The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study.

BACKGROUND: Effective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy. METHODS: A total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR). RESULTS: The median follow-up period was 28.6 months (range: 2.3-54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2-7.4 months), and the median OS was 17.1 months (95% CI 12.0-22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1-2, and no increase in adverse events was observed compared to monotherapy. CONCLUSION: Anlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.

Essential role of pyrophosphate homeostasis mediated by the pyrophosphate-dependent phosphofructokinase in Toxoplasma gondii.

Many biosynthetic pathways produce pyrophosphate (PPi) as a by-product, which is cytotoxic if accumulated at high levels. Pyrophosphatases play pivotal roles in PPi detoxification by converting PPi to inorganic phosphate. A number of apicomplexan parasites, including Toxoplasma gondii and Cryptosporidium parvum, express a PPi-dependent phosphofructokinase (PPi-PFK) that consumes PPi to power the phosphorylation of fructose-6-phosphate. However, the physiological roles of PPi-PFKs in these organisms are not known. Here, we report that Toxoplasma expresses both ATP- and PPi-dependent phosphofructokinases in the cytoplasm. Nonetheless, only PPi-PFK was indispensable for parasite growth, whereas the deletion of ATP-PFK did not affect parasite proliferation or virulence. The conditional depletion of PPi-PFK completely arrested parasite growth, but it did not affect the ATP level and only modestly reduced the flux of central carbon metabolism. However, PPi-PFK depletion caused a significant increase in cellular PPi and decreased the rates of nascent protein synthesis. The expression of a cytosolic pyrophosphatase in the PPi-PFK depletion mutant reduced its PPi level and increased the protein synthesis rate, therefore partially rescuing its growth. These results suggest that PPi-PFK has a major role in maintaining pyrophosphate homeostasis in T. gondii. This role may allow PPi-PFK to fine-tune the balance of catabolism and anabolism and maximize the utilization efficiency for carbon nutrients derived from host cells, increasing the success of parasitism. Moreover, PPi-PFK is essential for parasite propagation and virulence in vivo but it is not present in human hosts, making it a potential drug target to combat toxoplasmosis.

The application of different machine learning models based on PET/CT images and EGFR in predicting brain metastasis of adenocarcinoma of the lung.

OBJECTIVE: To explore the value of six machine learning models based on PET/CT radiomics combined with EGFR in predicting brain metastases of lung adenocarcinoma. METHODS: Retrospectively collected 204 patients with lung adenocarcinoma who underwent PET/CT examination and EGFR gene detection before treatment from Cancer Hospital Affiliated to Shandong First Medical University in 2020. Using univariate analysis and multivariate logistic regression analysis to find the independent risk factors for brain metastasis. Based on PET/CT imaging combined with EGFR and PET metabolic indexes, established six machine learning models to predict brain metastases of lung adenocarcinoma. Finally, using ten-fold cross-validation to evaluate the predictive effectiveness. RESULTS: In univariate analysis, patients with N2-3, EGFR mutation-positive, LYM%≤20, and elevated tumor markers(P<0.05) were more likely to develop brain metastases. In multivariate Logistic regression analysis, PET metabolic indices revealed that SUVmax, SUVpeak, Volume, and TLG were risk factors for lung adenocarcinoma brain metastasis(P<0.05). The SVM model was the most efficient predictor of brain metastasis with an AUC of 0.82 (PET/CT group),0.70 (CT group),0.76 (PET group). CONCLUSIONS: Radiomics combined with EGFR machine learning model as a new method have higher accuracy than EGFR mutation alone. SVM model is the most effective method for predicting brain metastases of lung adenocarcinoma, and the prediction efficiency of PET/CT group is better than PET group and CT group.

Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer.

BACKGROUND: The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS: The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT: A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION: Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.

MFGAN: Multimodal Fusion for Industrial Anomaly Detection Using Attention-Based Autoencoder and Generative Adversarial Network.

Anomaly detection plays a critical role in ensuring safe, smooth, and efficient operation of machinery and equipment in industrial environments. With the wide deployment of multimodal sensors and the rapid development of Internet of Things (IoT), the data generated in modern industrial production has become increasingly diverse and complex. However, traditional methods for anomaly detection based on a single data source cannot fully utilize multimodal data to capture anomalies in industrial systems. To address this challenge, we propose a new model for anomaly detection in industrial environments using multimodal temporal data. This model integrates an attention-based autoencoder (AAE) and a generative adversarial network (GAN) to capture and fuse rich information from different data sources. Specifically, the AAE captures time-series dependencies and relevant features in each modality, and the GAN introduces adversarial regularization to enhance the model's ability to reconstruct normal time-series data. We conduct extensive experiments on real industrial data containing both measurements from a distributed control system (DCS) and acoustic signals, and the results demonstrate the performance superiority of the proposed model over the state-of-the-art TimesNet for anomaly detection, with an improvement of 5.6% in F1 score.

A Randomized Controlled Study of Enhanced External Counterpulsation with Cardiac Rehabilitation in Patients with Nonobstructive Coronary Artery Disease and Coronary Microvascular Dysfunction.

Treatment with enhanced external counterpulsation (EECP) or cardiac rehabilitation (CR) benefits patients with coronary heart disease; this paper intends to explore the feasibility of EECP combined with CR in patients with nonobstructive coronary heart disease (NOCAD) and coronary microcirculation disorders (CMD).In January 2021-2022 month June our income NOCAD patients as the research object, the line of cardiac magnetic resonance (CMR), myocardial perfusion reserve (MPR) < 2.0 coronary microcirculation disorders (CMD, 80 cases). Random indicator method 80 CMD patients divided into two groups, 40 cases in each. Usual treatment group: conventional drugs and CR therapy. EECP treatment group: on the basis of standard treatment group, employ EECP therapy. Comparing the two groups before and after the treatment curative effect cardiac function index, endothelial unction index, adverse cardiovascular events, etc.After EECP treatment, the treatment group showed a higher effective rate compared to the usual treatment group (P < 0.05). EECP group curative effect, left ventricular ejection fraction,plasma NO and vascular endothelial growth factor levels higher than the usual group, the incidence of adverse cardiovascular events is lower than the usual group. The difference was statistically significant (P < 0.05).EECP combined with cardiac rehabilitation in patients with CMD symptoms has better effect and safety and provides reference for treatment of CMD patients.

Vaginal flora in HPV infection: a cross­sectional analysis.

OBJECTIVE: The vaginal flora has been reported to be associated with human papillomavirus (HPV) infection. The purpose of this study was to investigate the characteristics of the cervical microbiota in patients with HPV infection and to analyse the changes in the vaginal flora and enzyme profiles in females with HPV infection. METHODS: We conducted a cross-sectional study involving 206 participants who underwent HPV genotyping, sexually transmitted diseases pathogen testing, cytology examination, and microbiome analysis. Additionally, we collected 115 HPV-negative samples and 48 HPV-positive samples for 16S rRNA amplicon sequencing. The vaginal microbial communities of both groups were analysed for diversity and differences to explore their association with HPV infection. RESULTS: The abundance of Lactobacillus was found to be reduced, while Gardnerella vaginalis was significantly more prevalent in the HPV + group. In terms of alpha diversity indices, the Shannon index (P = .0036) and Simpson index (P = .02) were higher in the HPV + group compared to the HPV - group, indicating greater community diversity in the HPV + group. Among the 10 sexually transmitted diseases pathogens analysed, Uup3 and Uup6 were significantly associated with HPV infection. Statistically significant differences were observed in Nugent scores and bacterial vaginosis between the two groups (P < .05). In functional analysis, 11 proteins and 13 enzymes were found to be significantly altered in the HPV + group. CONCLUSION: Our study demonstrates that disruptions in the vaginal flora are associated with HPV infection. Reduced levels of Lactobacillus, increased prevalence of Gardnerella, and abnormal enzyme profiles are closely linked to HPV infection.

The purpose of this study was to investigate the characteristics of the cervical microbiota in patients with human papillomavirus infection and to analyse the changes in the vaginal flora and enzyme profiles in females with human papillomavirus infection. We conducted a cross-sectional study involving 206 participants who underwent human papillomavirus genotyping, sexually transmitted diseases pathogen testing, cytology examination, and microbiome analysis. Additionally, we collected 115 HPV-negative samples and 48 HPV-positive samples for 16S rRNA amplicon sequencing. The abundance of Lactobacillus was found to be reduced, while Gardnerella vaginalis was significantly more prevalent in the HPV + group. In functional analysis, 11 proteins and 13 enzymes were found to be significantly altered in the HPV + group. Our study demonstrates that disruptions in the vaginal flora are associated with HPV infection. Reduced levels of Lactobacillus, increased prevalence of Gardnerella, and abnormal enzyme profiles are closely linked to HPV infection.

Evaluation of a multiphasic parasite clearance profile after treatment of experimental human infection with the investigational anti-malarial M5717 using segmented mixed effect models.

BACKGROUND: Evaluation of parasite clearance patterns in experimental human infection trials helps increase understanding of drug action. In a previously reported phase Ib trial of a new investigational anti-malarial drug M5717, parasite clearance showed a biphasic linear pattern: slow removal phase with a near flat clearance rate followed by a fast clearance phase with a steep slope. In this study three statistical approaches were implemented and compared to estimate the parasite clearance rate for each phase and the time point corresponding to the change of clearance rates (changepoint between the two phases). METHODS: Data using three M5717 doses 150 mg (n = 6), 400 mg (n = 8), 800 mg (n = 8) were used to estimate biphasic clearance rates. Three models were investigated: firstly, segmented mixed models with estimated changepoint-models with/without random effects in various parameters were compared. Secondly, a segmented mixed model using grid search-this method is similar to the first except that changepoints were not estimated, instead they were selected based on model fit from given candidate values. Thirdly, a two-stage approach whereby a segmented regression model fit to each participant followed by a meta-analysis method. Hourly rate of parasite clearance (HRPC) interpreted as the percentage of parasites removed each hour was calculated. RESULTS: The three models generated similar results. Using segmented mixed models, the estimated changepoints after treatment in hours (95% CI) were: 150 mg: 33.9 (28.7, 39.1); 400 mg: 57.4 (52.5, 62.4); and 800 mg: 52.8 (47.4, 58.1). For all three treatment groups, there was nearly no clearance before the changepoints, but rapid clearance in the second phase (HRPC [95% CI]): 150 mg: 16.8% (14.3, 19.1%); 400 mg: 18.6% (16.0, 21.1%); and 800 mg: 11.7% (9.3, 14.1%). CONCLUSIONS: All three statistical approaches are effective tools to characterize the bi-phasic clearance of M5717 in the phase 1b experimental Plasmodium falciparum malaria human infection study. The statistical approaches produced similar results to estimate the two-phase clearance rates and the changepoint for each treatment dose of M5717. However, the segmented mixed model with random changepoints has several advantages: it is computationally efficient, provides precision for changepoint estimates and is robust concerning outlying datapoints or individuals.

Association between second- and third-trimester maternal lipid profiles and adverse perinatal outcomes among women with GDM and non-GDM: a retrospective cohort study.

BACKGROUND: Lipid metabolism disorder during pregnancy has been reported in women with gestational diabetes mellitus (GDM). However, controversy remains regarding the relationship between maternal changes in lipid profiles and perinatal outcomes. This study investigated the association between maternal lipid levels and adverse perinatal outcomes in women with GDM and non-GDM. METHODS: In total, 1632 pregnant women with GDM and 9067 women with non-GDM who delivered between 2011-2021 were enrolled in this study. Serum samples were assayed for fasting total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels during the second and third trimesters of pregnancy. Adjusted odds ratios (AOR) and 95% confidence intervals (95% CI) were calculated via multivariable logistic regression analysis to determine the association of lipid levels with perinatal outcomes. RESULTS: The serum TC, TG, LDL, and HDL levels in the third trimester were significantly higher than those in the second trimester (p < 0.001). Women with GDM had significantly higher levels of TC and TG in the second and third trimesters than those with non-GDM in the same trimesters, while HDL levels decreased in women with GDM (all p < 0.001). After adjusting for confounding factors by multivariate logistic regression, every mmol/L elevation in TG levels of women with GDM in second and third trimesters was associated with a higher risk of caesarean section (AOR = 1.241, 95% CI: 1.103-1.396, p < 0.001; AOR = 1.716, 95% CI: 1.556-1.921, p < 0.001), large for gestational age infants (LGA) (AOR = 1.419, 95% CI: 1.173-2.453, p = 0.001; AOR = 2.011, 95% CI: 1.673-2.735, p < 0.001), macrosomia (AOR = 1.220, 95% CI: 1.133-1.643, p = 0.005; AOR = 1.891, 95% CI: 1.322-2.519, p < 0.001), and neonatal unit admission (NUD; AOR = 1.781, 95% CI: 1.267-2.143, p < 0.001; AOR = 2.052, 95% CI: 1.811-2.432, p < 0.001) cesarean delivery (AOR = 1.423, 95% CI: 1.215-1.679, p < 0.001; AOR = 1.834, 95% CI: 1.453-2.019, p < 0.001), LGA (AOR = 1.593, 95% CI: 1.235-2.518, p = 0.004; AOR = 2.326, 95% CI: 1.728-2.914, p < 0.001), macrosomia (AOR = 1.346, 95% CI: 1.209-1.735, p = 0.006; AOR = 2.032, 95% CI: 1.503-2.627, p < 0.001), and neonatal unit admission (NUD) (AOR = 1.936, 95% CI: 1.453-2.546, p < 0.001; AOR = 1.993, 95% CI: 1.724-2.517, p < 0.001), which were higher than the relative risk of these perinatal outcomes in women with non-GDM. Additionally, every mmol/L increase in second and third-trimester HDL levels of women with GDM was associated with decreased risk of LGA(AOR = 0.421, 95% CI: 0.353-0.712, p = 0.007; AOR = 0.525, 95% CI: 0.319-0.832, p = 0.017) and NUD (AOR = 0.532, 95% CI: 0.327-0.773, p = 0.011; AOR = 0.319, 95% CI: 0.193-0.508, p < 0.001), and the risk reduction was not strong than that of women with GDM. CONCLUSIONS: Among women with GDM, high maternal TG in the second and third trimesters was independently associated with an increased risk of cesarean section, LGA, macrosomia, and NUD. High maternal HDL during the second and third trimesters was significantly associated with decreased risk of LGA and NUD. These associations were stronger than those in women with non-GDM, suggesting the importance of monitoring second and third-trimester lipid profiles in improving clinical outcomes, especially in GDM pregnancies.

CaFANet: Causal-Factors-Aware Attention Networks for Equipment Fault Prediction in the Internet of Things.

Existing fault prediction algorithms based on deep learning have achieved good prediction performance. These algorithms treat all features fairly and assume that the progression of the equipment faults is stationary throughout the entire lifecycle. In fact, each feature has a different contribution to the accuracy of fault prediction, and the progress of equipment faults is non-stationary. More specifically, capturing the time point at which a fault first appears is more important for improving the accuracy of fault prediction. Moreover, the progress of the different faults of equipment varies significantly. Therefore, taking feature differences and time information into consideration, we propose a Causal-Factors-Aware Attention Network, CaFANet, for equipment fault prediction in the Internet of Things. Experimental results and performance analysis confirm the superiority of the proposed algorithm over traditional machine learning methods with prediction accuracy improved by up to 15.3%.

Different Photosynthetic Response to High Light in Four Triticeae Crops.

Photosynthetic capacity is usually affected by light intensity in the field. In this study, photosynthetic characteristics of four different Triticeae crops (wheat, triticale, barley, and highland barley) were investigated based on chlorophyll fluorescence and the level of photosynthetic proteins under high light. Compared with wheat, three cereals (triticale, barley, and highland barley) presented higher photochemical efficiency and heat dissipation under normal light and high light for 3 h, especially highland barley. In contrast, lower photoinhibition was observed in barley and highland barley relative to wheat and triticale. In addition, barley and highland barley showed a lower decline in D1 and higher increase in Lhcb6 than wheat and triticale under high light. Furthermore, compared with the control, the results obtained from PSII protein phosphorylation showed that the phosphorylation level of PSII reaction center proteins (D1 and D2) was higher in barley and highland barley than that of wheat and triticale. Therefore, we speculated that highland barley can effectively alleviate photodamages to photosynthetic apparatus by high photoprotective dissipation, strong phosphorylation of PSII reaction center proteins, and rapid PSII repair cycle under high light.

Fast-moving bat ears create informative Doppler shifts.

Many animals have evolved adept sensory systems that enable dexterous mobility in complex environments. Echolocating bats hunting in dense vegetation represent an extreme case of this, where all necessary information about the environment must pass through a parsimonious channel of pulsed, 1D echo signals. We have investigated whether certain bats (rhinolophids and hipposiderids) actively create Doppler shifts with their pinnae to encode additional sensory information. Our results show that the bats' active pinna motions are a source of Doppler shifts that have all attributes required for a functional relevance: (i) the Doppler shifts produced were several times larger than the reported perception threshold; (ii) the motions of the fastest moving pinna portions were oriented to maximize the Doppler shifts for echoes returning from the emission direction, indicating a possible evolutionary optimization; (iii) pinna motions coincided with echo reception; (iv) Doppler-shifted signals from the fast-moving pinna portion entered the ear canal of a biomimetic pinna model; and (v) the time-frequency Doppler shift signatures were found to encode target direction in an orderly fashion. These results indicate that instead of avoiding or suppressing all self-produced Doppler shifts, rhinolophid and hipposiderid bats actively create Doppler shifts with their own pinnae. These bats could hence make use of a previously unknown nonlinear mechanism for the encoding of sensory information, based on Doppler signatures. Such a mechanism could be a source for the discovery of sensing principles not only in sensory physiology but also in the engineering of sensory systems.

Multi-Modal Learning-Based Equipment Fault Prediction in the Internet of Things.

The timely detection of equipment failure can effectively avoid industrial safety accidents. The existing equipment fault diagnosis methods based on single-mode signal not only have low accuracy, but also have the inherent risk of being misled by signal noise. In this paper, we reveal the possibility of using multi-modal monitoring data to improve the accuracy of equipment fault prediction. The main challenge of multi-modal data fusion is how to effectively fuse multi-modal data to improve the accuracy of fault prediction. We propose a multi-modal learning framework for fusion of low-quality monitoring data and high-quality monitoring data. In essence, low-quality monitoring data are used as a compensation for high-quality monitoring data. Firstly, the low-quality monitoring data is optimized, and then the features are extracted. At the same time, the high-quality monitoring data is dealt with by a low complexity convolutional neural network. Moreover, the robustness of the multi-modal learning algorithm is guaranteed by adding noise to the high-quality monitoring data. Finally, different dimensional features are projected into a common space to obtain accurate fault sample classification. Experimental results and performance analysis confirm the superiority of the proposed algorithm. Compared with the traditional feature concatenation method, the prediction accuracy of the proposed multi-modal learning algorithm can be improved by up to 7.42%.

Acute Nitrite Exposure Induces Dysfunction and Oxidative Damage in Grass Carp Isolated Hemocytes.

To evaluate the effects of nitrite on the oxidative damage of blood cells of Grass Carp Ctenopharyngodon idella, the isolated hemocytes were exposed to nitrite (0, 1, 10, or 100 mg/L) for up to 24 h. Hemoglobin (Hb) and methemoglobin (MetHb) concentrations, reactive oxygen species (ROS) and malondialdehyde (MDA) levels, mitochondrial membrane potential (∆Ψm), and antioxidant enzyme activity were assayed to assess hematological parameters and the antioxidant defense mechanism. Results showed a remarkable decrease in Hb concentration with increasing nitrite concentration after a 24-h exposure, while the MetHb concentration increased significantly in nitrite exposure groups. The levels of ROS, ∆Ψm, and MDA increased to varying degrees with increases in nitrite exposure concentration and time. The total antioxidant capacity, catalase (CAT) activity, glutathione peroxidase (GPx) activity, and glutathione content showed a trend of rising initially and then decreasing with prolonged exposure time. Superoxide dismutase (SOD) activity was higher in the 1-mg/L nitrite exposure group and lower in the 100-mg/L group than in the control. The relative messenger RNA expression ratios of cat, sod1, and gpx were up-regulated significantly in the 1- and 10-mg/L groups and then declined in the 100-mg/L group. Therefore, it can be concluded that nitrite exposure activates the antioxidant defense mechanism of Grass Carp hemocytes and that the balance of oxidant-antioxidant homeostasis will be undermined by higher nitrite doses or longer exposure periods.

Anti-CD47 antibody synergizes with cisplatin against laryngeal cancer by enhancing phagocytic ability of macrophages.

Cisplatin is mainly used in late-stage or recurrent laryngeal cancer patients. However, the effect of the chemotherapy is limited due to cisplatin resistance. Therefore, we explored the synergized role of immunosuppressive mediator with cisplatin in laryngeal cancer. Cancer cells isolated from tissues of patients with laryngeal cancer were treated with cisplatin to screen the potential immunosuppressive mediator, whose synergized effects with cisplatin were explored both in vivo and in vitro. CD47 was selected for its high expression in cisplatin-treated laryngeal cancer cells. Blocking CD47 expression using its neutralizing antibody (aCD47) synergized with cisplatin to increase macrophage phagocytosis in a co-culture system of human epithelial type 2 (Hep-2) cancer cells with tumor-associated macrophages (TAMs). Moreover, aCD47 together with cisplatin prevented tumor growth by inhibiting proliferation of cancer cells and the secretion of proinflammatory cytokines, as well as by inducing the apoptosis of cancer cells and phagocytosis of TAMs in a Hep-2-implanted mouse tumor model. aCD47 synergized with cisplatin against laryngeal cancer by enhancing the phagocytic ability of TAMs, and the combined therapy of cisplatin and aCD47 might serve as a novel therapeutic strategy against laryngeal cancer.

Dose adjustment of follicle-stimulating hormone (FSH) during ovarian stimulation as part of medically-assisted reproduction in clinical studies: a systematic review covering 10 years (2007-2017).

BACKGROUND: Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. METHODS: We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in < 10% of patients; otherwise, a normal approximation method was used. RESULTS: Initially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively. CONCLUSIONS: This systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%.

Association between gestational weight gain in women with gestational diabetes mellitus and adverse pregnancy outcomes: a retrospective cohort study.

BACKGROUND: To examine association between gestational weight gain (GWG) in women with gestational diabetes mellitus (GDM) and adverse pregnancy outcomes (APOs). METHODS: This retrospective cohort study enrolled women with GDM who delivered at 2010-2020 in Changzhou, Jiangsu. Total GWG, rates of GWG in second trimester and third trimesters were stratified into three categories according to IOM guidelines: within, below, and above IOM guidelines. Univariable and multivariable logistic regression analyses were used. RESULTS: Overall, 1606 women with GDM fulfilled inclusion criteria. Compared with within IOM guidelines and after adjusting for confounders, total GWG above IOM guidelines in pregnancy was associated with an increased odds of caesarean delivery [adjusted odds ratio (aOR) = 1.34, 95% confidence interval (CI): 1.04-1.72], hypertensive disorders of pregnancy (HDP) (aOR = 2.00, 1.28-3.12), preeclampsia (aOR = 2.06, 1.01-3.12), macrosomia (aOR = 1.55, 1.13-2.13) and large for gestational age (LGA) (aOR = 2.82, 1.94-3.23), and a decreased odds of premature rupture of membrane (PROM) (aOR = 0.46, 0.36-0.60) and preterm birth (aOR = 0.35, 0.26-0.44); total GWG below IOM guidelines in pregnancy was associated with an increased risk of preterm birth (aOR = 1.96, 1.44-2.66), small for gestational age (SGA) (aOR = 1.32, 1.11-1.50) and a decreased odds of macrosomia (aOR = 0.35, 0.23-0.53) and LGA (aOR = 0.54, 0.42-0.72). Further, in both second and third trimesters of pregnancy, rates of GWG above IOM guidelines was found to be associated with a high odds of HDP (aOR = 2.55, 1.86-3.38; aOR = 1.93, 1.08-2.98), preeclampsia (aOR = 2.28, 1.21-3.81; aOR = 2.17, 1.35-4.37), macrosomia (aOR = 1.20, 1.02-1.82; aOR = 2.02, 1.51-2.64) and LGA (aOR = 1.42, 1.24-1.97; aOR = 1.79, 1.51-2.54). Rates of GWG above IOM guidelines in third trimester of pregnancy also increased odds of caesarean delivery (aOR = 1.48, 1.16-2.34) when compared with within IOM guidelines. While rates of GWG below IOM guidelines in both second and third trimesters of pregnancy was associated with a decreased odds of macrosomia (aOR = 0.66, 95% CI: 0.52-0.78; aOR = 0.52, 0.39-0.63) and LGA(aOR = 0.71, 0.51-0.82; aOR = 0.67, 0.55-0.79). In addition, rate of GWG below IOM guidelines in third trimester of pregnancy was associated with an increased odds of preterm birth (aOR = 1.52, 1.12-2.05) and SGA (aOR = 1.21, 1.10-1.69). CONCLUSION: GWG, outside IOM guidelines has increased risks of APOs among women with GDM, implying that careful surveillance for GWG during different stages of pregnancy is warranted.

Preclinical Antimalarial Combination Study of M5717, a Plasmodium falciparum Elongation Factor 2 Inhibitor, and Pyronaridine, a Hemozoin Formation Inhibitor.

Antimalarial drug resistance in the Plasmodium falciparum parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing the targeted parasitological and clinical profile of the final drug product. Here, we have studied the combination of M5717, a P. falciparum translation elongation factor 2 inhibitor, and pyronaridine, an inhibitor of hemozoin formation. Our test cascade consisted of in vitro isobolograms as well as in vivo studies in the P. falciparum severe combined immunodeficient (SCID) mouse model. We also analyzed pharmacokinetic and pharmacodynamic parameters, including genomic sequencing of recrudescent parasites. We observed no pharmacokinetic interactions with the combination of M5717 and pyronaridine. M5717 did not negatively impact the rate of kill of the faster-acting pyronaridine, and the latter was able to suppress the selection of M5717-resistant mutants, as well as significantly delay the recrudescence of parasites both with suboptimal and optimal dosing regimens.

Diffusion behavior of peptide amphiphiles containing different numbers of alkyl tails at a hydrophobic solid-liquid interface: single molecule tracking investigation.

Using the single molecule tracking technique, the diffusion behavior of peptide amphiphiles (PAs) with different numbers of alkyl tails at a hydrophobic solid-liquid interface has been investigated. The effect of the number of alkyl tails of PAs on molecular trajectories at the hydrophobic solid-liquid interface has been systematically studied. PA molecules display an intermittent motion consisting of immobilization and hopping processes, which has been well simulated by the continuous time random walk (CTRW) model. The results reveal that the hydrophobic interaction between the PAs and hydrophobic surface plays an important role in the diffusion behavior of PAs. Increasing the number of alkyl tails in PAs systematically reduces the mobility of PAs on the hydrophobic surface. Moreover, the diffusion behavior of PAs at the hydrophobic interface also shows pH dependence. A decrease in pH is beneficial to the motion of all PAs on the hydrophobic surface, which can be ascribed to the protonation of PAs in acidic solutions. Therefore, the hydrophobic interaction is crucial to the transport of peptide amphiphiles at hydrophobic interfaces which would be important for the design of peptides in biological applications.

Genetic Risk Prediction of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. METHODS: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10-3 to <1×10-8 in a prior independent genetic association study. RESULTS: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10-4) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01). CONCLUSIONS: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.