Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells.

BACKGROUND: Immune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting. METHODS: We utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release. RESULTS: In ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models. CONCLUSIONS: APG-1387 has the potential to turn "cold tumors" into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).

Complete Shrinking of Mixed Growth Hormone and Prolactin-Secreting Pituitary Adenoma With Bromocriptine Therapy Alone.

A 40-year-old man presented with acromegaly, reduction of visual acuity and visual field, and elevated blood sugar. Imaging examinations demonstrated a large sellar adenoma with suprasellar extension that compresses the optic chiasma upward, spreads downward to the sphenoid sinus, and invades the cavernous sinus bilaterally. Random prolactin and growth hormone were beyond the scope of normal. The patient achieved complete shrinking of the adenoma by taking bromocriptine orally. For some kinds of giant mixed growth hormone-prolactin adenomas, surgical treatment is not necessary, and drug treatment can also achieve good results.

A novel prognosis-prediction model based on coagulation indicators in secondary hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In the present retrospective study, we aimed to investigate coagulation disorders and their outcome implications in patients with secondary HLH. We evaluated clinical characteristics and the relationship between coagulation indices and prognosis in HLH patients (n = 141). The information, including clinical symptoms, laboratory indicators, and coagulation indices, was evaluated. Coagulation disorders and bleeding events occurred in 95 (67.4%) and 60 (42.6%) patients, respectively. A coagulation index analysis primarily showed elevated levels of D-Dimer, the international standardized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), while the prothrombin activity, fibrinogen levels, and platelet levels were significantly decreased. Dominant disseminated intravascular coagulation (DIC) occurred in 76 patients (53.9%). Patients with lymphoma-associated hemophagocytic syndrome (LAHS) frequently exhibited apparent coagulation disorders. Multivariate analysis revealed that age ≥ 29.5 years, bleeding events, APTT ≥ 47.3 s, fibrinogen ≤ 1.68 g/L, and absolute neutrophil counts (ANC) of ≤ 1.21 × 109/L were independent prognostic factors. We thereby devised a prognostic scoring system and stratified patients into low-risk (0-2 points), intermediate-risk (3-4 points), and high-risk (5-7 points) groups, and the 1-year overall survival rates in the above-mentioned groups were 66.40%, 40.00%, and 2.30%, respectively (P < 0.0001). In conclusion, coagulation dysfunctions and bleeding tendencies were common characteristics in HLH patients. We constructed a novel prognostic score model based on APTT, fibrinogen level, ANC, age, and bleeding events, which had superior prognostic value compared with these markers alone.

Two-dimensional InTeClO3: an ultrawide-bandgap material with potential application in a deep ultraviolet photodetector.

Ultrawide-bandgap semiconductors, possessing bandgaps distinctly larger than the 3.4 eV of GaN, have emerged as a promising class capable of achieving deep ultraviolet (UV) light detection. Based on first-principles calculations, we propose an unexplored two-dimensional (2D) InTeClO3 layered system with ultrawide bandgaps ranging from 4.34 eV of bulk to 4.54 eV of monolayer. Our calculations demonstrate that 2D InTeClO3 monolayer can be exfoliated from its bulk counterpart and maintain good thermal and dynamic stability at room temperature. The ultrawide bandgaps may be modulated by the small in-plane strains and layer thickness in a certain range. Furthermore, the 2D InTeClO3 monolayer shows promising electron transport behavior and strong optical absorption capacity in the deep UV range. A two-probe InTeClO3-based photodetection device has been constructed for evaluating the photocurrent. Remarkably, the effective photocurrent (5.7 A m-2 at photon energy of 4.2 eV) generation under polarized light has been observed in such a photodetector. Our results indicate that 2D InTeClO3 systems have strong photoresponse capacity in the deep UV region, accompanying the remarkable polarization sensitivity and high extinction ratio. These distinctive characteristics highlight the promising application prospects of InTeClO3 materials in the field of deep UV optoelectronics.

The comparative analysis of laparoscopic or transvaginal cerclage in pregnancies with cervical insufficiency: a retrospective cohort study.

OBJECTIVE: To evaluate the efficacy and safety of prophylactic cervical cerclage by laparoscopy in pregnant women versus transvaginal way. DESIGN: Retrospective, monocentric cohort study was performed. SETTING: The First Affiliated Hospital of Sun Yat-sen University. PATIENTS: Cases with cervical insufficiency (defined by previous history of painless second or early third trimester pregnancy loss/losses) were selected. INTERVENTIONS: Laparoscopic or transvaginal cerclage were conducted. The maternal information and the neonatal data were collected and compared. The pregnancy outcomes including the incidence of full-term labor and gestational weeks at delivery were defined as the primary outcomes. Neonatal survival and birth weight, neonatal complications were evaluated as the secondary outcomes. MEASUREMENTS AND MAIN RESULTS: Totally 36 twin pregnant cases and 82 singleton pregnant cases were managed with cerclage, either trans-laparoscopy (totally 78 cases) or transvaginal (totally 40 cases). Demographic characteristics showed no significant differences. Cases in laparoscopic group had a prolonged gestational age at delivery (36.43 ± 0.93 weeks and 33.60 ± 2.78 weeks, respectively, P < 0.001), a higher incidence of full-term labor (60.26% vs 42.50%, P = 0.05) with no significant difference of perinatal mortality (P = 0.661). Meanwhile, higher incidence of normal birth weight infants (88.46% vs 67.50%, P = 0.007) was shown in laparoscopic group with no more complications such as the cases of neonatal with Apgar < 7 (P = 0.296), and the incidence of NICU admission (P = 0.237). Besides, LTC showed good efficiency on VTC in the incidence of full-term labor: HR 0.24 (95% CI 0.070-0.85), P < 0.001. While LSC showed the similar efficiency on VSC: HR 0.734 (95% CI 0.36-1.49), P = 0.857, showing that cases with twin pregnancy may benefit more from laparoscopic cerclage. CONCLUSIONS: The comparative effect between laparoscopic and transvaginal cerclage in pregnant women showed that laparoscopic cerclage may be a relatively effective and safety prophylactic way for cervical insufficiency. This would be an acceptable and safe replace for traditional transvaginal cervical cerclage.

DNA-Binding One Finger Transcription Factor PhDof28 Regulates Petal Size in Petunia.

Petal size is a key indicator of the ornamental value of plants, such as Petunia hybrida L., which is a popular ornamental species worldwide. Our previous study identified a flower-specific expression pattern of a DNA-binding one finger (Dof)-type transcription factor (TF) PhDof28, in the semi-flowering and full-flowering stages of petunia. In this study, subcellular localization and activation assays showed that PhDof28 was localized in the cell nucleus and could undergo in vitro self-activation. The expression levels of PhDof28 tended to be significantly up-regulated at the top parts of petals during petunia flower opening. Transgenic petunia 'W115' and tobacco plants overexpressing PhDof28 showed similar larger petal phenotypes. The cell sizes at the middle and top parts of transgenic petunia petals were significantly increased, along with higher levels of endogenous indole-3-acetic acid (IAA) hormone. Interestingly, the expression levels of two TFs, PhNAC100 and PhBPEp, which were reported as negative regulators for flower development, were dramatically increased, while the accumulation of jasmonic acid (JA), which induces PhBPEp expression, was also significantly enhanced in the transgenic petals. These results indicated that PhDof28 overexpression could increase petal size by enhancing the synthesis of endogenous IAA in petunias. Moreover, a JA-related feedback regulation mechanism was potentially activated to prevent overgrowth of petals in transgenic plants. This study will not only enhance our knowledge of the Dof TF family, but also provide crucial genetic resources for future improvements of plant ornamental traits.

Farnesoid X receptor functions in cervical cancer via the p14ARF-mouse double minute 2-p53 pathway.

BACKGROUND: Cervical cancer is the second most common cancer among women living in developing countries. Farnesoid X receptor (FXR) is a member of the nuclear receptor family, which regulates the development and proliferation of cancer. However, the role of and molecular mechanism by which FXR acts in cervical cancer are still unknown. METHODS AND RESULTS: The relationship between FXR and the proliferation of cervical cancer cell lines was detected by MTT and colony formation assays. Immunohistochemistry was used to detect the expression of FXR in cervical cancer tissue slides. Western blotting was used to detect the expression of p14ARF, mouse double minute 2 (MDM2) and p53 when FXR was overexpressed or siRNA was applied. Western blotting was used to detect the expression of MDM2 and p53 when pifithrin-α (PFT-α) was applied. FXR activation inhibited the proliferation of cervical cancer cell lines. FXR was significantly decreased in cervical squamous cell carcinoma, which was correlated with TNM stage, but not with metastasis. Overexpression of FXR activated the p14ARF-MDM2-p53 pathway. As a p53 inhibitor, PFT-α increased MDM2 in Lenti-vector cells, but had no effect on MDM2 in Lenti-FXR cells. CONCLUSIONS: FXR inhibits cervical cancer by upregulating the p14ARF-MDM2-p53 pathway. Activation of FXR may be a potential strategy for the treatment of cervical cancer.

High electron mobility and wide-bandgap properties in a novel 1D PdGeS3 nanochain.

As a versatile platform, one-dimensional (1D) electronic systems host plenty of excellent merits, such as high length-to-diameter ratios, flexible mechanical properties, and manageable electronic characteristics, which endow them with significant potential applications in catalysts, flexible wearable devices, and multifunctional integrated circuits. Herein, based on first-principles calculations, we propose a versatile 1D PdGeS3 nanochain system. Our calculations show that the 1D PdGeS3 nanochain can be synthesized simply from its bulk crystal by exfoliation methods and can stably exist at room temperature. The 1D PdGeS3 nanochain is an indirect semiconductor with a wide bandgap of 2.86 eV, and such a bandgap can be effectively modulated by strain. Remarkably, the electron mobility of the 1D PdGeS3 nanochain reaches as high as 1506 cm2 V-1 s-1, which is one to two orders of magnitude larger than those of most reported 1D materials and even some 2D materials. Such high electron mobility accompanied with low hole mobility endow the 1D PdGeS3 nanochain with the capacity of the separation of carriers. Our work shows that the 1D PdGeS3 nanochain is a promising candidate for applications in novel multifunctional nanoelectronic devices.

Insights into the Cytochrome P450 Monooxygenase Superfamily in Osmanthus fragrans and the Role of OfCYP142 in Linalool Synthesis.

Osmanthus fragrans flowers have long been used as raw materials in food, tea, beverage, and perfume industries due to their attractive and strong fragrance. The P450 superfamily proteins have been reported to widely participate in the synthesis of plant floral volatile organic compounds (VOCs). To investigate the potential functions of P450 superfamily proteins in the fragrance synthesis of O. fragrans, we investigated the P450 superfamily genome wide. A total of 276 P450 genes were identified belonging to 40 families. The RNA-seq data suggested that many OfCYP genes were preferentially expressed in the flower or other organs, and some were also induced by multiple abiotic stresses. The expression patterns of seven flower-preferentially expressed OfCYPs during the five different flower aroma content stages were further explored using quantitative real-time PCR, showing that the CYP94C subfamily member OfCYP142 had the highest positive correlation with linalool synthesis gene OfTPS2. The transient expression of OfCYP142 in O. fragrans petals suggested that OfCYP142 can increase the content of linalool, an important VOC of the O. fragrans floral aroma, and a similar result was also obtained in flowers of OfCYP142 transgenic tobacco. Combined with RNA-seq data of the transiently transformed O. fragrans petals, we found that the biosynthesis pathway of secondary metabolites was significantly enriched, and many 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway genes were also upregulated. This evidence indicated that the OfCYP proteins may play critical roles in the flower development and abiotic response of O. fragrans, and that OfCYP142 can participate in linalool synthesis. This study provides valuable information about the functions of P450 genes and a valuable guide for studying further functions of OfCYPs in promoting fragrance biosynthesis of ornamental plants.

Robust Estimation of Contact Force and Location for Magnetic-Field-Based Soft Tactile Sensor Considering Magnetic Source Inconsistency.

Flexible magnetic-field-based tactile sensors (FMFTS) have numerous advantages including low cost, ease of manufacture, simple wiring, high sensitivity, and so on. Flexible magnetic-field-based tactile sensors need to be calibrated before use to build accurate mapping between contact force and magnetic field intensity measured by magnetic sensors; however, when considering remanence inconsistency of magnetic source, each FMFTS needs to be calibrated independently to enhance accuracy, and the complex preparation prevents FMFTS from being used conveniently. A robust estimation method of contact force and location that can tolerate remanence inconsistency of magnetic source in FMFTS is proposed. Firstly, the position and orientation of magnetic source were tracked using the Levenberg-Marquart algorithm, and the tracking results were insensitive to the remanence of magnetic source with appropriate cost function. Secondly, the mapping between magnitude and location of contact force and position and orientation of magnetic source was built with calibration of one sensor; the mapping only depends on the structural response of flexible substrate, and thus can be extended to estimate external force and location for other sensors with the same structure. The proposed method was evaluated in both simulations and experiments, and the results confirm that the estimation of magnitude and location of external force for FMFTS with the same structure and different remanence could reach acceptable accuracy, depending on single calibration. The proposed method can be used to simplify the calibration procedure and remove the barrier for large-scale application of FMFTS and replacement of damaged FMFTS.

A Cascade Graph Convolutional Network for Predicting Protein-Ligand Binding Affinity.

Accurate prediction of binding affinity between protein and ligand is a very important step in the field of drug discovery. Although there are many methods based on different assumptions and rules do exist, prediction performance of protein-ligand binding affinity is not satisfactory so far. This paper proposes a new cascade graph-based convolutional neural network architecture by dealing with non-Euclidean irregular data. We represent the molecule as a graph, and use a simple linear transformation to deal with the sparsity problem of the one-hot encoding of original data. The first stage adopts ARMA graph convolutional neural network to learn the characteristics of atomic space in the protein-ligand complex. In the second stage, one variant of the MPNN graph convolutional neural network is introduced with chemical bond information and interactive atomic features. Finally, the architecture passes through the global add pool and the fully connected layer, and outputs a constant value as the predicted binding affinity. Experiments on the PDBbind v2016 data set showed that our method is better than most of the current methods. Our method is also comparable to the state-of-the-art method on the data set, and is more intuitive and simple.

Feminine Hygiene Products-A Neglected Source of Phthalate Exposure in Women.

Phthalates have been associated with reproductive toxicity and precocious puberty in females, but the occurrence of these toxicants in feminine hygiene products is rarely reported. In this study, eight phthalates were determined in 120 feminine hygiene products (56 feminine care products and 64 sanitary napkins) collected from China. Phthalates were found in 86% and 98% of feminine care products and sanitary napkins, respectively, with the total concentrations varying between not detectable and 813 µg/g (median: 0.26 µg/g) and 0.25 and 8.76 µg/g (1.43 µg/g), respectively. Diethyl phthalate, dibutyl phthalate, and bis(2-ethylhexyl)phthalate were the major compounds, accounting for >60% of the total concentrations. The plastic materials used on the top and bottom layers and the hot melt adhesive used during the manufacturing process are the potential sources of phthalates in sanitary napkins. The range of daily exposure doses of phthalates in women from the use of feminine care products and sanitary napkins was <0.001-0.156 µg/kg-bw/day and <0.001-0.731 µg/kg-bw/day, respectively. Sanitary napkins contributed to 8.2% of the total exposure, and the levels of exposure to several phthalates from sanitary napkins were much higher than those reported from indoor dust ingestion but were lower than those of dietary intakes. Our study confirmed a new source of women's exposure to phthalates, sanitary napkins.

Shock Index on Admission Is Associated with Coronary Slow/No Reflow in Patients with Acute Myocardial Infarction Undergoing Emergent Percutaneous Coronary Intervention.

OBJECTIVE: Coronary slow/no reflow is not rare after successfully undergoing primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI), and shock index (SI) is an important factor for adverse cardiovascular prognosis. In this study, we are to explore whether SI is associated with coronary slow/no reflow in patients with AMI following primary PCI. METHODS: A total of 153 consecutive AMI patients undergoing primary PCI within 24 hours of symptom onset were included in this study. The participants were divided into normal flow group (n=124) and slow/no reflow group (n=29) according to cineangiograms recorded during the period of PCI. Cardiovascular risk factors, hematologic parameters, preoperative management of antithrombotic therapy, and baseline angiography were collected. RESULTS: SI, plasma glucose, white blood cells (WBC) and neutrophil count, neutrophil to lymphocyte ratio (PLR), high sensitivity C-reactive protein (hs-CRP), probrain natriuretic peptide (pro-BNP), and Killip classification on admission and thrombus burden on initial angiography were significantly different between patients with and without slow/no reflow. Multivariate analysis revealed that SI≥0.66, thrombus burden, and plasma glucose on admission were independent predictors for coronary slow/no reflow. Preoperative management of tirofiban therapy improves initial thrombolysis in myocardial infarction (TIMI). However, it has no effect on prognosis of slow/no reflow. CONCLUSION: Our findings demonstrated that slow/no reflow in patients with AMI following primary PCI was more likely associated with SI≥0.66, thrombus burden, and plasma glucose on admission. SI as a predictor for coronary slow/no reflow should be further confirmed in the following more large-scale and prospective studies. The clinical registration number is ChiCTR1900024447.

Integrated Giant Magnetoresistance Technology for Approachable Weak Biomagnetic Signal Detections.

With the extensive applications of biomagnetic signals derived from active biological tissue in both clinical diagnoses and human-computer-interaction, there is an increasing need for approachable weak biomagnetic sensing technology. The inherent merits of giant magnetoresistance (GMR) and its high integration with multiple technologies makes it possible to detect weak biomagnetic signals with micron-sized, non-cooled and low-cost sensors, considering that the magnetic field intensity attenuates rapidly with distance. This paper focuses on the state-of-art in integrated GMR technology for approachable biomagnetic sensing from the perspective of discipline fusion between them. The progress in integrated GMR to overcome the challenges in weak biomagnetic signal detection towards high resolution portable applications is addressed. The various strategies for 1/f noise reduction and sensitivity enhancement in integrated GMR technology for sub-pT biomagnetic signal recording are discussed. In this paper, we review the developments of integrated GMR technology for in vivo/vitro biomagnetic source imaging and demonstrate how integrated GMR can be utilized for biomagnetic field detection. Since the field sensitivity of integrated GMR technology is being pushed to fT/Hz0.5 with the focused efforts, it is believed that the potential of integrated GMR technology will make it preferred choice in weak biomagnetic signal detection in the future.

MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling.

Several studies have revealed that MFG-E8 (milk fat globule-epidermal growth factor 8) is related to tumour development and progression. However, the relationship between MFG-E8 expression and metastasis in colorectal cancer patients and the role of MFG-E8 in colorectal cancer invasion and progression remain unknown. In this study, we performed immunohistochemistry and quantitative real-time polymerase chain reaction to assess MFG-E8 expression in colorectal cancer and adjacent non-cancerous tissues. Colorectal cancer RNAseq data from The Cancer Genome Atlas project were downloaded and MFG-E8 expression was analysed. Gene set enrichment analysis was performed for gene ontology and pathway analysis associated with MFG-E8 expression. For in vitro studies, we used lentivirus-mediated MFG-E8 RNA interference and commercialized recombinant human MFG-E8 to investigate its role in colorectal cancer cell growth, migration and invasion. It seems that MFG-E8 was overexpressed in advanced colorectal cancer tissues compared with early-stage colorectal cancer tissues and adjacent non-cancerous tissues. Correlation analysis revealed that MFG-E8 expression was significantly related to plasma membrane invasion, lymph node metastasis, distant metastasis and tumour-node-metastasis stage. Survival analysis revealed that high MFG-E8 expression predicted a poorer prognosis than low MFG-E8 expression group both in our colorectal cancer cohort and The Cancer Genome Atlas colorectal cancer cohort. In vitro study suggested that MFG-E8 knockdown can suppress the growth of colorectal cancer cells without affecting the expression of the proliferation-related gene Ki67. MFG-E8 knockdown also suppressed colorectal cancer cell migration and invasion, a change accompanied by MMP-2 and MMP-9 downregulation. Moreover, MFG-E8 knockdown induced a shift from mesenchymal makers to epithelial makers, while pretreatment with rhMFG-E8 had the opposite effect. The effect of MFG-E8 on colorectal cancer cell migration, invasion and epithelial-to-mesenchymal was partially dependent on the PI3K/AKT signalling pathway. These findings provide a better understanding of the molecular mechanism underlying colorectal cancer progression and suggest a predictive role for MFG-E8 in colorectal cancer metastasis and prognosis.

Dispersive admicelle solid-phase extraction based on sodium dodecyl sulfate coated Fe3 O4 nanoparticles for the selective adsorption of three alkaloids in Gegen-Qinlian oral liquid before high-performance liquid chromatography.

A novel dispersive admicelle solid-phase extraction method based on sodium dodecyl sulfate-coated Fe3 O4 nanoparticles was developed for the selective adsorption of berberine, coptisine, and palmatine in Gegen-Qinlian oral liquid before high-performance liquid chromatography. Fe3 O4 nanoparticles were synthesized by a chemical coprecipitation method and characterized by using transmission electron microscopy. Under acidic conditions, the surface of Fe3 O4 nanoparticles was coated with sodium dodecyl sulfate to form a nano-sized admicelle magnetic sorbent. Owing to electrostatic interaction, the alkaloids were adsorbed onto the oppositely charged admicelle magnetic nanoparticles. The quick separation of the analyte-adsorbed nanoparticles from the sample solution was performed by using Nd-Fe-B magnet. Best extraction efficiency was achieved under the following conditions: 800 µL Fe3 O4 nanoparticles suspension (20 mg/mL), 150 µL sodium dodecyl sulfate solution (10 mg/mL), pH 2, and vortexing time 2 min for the extraction of alkaloids from 10 mL of diluted sample. Four hundred microliters of methanol was used to desorb the alkaloids by vortexing for 1 min. Satisfactory extraction recoveries were obtained in the range of 85.9-120.3%, relative standard deviations for intra- and interday precisions were less than 6.3 and 10.0%, respectively. Finally, the established method was successfully applied to analyze the alkaloids in two batches of Gegen-Qinlian oral liquids.

[Long-term oncological outcomes after laparoscopic versus abdominal radical hysterectomy in stage I a2- II a2 cervical cancer: a matched cohort study].

OBJECTIVE: To investigate the long- term oncological outcomes of laparoscopic radical hysterectomy (LRH) plus lymph node dissection (LND) and abdominal radical hysterectomy (ARH) plus LND for patients with stage Ia2-IIa2 cervical cancer. METHODS: A retrospective review of stage Ia2- II a2 cervical cancer patients who underwent LRH + LND (n=372) and ARH + LND (n=434) at the First Affiliated Hospital of Sun Yat- sen University from Jan. 2005 to Aug. 2013 was performed. Individual patient matching was performed by the risk factors for recurrence [tumor size, lymph vascular space invasion (LVSI), depth of cervical stromal invasion, lymph node metastasis, parametrial involvement, and resection margin involvement] between two groups. After matched, a total of 203 patient pairs (LRH- ARH) were enrolled. The survival data, surgery data, intraoperative and postoperative complications were compared between the two groups. To assess the prognosis factors, the univariate and multivariate Cox's proportional hazards model analysis were conducted. Stratified analysis was performed based on the independent prognosis factors to investigate the survival data between the two surgery groups. RESULTS: (1) Surgery data: The operating time [(239±44) vs (270±42) minutes], estimated blood loss [(210±129) vs (428±320) ml], the duration of bowel motility return [(2.0±0.8) vs (3.0±1.6) days] and hospital stay [(11±6) vs (13±6) days] in the LRH group were significantly shorter than those in ARH group (all P<0.01). (2) Intraoperative and postoperative complications: The intraoperative complications rate was similar betweentwo groups [6.4%(13/203) vs 6.9%(14/203), P=1.000]. The rate of postoperative complications (excluded bladder dysfunction) in the LRH group were significantly lower than those in the ARH group [9.4% (19/203) vs 20.2% (41/203), P=0.002]. While there was no significant difference in the rates of bladder dysfunction between two groups [36.5% (74/203) vs 37.4% (76/203), P=0.910]. (3) Recurrence and survival data: There was no significant difference in the recurrence rates between the LRH group and ARH groups [7.9% (16/203) vs 9.4% (19/203), P=0.850]. There were similar 5-year recurrence-free survival (RFS; 92.1% vs 91.1%, P=0.790) and 5-year overall survival (OS; 93.7% vs 96.1%, P=0.900). (4) Prognosis factor: In univariate analysis, the results showed that tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage, adjuvant therapy, LVSI, stromal invasion, parametrium invasion, pelvic lymph node metastasis, and para-aortic lymph node metastasis were significantly associated with poor prognosis (all P<0.01). However, age, body mass index (BMI), surgery type, histological type, grade were not significantly associated with poor prognosis (all P>0.05). The multivariate analysis results, showed that tumor size, pelvic lymph node metastasis,and para- aortic lymph node metastasis were significantly associated with poor prognosis (all P<0.01). Stratified analysis showed that, even in patients with tumor size >4 cm, pelvic lymph node metastasis positive, and para-aortic lymph node metastasis positive in all subgroups, there were not significant difference for the estimated 5-year RFS and 5-year OS between LRH and ARH group (all P>0.05). CONCLUSION: For patients with stage Ia2-IIa2 cervical cancer, LRH plus lymph node dissection is an oncologically safe and surgical feasible alternative to ARH.

Overexpression of RFC3 is correlated with ovarian tumor development and poor prognosis.

Replication factor C3 (RFC3) is an oncogene that can potentially predict prognosis in a variety of human cancers. RFC3 expression in ovarian carcinoma has not yet been determined. In this study, we evaluated the messenger RNA (mRNA) and protein expression levels of RFC3 in normal ovarian and ovarian carcinoma tissues using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blots (WB). Results showed that higher RFC3 mRNA and protein levels were detected in ovarian carcinoma tissues by RT-PCR and WB. High RFC3 expression was defined as positive staining in >70 % of each tumor cell. High RFC3 expression was detected in 28.1, 17.6, 11.1, and 5.0 % of invasive carcinomas, borderline tumors, cystadenomas, and in normal ovary cells, respectively. Overexpression of RFC3 was associated with later pN status (p = 0.001), pM status (p = 0.001), and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.012) in ovarian carcinomas. Univariate survival analyses showed that RFC3 overexpression was also associated with shortened patient survival (mean 7.7 months in tumors with RFC3 overexpression vs 92.9 months in tumors with normal RFC3 levels; p < 0.001). In multivariate analyses, RFC3 protein levels were a significant prognostic factor for ovarian carcinoma (p < 0.001). In conclusion, our findings suggest that RFC3 protein is an important and independent biomarker with prognostic implications for patients with ovarian carcinoma.

Developing oxaliplatin and IL-15 Co-carried gels as drug depots to enable triple-interlocked combination therapy for colorectal cancer.

Chemo-immunotherapy, which involves the simultaneous use of chemotherapy drug and immunotherapeutic agent to achieve synergistic effects, plays a crucial role in cancer treatment. However, the immunosuppressive microenvironment, insufficient tumor specificity, and serious systemic side effects hinder their synergistic therapeutic effects and clinical applications. Herein, T cell and natural killer (NK) cell, which are the most important immune effector cells, were both activated to reverse the immunosuppressive microenvironment. To simplify drug carriers, oxaliplatin was selected as the chemotherapy drug which can both induce the ICD effect and activate T cells. IL-15 was selected to activate NK cells. To enhance the productivity of the carrier and reduce side effects, the easy-prepared thermosensitive hydrogel (OXL/IL-15 TG) was developed to co-load oxaliplatin-loaded liposomes (OXL) and IL-15. Colorectal cancer, suitable for in situ administration, was selected as model cancer. The resulting novel triple-interlocked combination therapy could directly kill the tumor cells, induces ICD effect and activate NK cells. After administration, OXL/IL-15 TG was formed serving as a drug depot, slowing releasing OXL and IL-15 non-interferencely. OXL around 165.47±7.04 nm was passively delivered to tumor tissue, killing tumor cells and inducing ICD effect. The results demonstrated that IL-15 stimulated the activation of NK cells. In tumor-bearing mice models, OXL/IL-15 TG exhibited a remarkable and noteworthy anti-tumor efficacy, and expanded survival rate. Notably, OXL/IL-15 TG led to an enhanced infiltration of CD3+CD8+ T cells and CD3-CD49+ NK cells within the tumor tissue. Overall, the triple-interlocked combination therapy provided a new idea for colorectal cancer therapy.