, while the expressions of vimentin, Snail, Slug, SREBF1, FASN, ACC1, MMP2, MMP9 significantly decreased; the phosphorylation levels of AMPK, JNK and P38 proteins significantly increased. Conclusion Cordycepin inhibits the proliferation and migration of gastric cancer cells by suppressing the lipid metabolism and EMT process via activating AMPK and MAPK signaling pathway.

Potential Values of Circulating microRNA-21 to Predict Early Recurrence in Patients with Colorectal Cancer after Treatments.

Insufficient prognosis of local recurrence contributes to the poor progression-free survival rate and death in colorectal cancer (CRC) patients. Various biomarkers have been explored in predicting CRC recurrence. This study investigated the expressions of plasma/exosomal microRNA-21 (miR-21) in 113 CRC patients by qPCR, their values of predicting CRC recurrence, and the possibility to improve the prognostic efficacy in early CRC recurrence in stratified patients by combined biomarkers including circulating miR-21s, circulating tumour cells/microemboli (CTCs/CTM), and serum carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA19-9). Expressions of plasma and exosomal miR-21s were significantly correlated (p < 0.0001) in all and late-stage patients, presenting similar correlations with other biomarkers. However, stage IV patients stratified by a high level of exosomal miR-21 and stage I to III patients stratified by a high level of plasma miR-21 displayed significantly worse survival outcomes in predicting CRC recurrence, suggesting their different values to predict CRC recurrence in stratified patients. Comparable and even better performances in predicting CRC recurrence in late-stage patients were found by CTCs/CTM from our blood samples as sensitive biomarkers. Improved prognosing efficacy in CRC recurrence and better outcomes to significantly differentiate recurrence in stratified patients could be obtained by analysing combined biomarkers.

Risk Stratifying and Prognostic Analysis of Subclinical Cardiac Implantable Electronic Devices Infection: Insight From Traditional Bacterial Culture.

Background Subclinical infection of cardiac implantable electronic devices (CIEDs) is a common condition and increases the risk of clinical infection. However, there are limited studies focused on risk stratifying and prognostic analysis of subclinical CIED infection. Methods and Results Data from 418 consecutive patients undergoing CIED replacement or upgrade between January 2011 and December 2019 were used in the analysis. Among the patients included, 50 (12.0%) were detected as positive by bacterial culture of pocket tissues. The most frequently isolated bacteria were coagulase-negative staphylococci (76.9%). Compared with the noninfection group, more patients in the subclinical infection group were taking immunosuppressive agents, received electrode replacement, or received CIED upgrade and temporary pacing. Patients in the subclinical infection group had a higher PADIT (Prevention of Arrhythmia Device Infection Trial) score. Univariable and multivariable logistic regression analysis found that use of immunosuppressive agents (odds ratio [OR], 6.95 [95% CI, 1.44-33.51]; P=0.02) and electrode replacement or CIED upgrade (OR, 6.73 [95% CI, 2.23-20.38]; P=0.001) were significantly associated with subclinical CIED infection. Meanwhile, compared with the low-risk group, patients in the intermediate/high-risk group had a higher risk of subclinical CIED infection (OR, 3.43 [95% CI, 1.58-7.41]; P=0.002). After a median follow-up time of 36.5 months, the end points between the subclinical infection group and noninfection group were as follows: composite events (58.0% versus 41.8%, P=0.03), rehospitalization (54.0% versus 32.1%, P=0.002), cardiovascular rehospitalization (32.0% versus 13.9%, P=0.001), CIED infection (2.0% versus 0.5%, P=0.32), all-cause mortality (28.0% versus 21.5%, P=0.30), and cardiovascular mortality (10.0% versus 7.6%, P=0.57). Conclusions Subclinical CIED infection was a common phenomenon. The PADIT score had significant value for stratifying patients at high risk of subclinical CIED infection. Subclinical CIED infection was associated with increased risks of composite events, rehospitalization, and cardiovascular rehospitalization.

Layers of interstitial fluid flow along a "slit-shaped" vascular adventitia.

Interstitial fluid (ISF) flow through vascular adventitia has been discovered recently. However, its kinetic pattern was unclear. We used histological and topographical identification to observe ISF flow along venous vessels in rabbits. By magnetic resonance imaging (MRI) in live subjects, the inherent pathways of ISF flow from the ankle dermis through the legs, abdomen, and thorax were enhanced by paramagnetic contrast. By fluorescence stereomicroscopy and layer-by-layer dissection after the rabbits were sacrificed, the perivascular and adventitial connective tissues (PACTs) along the saphenous veins and inferior vena cava were found to be stained by sodium fluorescein from the ankle dermis, which coincided with the findings by MRI. The direction of ISF transport in a venous PACT pathway was the same as that of venous blood flow. By confocal microscopy and histological analysis, the stained PACT pathways were verified to be the fibrous connective tissues, consisting of longitudinally assembled fibers. Real-time observations by fluorescence stereomicroscopy revealed at least two types of spaces for ISF flow: one along adventitial fibers and another one between the vascular adventitia and its covering fascia. Using nanoparticles and surfactants, a PACT pathway was found to be accessible by a nanoparticle of <100 nm and contained two parts: a transport channel and an absorptive part. The calculated velocity of continuous ISF flow along fibers of the PACT pathway was 3.6‒15.6 mm/s. These data revealed that a PACT pathway was a "slit-shaped" porous biomaterial, comprising a longitudinal transport channel and an absorptive part for imbibition. The use of surfactants suggested that interfacial tension might play an essential role in layers of continuous ISF flow along vascular vessels. A hypothetical "gel pump" is proposed based on interfacial tension and interactions to regulate ISF flow. These experimental findings may inspire future studies to explore the physiological and pathophysiological functions of vascular ISF or interfacial fluid flow among interstitial connective tissues throughout the body.

Highly Correlated Recurrence Prognosis in Patients with Metastatic Colorectal Cancer by Synergistic Consideration of Circulating Tumor Cells/Microemboli and Tumor Markers CEA/CA19-9.

Circulation tumor cells (CTCs) play an important role in metastasis and highly correlate with cancer progression; thus, CTCs could be considered as a powerful diagnosis tool. Our previous studies showed that the number of CTCs could be utilized for recurrence prediction in colorectal cancer (CRC); however, the odds ratio was still lower than five. To improve prognosis in CRC patients, we analyzed CTC clusters/microemboli, CTC numbers, and carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA19-9) levels using a self-assembled cell array (SACA) chip system for recurrence prediction. In CRC patients, the presence of CTC clusters/microemboli may have higher correlation in metastasis when compared to the high number of CTCs. Additionally, when both the number of CTCs and serum CEA levels are high, very high odds ratios of 24.4 and 17.1 are observed in patients at all stages and stage III of CRC, respectively. The high number of CTCs and CTC clusters/microemboli simultaneously suggests the high chance of relapse (odds ratio 8.4). Overall, the characteristic of CTC clusters/microemboli, CEA level, and CTC number have a clinical potential to enhance CRC prognosis.

A Novel Application of Non-Negative Matrix Factorization to the Prediction of the Health Status of Undocumented Immigrants.

Introduction: Undocumented immigrants (UIs) in the United States are less likely to be able to afford health insurance. As a result, UIs often lack family doctors and are rarely involved in annual screening programs, which makes estimating their health status remarkably challenging. This is especially true if the laboratory results from limited screening programs fail to provide sufficient clinical information. Methods: To address this issue, we have developed a machine learning model based on the non-negative matrix factorization technique. The data set we used for model training and testing was obtained from the 2004 cost-free hepatitis B screening program at the Omni Health Center located in Plano, Texas. Total 300 people were involved, with 199 identified as UIs. Results: People in the UIs group have higher cholesterol (219.6 mg/dL, p=0.038) and triglycerides (173.2 mg/dL, p=0.03) level. They also have a lower hepatitis B vaccination rate (38%, p=0.0247). No significant difference in hepatitis B(+) was found (p=0.8823). Using 16 individual clinical measurements as training features, our newly developed model has a 67.56% accuracy in predicting the ratio of cholesterol to high-density lipoprotein; in addition, this newly developed model performs 9.1% better than a comparable multiclass logistic regression model. Conclusions: Elderly UIs have poorer health status compared with permanent residents and citizens in the United States. Our newly developed machine learning model demonstrates a powerful support tool for designing health intervention programs that target UIs in the United States.

In silico prediction of the mutagenicity of nitroaromatic compounds using a novel two-QSAR approach.

Certain drugs are nitroaromatic compounds, which are potentially toxic. As such, it is of practical importance to assess and predict their mutagenic potency in the process of drug discovery. A classical quantitative structure-activity relationship (QSAR) model was developed using the linear partial least square (PLS) scheme to understand the underline mutagenic mechanism and a non-classical QSAR model was derived using the machine learning-based hierarchical support vector regression (HSVR) to predict the mutagenicity of nitroaromatic compounds based on a series of mutagenicity data (TA98-S9). It was observed that HSVR performed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical validations. A mock test designated to mimic real challenges also confirmed the better performance of HSVR. Furthermore, HSVR exhibited superiority in predictivity, generalization capabilities, consistent performance, and robustness when compared with various published predictive models. PLS, conversely, revealed some mechanistically interpretable relationships between descriptors and mutagenicity. Thus, this two-QSAR approach using the predictive HSVR and interpretable PLS models in a synergistic fashion can be adopted to facilitate drug discovery and development by designing safer drug candidates with nitroaromatic moiety.

Effects of Leptospira interrogans infection on the activation of NLRP3 in THP-1 and J774A. 1 cells / 中华微生物学和免疫学杂志

Objective To analyze the effects of Leptospira interrogans ( L. interrogans) infection on the activation of NLRP3 in THP-1 and J774A. 1 cells and to further understand the mechanism of inflam-mation caused by L. interrogans in different hosts. Methods Human mononuclear macrophage cell line (THP-1) and murine mononuclear macrophage cell line (J774A. 1) were infected with L. interrogans strain 56601. The expression of NLRP3 at mRNA and protein levels were measured by using real-time RT-PCR and flow cytometry analysis, respectively. The NLRP3-mediated secretion of IL-1β, IL-18 and IL-33 was detec-ted by ELISA combined with the NLRP3 inhibitory test. Results Compared with the normal cells, the ex-pression of NLRP3 at mRNA level in L. interrogans-infected THP-1 cells was respectively increased by 4. 05, 0. 34, 0. 33, 0. 06 and 1. 66 times at the time points of 1 h, 2 h, 4 h, 12 h and 24 h after infection ( P0. 05). Results of the inhibitory test showed that the up-regulation of IL-1β , IL-18 and IL-33 in THP-1 and J774A. 1 cells were effectively inhibited by the specific inhibitor of NLRP3. Conclusion NL-RP3 inflammasome was activated and involved in the production of specific inflammatory cytokines IL-1βand IL-18 in both THP-1 and J774A. 1 cells after L. interrogans infection, but the inflammatory cytokines induced by L. interrogans infection varied in different cells. L. interrogans induced earlier and higher level of IL-1βand IL-18 production in human macrophages than in murine macrophages.

Expression of iNOS and levels of NO in THP-1 and J774A. 1 cells during Leptospira interrogans infec-tion / 中华微生物学和免疫学杂志

Objective To investigate the expression of inducible nitric oxide synthase ( iNOS) and the levels of nitric oxide (NO) in THP-1 and J774A. 1 cells during Leptospira interrogans (L. interrogans) infection for a better understanding of the mechanism of macrophages involved defense against L. interrogans strains in different hosts. Methods The human mononuclear macrophages (THP-1) and the murine mono-nuclear macrophages (J774A. 1) were infected with L. interrogans strain 56601. The expression of iNOS at mRNA and protein levels were determined by using real-time RT-PCR and flow cytometry analysis. The lev-els of NO were detected with Griess test. Results The expression of iNOS at mRNA level in J774A. 1 and THP-1 cells infected with L. interrogans strains for 2, 4, 12 and 24 hours were respectively 1. 37, 2. 82, 25. 76, 27. 47 times and 1. 59, 3. 98, 3. 89, 8. 81 times than that of cells without infection (P<0. 05). The expression rates of iNOS protein in J774A. 1 cells were increased from 34. 16% to 85. 85%, 93. 82%, 91. 77% and 93. 65% along with the increased time of infection time (P<0. 05). The expression rates of iNOS protein in THP-1 cells were up-regulated from 22. 08% to 72. 64%, 81. 33%, 80. 03% and 65. 72%after 2, 4, 12 and 24 hours of infection (P<0. 05), respectively. Results of the Griess test indicated that the levels of NO in J774A. 1 and THP-1 cells were respectively increased from 0. 1588 μmol/L to 0. 2208μmol/L, 0. 2668μmol/L, 0. 3808μmol/L, 0. 3828μmol/L and from 0. 0988μmol/L to 0. 2848μmol/L,0. 3228 μmol/L, 0. 2608μmol/L and 0. 3308μmol/L after infection with L. interrogans strains for 2, 4, 12 and 24 hours (P<0. 05). Conclusion The expression of iNOS and the levels of NO in J774A. 1 and THP-1 cells were significantly increased during L. interrogans infection. This study might help to explain the bactericidal mechanism of macrophages derived from different hosts against L. interrogans infection.