Clinical analysis of 314 patients with high-grade squamous intraepithelial lesion who underwent total hysterectomy directly: a multi-center, retrospective cohort study.

OBJECTIVE: To identify the risk factors of cervical high-grade squamous intraepithelial lesion(HSIL) complicated with occult cervical cancer and standardize the management of initial treatment for HSIL. METHOD: The clinical data of patients who underwent total hysterectomy directly due to HSIL in the obstetrics and gynecology department of two tertiary hospitals and three secondary hospitals from 2018 to 2023 were collected. Their general characteristics, pathological parameters and survival status were analyzed. Logistic regression model was used to analyze the correlation between clinical parameters and postoperative pathological upgrading. RESULT: 1. Among the 314 patients with HSIL who underwent total hysterectomy directly, 73.2% were from primary hospitals. 2. 25 patients (7.9%) were pathologically upgraded to cervical cancer, all of which were early invasive cancer. 3. Up to now, there was no recurrence or death in the 25 patients with early-stage invasive cancer, and the median follow-up period was 21 months(range 2-59 months). 4. Glandular involvement(OR 3.968; 95%CI 1.244-12.662) and lesion range ≥ 3 quadrants (OR 6.527; 95% CI 1.78-23.931), HPV 16/18 infection (OR 5.382; 95%CI 1.947-14.872), TCT ≥ ASC-H (OR 4.719; 95%CI 1.892-11.766) were independent risk factors that affected the upgrading of postoperative pathology. 5. The area under the curve (AUC) calculated by the Logistic regression model was 0.840, indicating that the predictive value was good. CONCLUSION: There is a risk of occult cervical cancer in patients with HSIL. Glandular involvement, Lesion range ≥ 3 quadrants, HPV 16/18 infection and TCT ≥ ASC-H are independent risk factors for HSIL combined with occult cervical cancer. The prognosis of biopsy-proved HSIL patients who underwent extrafascial hysterectomy and unexpected early invasive cancer was later identified on specimen may be good.

Development of a machine learning-based model for predicting positive margins in high-grade squamous intraepithelial lesion (HSIL) treatment by Cold Knife Conization(CKC): a single-center retrospective study.

OBJECTIVES: This study aims to analyze factors associated with positive surgical margins following cold knife conization (CKC) in patients with cervical high-grade squamous intraepithelial lesion (HSIL) and to develop a machine-learning-based risk prediction model. METHOD: We conducted a retrospective analysis of 3,343 patients who underwent CKC for HSIL at our institution. Logistic regression was employed to examine the relationship between demographic and pathological characteristics and the occurrence of positive surgical margins. Various machine learning methods were then applied to construct and evaluate the performance of the risk prediction model. RESULTS: The overall rate of positive surgical margins was 12.9%. Independent risk factors identified included glandular involvement (OR = 1.716, 95% CI: 1.345-2.189), transformation zone III (OR = 2.838, 95% CI: 2.258-3.568), HPV16/18 infection (OR = 2.863, 95% CI: 2.247-3.648), multiple HR-HPV infections (OR = 1.930, 95% CI: 1.537-2.425), TCT ≥ ASC-H (OR = 3.251, 95% CI: 2.584-4.091), and lesions covering ≥ 3 quadrants (OR = 3.264, 95% CI: 2.593-4.110). Logistic regression demonstrated the best prediction performance, with an accuracy of 74.7%, sensitivity of 76.7%, specificity of 74.4%, and AUC of 0.826. CONCLUSION: Independent risk factors for positive margins after CKC include HPV16/18 infection, multiple HR-HPV infections, glandular involvement, extensive lesion coverage, high TCT grades, and involvement of transformation zone III. The logistic regression model provides a robust and clinically valuable tool for predicting the risk of positive margins, guiding clinical decisions and patient management post-CKC.

Risk factors predicting residual lesion in subsequent hysterectomy following cold knife conization (CKC) for high-grade squamous intraepithelial lesion (HSIL).

OBJECTIVE: To determine risk factors predicting residual lesion in a subsequent hysterectomy follow a cold knife conization (CKC) for high-grade squamous intraepithelial lesion (HSIL). METHOD: Between January 2010 and December 2021, a total of 740 patients who underwent a hysterectomy within 3 months after CKC for HSIL were included in this study. We analyzed their demographic features and pathological parameters. A logistic regression model was used to analyze the relationship between parameters and residual lesion in subsequent hysterectomy specimens. RESULTS: 104 (14.1%) had residual lesion in the hysterectomy specimen, 3 patients with microinvasive carcinoma. The rate of residual lesion in patients with positive endocervical margin was 31.3%, with positive ectocervical margin was 15.3%, with positive combine margin was 38.6%. In multivariate analysis, positive margin (OR 4.015; 95% CI 2.526-6.381; P < 0.001), glandular involvement (OR 3.484; 95% CI 1.457-8.330; P = 0.005), HPV16/18 infection (OR 2.804; 95% CI 1.705-4.611; P < 0.001) and multiple HR-HPV infection (OR 1.813; 95% CI 1.130-2.909; P < 0.014) were independent risk factors for residual lesion. The AUC calculated by logistic regression model was 0.78. CONCLUSION: Positive margin, positive glandular involvement, HPV16/18 and multiple HR-HPV infection were independent high risk factors of residual lesion in a subsequent hysterectomy following CKC for HSIL.

The effect of cinnamon on polycystic ovary syndrome in a mouse model.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent cause of anovulatory infertility and hyperandrogenism. Evidence favors insulin resistance and compensatory hyperinsulinemia as the predominant, perhaps primary, defects in PCOS. The use of insulin-sensitizing drugs has been shown to improve both the reproductive and the metabolic aspects of PCOS. Cinnamon has been found to have insulin sensitizing effect and improve menstrual cyclicity in women with PCOS. The aim of this study was to determine the effect and mechanism of cinnamon on PCOS using a dehydroepiandrosterone (DHEA) induced PCOS mouse model. METHODS: Prepubertal C57BL/6 mice (age 25 days) were raised to developed into control group, DHEA group and DHEA plus cinnamon group for 20 days. The stages of the estrous cycle were determined based on vaginal cytology; metabolic characteristics were examined by intraperitoneal glucose tolerance test and insulin tolerance test, the serum levels of hormones (testosterone, insulin, LH, FSH, IGF-1, IGFBP-1) were checked using enzyme-linked immunosorbent assay (ELISA) method, the ovarian morphology was observed by stained with hematoxylin and eosin. IGF-1 and IGFBP-1 expression in ovary were detected by immunohistochemical stain. RESULTS: Cinnamon restores the cyclicity and ovary morphology in PCOS mice model induced by DHEA. There are significant differences of serum level of total testosterone (0.033 ± 0.009 ng/ml), among control group, DHEA and cinnamon group (0.052 ± 0.011 ng/ml), and DHEA group (0.079 ± 0.015 ng/ml); There was an increasing tendency of serum FSH level from DHEA group (5.02 ± 0.31 ng/ml), DHEA and cinnamon group (5.81 ± 0.51 ng/ml), to control group (7.13 ± 0.74 ng/ml); and there was a decreasing trend of serum LH level from DHEA group (3.75 ± 0.57 ng/ml), DHEA and cinnamon group (1.35 ± 0.61 ng/ml), or control group (0.69 ± 0.34 ng/ml); serum insulin level is significantly higher in DHEA treated mice (1.61 ± 0.31 ng/ml) than control group (0.93 ± 0.19 ng/ml), or DHEA and cinnamon effect (1.27 ± 0.23 ng/ml) (p < 0.05). The DHEA group also has a higher serum IGF-1 level (0.35 ± 0.06 ng/ml) than control group (0.17 ± 0.04 ng/ml) or DHEA and cinnamon group (0.21 ± 0.05 ng/ml) (p < 0.05). While DHEA group has a lower IGFBP-1 level (5.5 ± 1.6 ng/ml) than control group (15.8 ± 2.1 ng/ml) or DHEA and cinnamon group (10.3 ± 2.5 ng/ml) (p < 0.05). Cinnamon also attenuates DHEA induced a higher IGF-1 and lower IGFBP-1 expression in ovary by immunohistochemistry. CONCLUSIONS: These preliminary data suggest that cinnamon supplementation improves insulin resistance and may be a potential therapeutic agent for the treatment of PCOS.

A Uniform Linear Multi-Coil Array-Based Borehole Transient Electromagnetic System for Non-Destructive Evaluations of Downhole Casings.

Borehole transient electromagnetic (TEM) techniques have been proven to be efficient for nondestructive evaluations (NDEs) of metal casings using eddy-current properties. However, physical limitations and bad borehole conditions restrict the use of eddy-current sensors, which makes downhole casing inspections very different from those of conventional NDE systems. In this paper, we present a uniform linear multi-coil array-based borehole TEM system for NDEs of downhole casings. On the basis of the borehole TEM signal model, a numerical multi-coil array approach using the Gauss⁻Legendre quadrature is derived. The TEM response can be divided into two independent parts related to the transmitting-receiving distance (TRD) and the observation time and casing thickness. Using this property, the signal received by the multi-coil array is weighted to cancel the influence of the TRDs of the different array elements to obtain the optimal response according to the linearly constrained minimum variance criterion, which can be shown to be identical to that of achieving the maximum signal-to-noise ratio. The effectiveness of the proposed method was verified by applying the uniform linear multi-coil array to a borehole TEM system for NDEs of oil-well casings. Field experiments were conducted, and the results demonstrate the effectiveness of the proposed method.

Task Assignment and Path Planning for Multiple Autonomous Underwater Vehicles Using 3D Dubins Curves †.

This paper investigates the task assignment and path planning problem for multiple AUVs in three dimensional (3D) underwater wireless sensor networks where nonholonomic motion constraints of underwater AUVs in 3D space are considered. The multi-target task assignment and path planning problem is modeled by the Multiple Traveling Sales Person (MTSP) problem and the Genetic Algorithm (GA) is used to solve the MTSP problem with Euclidean distance as the cost function and the Tour Hop Balance (THB) or Tour Length Balance (TLB) constraints as the stop criterion. The resulting tour sequences are mapped to 2D Dubins curves in the X - Y plane, and then interpolated linearly to obtain the Z coordinates. We demonstrate that the linear interpolation fails to achieve G 1 continuity in the 3D Dubins path for multiple targets. Therefore, the interpolated 3D Dubins curves are checked against the AUV dynamics constraint and the ones satisfying the constraint are accepted to finalize the 3D Dubins curve selection. Simulation results demonstrate that the integration of the 3D Dubins curve with the MTSP model is successful and effective for solving the 3D target assignment and path planning problem.

Aberrant expression of decoy receptor 3 in human breast cancer: relevance to lymphangiogenesis.

BACKGROUND: Decoy receptor 3 (DcR3), a decoy receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily, is overexpressed in some forms of cancer. It was recently reported that DcR3 could protect endothelial cells from apoptosis, implying a potential role in the development of vessels, whereas its role in the lymphangiogenesis remains unclear. In the present study, we studied the DcR3 expression and its relationship with the lymphatic microvessel density (LMVD) to investigate if it played a role in the lymph metastasis of human breast cancer. MATERIALS AND METHODS: Real-time polymerase chain reaction and immunohistochemistry were performed to measure the messenger RNA and protein expression of DcR3 in the breast cancer tissues, noncancerous counterparts, and axillary lymph node from 63 patients. LMVD in these specimens was assessed by counting the D2-40 labeled-microvessels. Furthermore, the correlations between DcR3 expression and LMVD and other clinicopathologic parameters were analyzed. RESULTS: DcR3 was overexpressed in the breast cancer tissue of 58 patients (92.1%) and was also expressed in vascular endothelial cells and tumor cells in the lymph nodes. LMVD in cancer tissue and lymph nodes were both positively correlated to the aberrant expression of DcR3. CONCLUSIONS: The relevance between DcR3 overexpression and LMVD revealed the existence of possible links between DcR3 and lymphangiogenesis. Based on these findings, it is important to further explore the regulation of lymphangiogenesis operated by the reverse tumor necrosis factor signaling of DcR3.

Human papillomavirus 16 E6 contributes HIF-1α induced Warburg effect by attenuating the VHL-HIF-1α interaction.

Cervical cancer is still one of the leading causes of cancer deaths in women worldwide, especially in the developing countries. It is a major metabolic character of cancer cells to consume large quantities of glucose and derive more energy by glycolysis even in the presence of adequate oxygen, which is called Warburg effect that can be exaggerated by hypoxia. The high risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. Hypoxia-inducible factor 1α (HIF-1α), a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth, is highly increased by HPV E6. HIF-1α is a best-known target of the von Hippel-Lindau tumor suppressor (VHL) as an E3 ligase for degradation. In the present work, we found that HPV16 E6 promotes hypoxia induced Warburg effect through hindering the association of HIF-1α and VHL. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These results suggest that oncoprotein E6 plays a major role in the regulation of Warburg effect and can be a valuable therapeutic target for HPV-related cancer.

Exploiting Propagation Delay in Underwater Acoustic Communication Networks via Deep Reinforcement Learning.

This article proposes a novel deep-reinforcement learning-based medium access control (DL-MAC) protocol for underwater acoustic networks (UANs) where one agent node employing the proposed DL-MAC protocol coexists with other nodes employing traditional protocols, such as time division multiple access (TDMA) or q -Aloha. The DL-MAC agent learns to exploit the large propagation delays inherent in underwater acoustic communications to improve system throughput by either a synchronous or an asynchronous transmission mode. In the sync-DL-MAC protocol, the agent action space is transmission or no transmission, while in the async-DL-MAC, the agent can also vary the start time in each transmission time slot to further exploit the spatiotemporal uncertainty of the UANs. The deep Q -learning algorithm is applied to both sync-DL-MAC and async-DL-MAC agents to learn the optimal policies. A theoretical analysis and computer simulations demonstrate the performance gain obtained by both DL-MAC protocols. The async-DL-MAC protocol outperforms the sync-DL-MAC protocol significantly in sum throughput and packet success rate by adjusting the transmission start time and reducing the length of time slot.

Single-carrier frequency-domain turbo equalization without cyclic prefix or zero padding for underwater acoustic communications.

A frequency-domain turbo equalization (FDTE) scheme without cyclic prefix (CP) or zero padding is proposed for single-carrier, multiple-input-multiple-output underwater acoustic communication. In the first iteration of the FDTE, the received continuous data stream is divided into consecutive blocks and a combined inter-block-interference (IBI) cancellation and overlapped windowing scheme is used to diagonalize each data block for low-complexity detection in the frequency domain. Since the second iteration, IBI cancellation and CP reconstruction are applied on each block to enable effective symbol detection. This work extends the authors' previous work on frequency-domain hard-decision equalization to soft-decision turbo equalization so that it not only retains high data transmission efficiency, but also improves the bit error rate performance with slightly increased complexity due to multiple iterations. Its feasibility and effectiveness have been tested by field trial data from the ACOMM09 underwater communication experiment.

Synergistic Microbicidal Effect of AUR and PEITC Against Staphylococcus aureus Skin Infection.

Given the increasing prevalence of Staphylococcus aureus antibiotic resistance, there is an urgent need to repurpose approved drugs with known pharmacology and toxicology as an alternative therapeutic strategy. We have reported that the sustained monotherapy of auranofin (AUR) inevitably resulted in reduced susceptibility or even the emergence of resistance to AUR in S. aureus. However, whether drug combination could increase antibacterial activity while preventing AUR resistance is still unknown. Here, we focused on the important role of AUR combined with phenethyl isothiocyanate (PEITC) in skin infection and determined the synergistic antimicrobial effect on S. aureus by using checkerboard assays and time-kill kinetics analysis. This synergistic antimicrobial activity correlated with increased reactive oxygen species (ROS) generation, disruption of bacterial cell structure, and inhibition of biofilm formation. We also showed that AUR synergized with PEITC effectively restored the susceptibility to AUR via regulating thioredoxin reductase (TrxR) and rescued mice from subcutaneous abscesses through eliminating S. aureus pathogens, including methicillin-resistant S. aureus (MRSA). Collectively, our study indicated that the AUR and PEITC combination had a synergistic antimicrobial impact on S. aureus in vitro and in vivo. These results suggest that AUR and PEITC treatment may be a promising option for S. aureus infection.

Evaluation efficacy and safety of epidural analgesia in second-trimester induced labor: A single-center, prospective, non-randomized, controlled study.

BACKGROUND: Second-trimester induced labor in pregnant women was often more likely to suffer from psychological and physiological double pain. However, the analgesic management received less attention, and the optimal analgesic mode for second-trimester induced labor had not been determined. Our objective was to evaluate the feasible of epidural analgesia (EA) in second-trimester induced labor. METHODS: From January 2020 to December 2021, Primipara who planned to undergo second-trimester induced labor in the First Affiliated Hospital of Yangtze University were collected. The method of labor induction was oral mifepristone + amniotic cavity injection of Ethacridine Lactate. Based on whether or not patients received epidural analgesia, which were divided into EA group (30 cases) and non-EA (NEA) group (30 cases). The primary outcome were visual analog scale (VAS) score of pain and result of follow-up, the secondary outcomes included relative clinical parameter and labor duration. RESULTS: Vaginal induction of labor was successful in both groups. There was no statistically significant difference in VAS of pain between the two groups before analgesia (P > .05), but the VAS of pain in the EA group was significantly lower than the NEA group (P < .05) after analgesia or at delivery. The following outcomes showed no statistical difference between two groups: labor duration, postpartum hemorrhage, hemorrhage ≥ 500 mL, intrapartum injury, second days hemoglobin, C-reactive protein, antibiotic therapy days, hospitalizations days, and placenta residue (P > .05). The median hospitalization costs of EA group was 4697.5 yuan, and NEA group was 3673 yuan, the difference was statistically significant (P < .001). No adverse events related to EA occurred during hospitalization, only 3 patients showed mild lumbago and back pain after follow-up to three months postpartum, which was significantly relieved after proper rest. CONCLUSION: EA can significantly reduce the pain of parturients, which may be effective and safe in the second-trimester induced labor.

Deoxycholic Acid and Lithocholic Acid Alleviate Liver Injury and Inflammation in Mice with Klebsiella pneumoniae-Induced Liver Abscess and Bacteremia.

PURPOSE: Klebsiella pneumoniae-induced liver abscess and baiacterem is a serious infectious disease with high mortality. Secondary bile acids (SBAs) are produced by intestinal flora through the metabolism of primary bile acids and play a role in promoting or inhibiting inflammation in some diseases. However, the immunomodulatory role of SBAs in bacterial infections of the liver remains unclear. This study aimed to investigate the anti-inflammatory and liver-protective effects of SBAs in K. pneumoniae-infected mice. METHODS: The absolute concentrations of deoxycholic acid (DCA) and lithocholic acid (LCA) in feces and serum were analyzed, and intestinal flora alterations between K. pneumoniae-infected and healthy control mice were examined. The effect of SBAs was investigated by analyzing the survival, tissue bacterial load, histopathology, and inflammatory factor levels in SBA-treated mice. The expression of crucial proteins implicated in the NF-κB pathway, as well as the G-protein-coupled bile acid receptor TGR5, was detected. RESULTS: The content of SBAs in feces and serum of the K. pneumoniae-infected group was significantly reduced, and significant changes in the composition of the intestinal flora were detected. The intestinal flora are directly related to the synthesis of SBAs. Ruminococcaceae levels in K. pneumoniae-infected mice were significantly lower than in healthy control mice. Oral administration of SBAs improved the survival and liver pathology of K. pneumoniae-infected mice, and reduced the bacterial load and the level of inflammatory factors. SBAs down-regulated the expression of key proteins in the NF-κB inflammatory signaling pathway, including the phosphorylation of IκBα and NF-κB p50 and the nuclear translocation of NF-κB p65. The protective effect of SBAs may be dependent on high TGR5 expression. CONCLUSION: SBAs downregulate the NF-κB inflammatory signaling pathway through TGR5, protecting the liver and inhibiting inflammation in K. pneumoniae-induced liver abscess and bacteremia.

Gut Microbiota Contributes to Host Defense Against Klebsiella pneumoniae-Induced Liver Abscess.

PURPOSE: Klebsiella pneumoniae-induced liver abscess (KLA) is a type of pyogenic liver abscess (PLA), which is a distinct invasive syndrome that has been increasingly reported worldwide over the past two decades. The intestinal microbiota is increasingly recognized as an important modulator that can promote and maintain host immune homeostasis. However, its precise role in liver abscess is unknown. We aimed to investigate the function of the gut microbiota in the host defense against K. pneumoniae infection. METHODS: We constructed C57BL/6J mice with KLA and analyzed the diversity and richness of the intestinal microflora by 16S rRNA sequencing. Next, to create a microbiota-depleted (MD) mouse model, we administered multiple broad-spectrum antibiotics and validated the model using 16S rRNA sequencing. At 48 h after K. pneumoniae infection, we assessed the general health condition, liver injury, bacterial loads, and inflammatory factor levels in MD+KLA mice. Additionally, fecal microbiota transplantation (FMT) was conducted in another group of MD+KLA mice prior to K. pneumoniae infection, and we assessed whether the transplantation changed the outcomes. RESULTS: The diversity of the intestinal flora was significantly changed in KLA mice compared to control mice, with a decrease in beneficial bacteria and an increase in harmful bacteria. The MD+KLA mice exhibited impaired antimicrobial capacity, reduced survival, increased inflammation and liver damage at 48 h after K. pneumoniae infection compared to the KLA mice. However, FMT normalized the inflammatory cytokine levels, reduced liver damage, and increased survival. CONCLUSION: This study identified the gut microbiota as a protective factor against K. pneumoniae infection. The role of FMT in KLA should be investigated in future clinical studies.

In vitro and in vivo Activity of Combinations of Polymyxin B with Other Antimicrobials Against Carbapenem-Resistant Acinetobacter baumannii.

PURPOSE: To study the in vitro and in vivo antibacterial activities of polymyxin B (PB) and other five antimicrobial agents, including imipenem (IMP), meropenem (MEM), tigecycline (TGC), sulbactam (SUL), and rifampicin (RIF), alone or in combination against carbapenem-resistant Acinetobacter baumannii (CRAB). METHODS: Microbroth dilution method was used to determine the minimum inhibitory concentration (MIC) of ten strains of CRAB against six antibacterial drugs, and the checkerboard method was used to determine the fractional inhibitory concentration index (FICI). A mouse pneumonia model was established by intranasal instillation of Ab5075 to evaluate the antibacterial activity in vivo. RESULTS: The resistance rate of ten CRAB strains to IMP, MEM, and SUL was 100%, that to PB and TGC was 0%, and that to RIF was 20%. When PB was used in combination with the other five antibiotics in vitro, it mainly showed synergistic and additive effects on CRAB. The synergistic effect of PB and RIF was maximal, followed by MEM and IMP but was weak with SUL and TGC. In vivo, compared to the model group (untreated with antibiotics), treatment group (six antibiotics alone and PB combined with the other five antibiotics) reduced the bacterial load in the lung tissue and the serum inflammatory factors (IL-1ß, IL-6, and TNF-α). The bacterial load and the inflammatory factors of the combined group decreased significantly than that of the single group (P<0.05). The IL-6 and TNF-α values of the PB combined with the RIF group were significantly lower than the two drugs used individually. CONCLUSION: The combination of PB and IMP, MEM, and RIF exerted robust in vitro synergistic effects on CRAB isolates. The combination of PB and the other five antimicrobial agents had a better effect in the mouse pneumonia model than single agent, while the combination of PB and RIF had the best effect.

Pygo2 as a novel biomarker in gastric cancer for monitoring drug resistance by upregulating MDR1.

Chemotherapy is the main therapy for gastric cancer (GC) both before and after surgery, but the emergence of multidrug resistance (MDR) often leads to disease progression and recurrence. P-glycoprotein, encoded by MDR1, is a well-known multidrug efflux transporter involved in drug resistance development. Pygo2 overexpression has been identified in several cancers. Previous studies have shown that abnormal expression of Pygo2 is related to tumorigenesis, chemoresistance, and tumor progression. In this study, to evaluate the underlying relationship between Pygo2 and MDR1 in GC, we constructed GC drug-resistant cell lines, SGC7901/cis-platinum (DDP), and collected tissue from GC patients' pre-and post-chemotherapy. We found that Pygo2 was overexpressed in GC, especially in GC drug-resistant cell lines and GC patients who underwent neoadjuvant DDP-based chemotherapy. Pygo2 overexpression may precede MDR1 and correlates with MDR1 in GC patients. Furthermore, knock-down of Pygo2 induced downregulation of MDR1 and restored SGC7901/DDP's sensitivity to DDP. Further mechanistic analysis demonstrated that Pygo2 could modulate MDR1 transcription by binding to the MDR1 promoter region and promoting MDR1 activation. The overall findings reveal that Pygo2 may be a promising biomarker for monitoring drug resistance in GC by regulating MDR1.

Doxofylline Protects Gram-Negative Pathogens against Antibiotic-Mediated Killing.

Given the growing rate of Gram-negative bacterial infections, antibiotics are now frequently prescribed for various respiratory diseases. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities, but its influence on antibiotics remains poorly understood. Here, we first report the discovery of doxofylline-induced high minimum inhibitory concentrations of antibiotics. We also showed that doxofylline blocked antimicrobial-mediated killing for Gram-negative pathogens in vitro and in murine lung infection models in vivo. By combining efflux pump inhibition tests, gene expression analyses, and using the gene tolC knockout strain, we found that doxofylline positively regulated gene expression of the AcrAB-TolC efflux pump and attenuated the effect of doxofylline on antibacterial activities in ΔtolC mutants. Notably, doxofylline-mediated protection correlated with decreased reactive oxygen species (ROS) production. Collectively, our study indicates that doxofylline protects Gram-negative bacteria from antimicrobial lethality by regulating the AcrAB-TolC efflux pump in a TolC-dependent manner and suppressing antibiotic-induced ROS accumulation. These results suggest caution when using antibiotics alongside doxofylline in clinical treatment.

Effects of Tigecycline Combined with Azithromycin Against Biofilms of Multidrug-Resistant Stenotrophomonas maltophilia Isolates from a Patient in China.

PURPOSE: Our aim was to investigate in vitro biofilm formation by S. maltophilia and the effects of antibacterial agents used to prevent biofilm formation. METHODS: Two trimethoprim/sulfamethoxazole-resistant S. maltophilia strains were isolated from the pleural effusion of a patient with cancer. The minimum inhibitory concentrations (MICs) of amikacin, azithromycin, cefoperazone/sulbactam, and tigecycline were determined. The checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A crystal violet biofilm assay and confocal laser scanning microscopy (CLSM) were used to observe biofilm formation. In vitro effects of azithromycin combined with tigecycline on biofilms of S. maltophilia strains were tested. RESULTS: The two S. maltophilia isolates were confirmed to produce strong biofilms. Crystal violet biofilm assay and CLSM analysis of S. maltophilia biofilm were in the initial adhesive stage after 2 h incubation. Biofilm was in the exponential phase of growth at 12 h and reached maximal growth at 36-48 h. Compared with tigecycline or azithromycin alone, the combination of tigecycline and azithromycin increased the inhibiting effect S. maltophilia biofilm biomass after incubation for 12 h. Compared with the control group, in almost all strains treated with tigecycline and azithromycin, the biofilm was significantly suppressed significance (P<0.001). We found that 2x MIC azithromycin combined with 1x MIC tigecycline had the best inhibiting effect against the biofilm, the biofilm inhibition rates of three strains were all over 60%, the biofilm thickness was inhibited from 36.00 ± 4.00 µm to 8.00 µm, from 40.00 µm to 6.67± 2.31 µm, and from 32.00 µm to 13.33 ± 2.31 µm in SMA1, SMA2 and ATCC17666, respectively. CONCLUSION: Azithromycin combined with tigecycline inhibited biofilm formation by S. maltophilia. Our study provides an experimental basis for a possible optimal treatment strategy for S. maltophilia biofilm-related infections.

Bandwidth-efficient frequency-domain equalization for single carrier multiple-input multiple-output underwater acoustic communications.

This paper proposes a single carrier (SC) receiver scheme with bandwidth-efficient frequency-domain equalization (FDE) for underwater acoustic (UWA) communications employing multiple transducers and multiple hydrophones. Different from the FDE methods that perform FDE on a whole data block, the proposed algorithm implements an overlapped-window FDE by partitioning a large block into small subblocks. A decision-directed channel estimation scheme is incorporated with the overlapped-window FDE to track channel variations and improve the error performance. The proposed algorithm significantly increases the length of each block and keeps the same number of training symbols per block, hence achieving better data efficiency without performance degradation. The proposed scheme is tested by the undersea data collected in the Rescheduled Acoustic Communications Experiment (RACE) in March 2008. Without coding, the 2-by-12 MIMO overlapped-window FDE reduces the average bit error rate (BER) over traditional SC-FDE schemes by 74.4% and 84.6% for the 400 m and 1000 m range systems, respectively, at the same data efficiency. If the same BER performance is required, the proposed algorithm has only 8.4% transmission overhead, comparing to over 20% overhead in other existing UWA OFDM and SC-FDE systems. The improved data efficiency and/or error performance of the proposed FDE scheme is achieved by slightly increased computational complexity over traditional SC-FDE schemes.

A Cross-Sectional Study on the Correlation Between Inflammatory Cytokines, Negative Emotions, and Onset of Peripheral Neuropathy in Type 2 Diabetes.

OBJECTIVE: This study explored the changes in the levels of IL-6, IL-17, TNF-α, and TNF-ß, whether such changes were associated with anxiety and depression in diabetic peripheral neuropathy (DPN), and what factors associated with the occurrence of DPN. METHODS: Forty-four patients diagnosed with DPN comprised the DPN group, including DPN1 (mild diabetic peripheral neuropathy, 29 cases) and DPN2 groups (moderate-severe diabetic peripheral neuropathy, 15 cases). Thirty-seven individuals with type 2 diabetes mellitus constituted the diabetes mellitus with no neuropathy (NDPN) group. Electromyography was applied to confirm DPN, and the Toronto clinical scoring system (TCSS) score was used to assess the severity of DPN. All subjects' emotions were evaluated using the self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Triiodothyronine (T3), tetraiodothyronine (T4), and thyroid-stimulating hormone (TSH) levels were measured using chemiluminescent immunoassay. The relevant biochemical indicators were detected using an automatic biochemical analyzer. The plasma levels of cytokines were detected using quantitative sandwich enzyme-linked immunosorbent assay. RESULTS: Patients with DPN had elevated levels of anxiety, IL-6, IL-17, and TNF-α. There were some positive associations between negative emotions and cytokines. The TCSS score positively correlated with IL-17, SAS score, and T3. DPN independently correlated with age, disease duration, fasting plasma glucose (FPG), and IL-17. The combination of IL-17 and TNF-α had higher diagnostic value for DPN than any single cytokine. CONCLUSION: Patients with DPN had elevated levels of inflammatory cytokines, which were associated with negative emotion, and IL-17 had independent correlation with DPN.