A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects.

Background: Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects. Methods: Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1-6 and once in the morning on day 7. Results: Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure. Conclusion: Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone. Clinical Trial Registration: clinicaltrials.gov, identifier CXHL1900206.

The effect of different drying temperatures on flavonoid glycosides in white tea: A targeted metabolomics, molecular docking, and simulated reaction study.

Drying is an important stage used to improve the quality of white tea (WT). However, the effect of the drying temperature on the key taste compounds in WT remains unclear. In this study, targeted metabolomics, molecular docking, and a simulated reaction were used to investigate the transformation mechanism of flavonoid glycosides (FGs) in WT during drying at 60, 80, and 100 °C and its impact on taste. There were 45 differential FGs in WT at three drying temperatures. Compared with the withering samples for 48 h, the total FGs contents at three drying temperatures showed a decreasing trend, with quercetin-3-O-galactoside and kaempferol-3-O-glucoside showing the most degradation. These results were confirmed via a simulated drying reaction of FGs standards. Drying at 80 and 100 °C contributed to the formation of flavonoid-C-glycosides, but only trace amounts of these compounds were observed. In addition, nine key taste FGs were selected using dose-over-threshold values. These FGs regulated the taste of WT, mainly by binding to taste receptors via hydrogen bond, hydrophobic and electrostatic interactions. Finally, the taste acceptability of WT dried at 60 °C was found to be the highest, as this method could properly reduce the contents of FGs, weaken the bitterness and astringency, and retain the sweet and umami taste. This study revealed for the first time the transformation mechanism of sensory-active FGs affected by drying temperature, which provides a novel perspective for the analysis of the formation mechanism of the unique flavor of WT and the optimization of this process.

Atmospheric organic nitrogen deposition around the Danjiangkou Reservoir: Fluxes, characteristics and evidence of agricultural source.

Dissolved organic nitrogen (DON) deposition was the substantial component of dissolved total nitrogen (DTN) deposition in the world's nitrogen deposition hot spots areas. However, the information on the importance for DON deposition and its sources was still scarce, which limited the comprehensive assessment of the ecological threat from nitrogen deposition. Six sampling sites around the Danjiangkou Reservoir were set up to collect the dry and wet deposition samples from October 2017 to September 2021. The results showed that dry and wet DTN deposition averaged 34.72 kg ha-1 yr-1 and 22.27 kg ha-1 yr-1, respectively. Dry NH4+-N, NO3--N and DON deposition averaged 14.28 kg ha-1 yr-1, 5.91 kg ha-1 yr-1 and 14.53 kg ha-1 yr-1, respectively. Wet NH4+-N, NO3--N and DON deposition averaged 11.14 kg ha-1 yr-1, 3.89 kg ha-1 yr-1and 7.24 kg ha-1 yr-1, respectively. The contributions of DON to DTN were 41.85% (in dry deposition) and 32.50% (in wet deposition), respectively. Dry DON deposition varied between 26.44 kg ha-1 yr-1 and 9.11 kg ha-1 yr-1, and significantly differed among six sampling sites (P < 0.05). The different intensity of agricultural activities disturbance at the sampling sites was the important reason for the spatial variations of DON deposition. DON deposition was significantly correlated with ammonium nitrogen (NH4+-N) deposition (P < 0.05). According to the results of positive matrix factorization (PMF) model, agriculture source contributed significantly to the DON deposition, the contributions at six sampling sites ranged from 45.8% to 73.7% in dry deposition, and from 56.8% to 81.6% in wet deposition. In summary, our findings found that agricultural activities were the important factors influencing the spatial patterns of DON deposition around Danjiangkou Reservoir and provided new evidence for the anthropogenic source of DON deposition in China.

Antibody responses to SARS-CoV-2 Omicron infection in patients with hematological malignancies: A multicenter, prospective cohort study.

Little is known about antibody responses to natural Omicron infection and the risk factors for poor responders in patients with hematological malignancies (HM). We conducted a multicenter, prospective cohort study during the latest Omicron wave in Chongqing, China, aiming to compare the antibody responses, as assessed by IgG levels of anti-receptor binding domain of spike protein (anti-S-RBD), to Omicron infection in the HM cohort (HMC) with healthy control cohort (HCC), and solid cancer cohort (SCC). In addition, we intend to explore the risk factors for poor responders in the HMC. Among the 466 HM patients in this cohort, the seroconversion rate was 92.7%, no statistically difference compared with HCC (98.2%, p = 0.0513) or SCC (100%, p = 0.1363). The median anti-S-RBD IgG titer was 29.9 ng/mL, significantly lower than that of HCC (46.9 ng/mL, p < 0.0001) or SCC (46.2 ng/mL, p < 0.0001). Risk factors associated with nonseroconversion included no COVID-19 vaccination history (odds ratio [OR] = 4.58, 95% confidence interval [CI]: 1.75-12.00, p = 0.002), clinical course of COVID-19 ≤ 7 days (OR = 2.86, 95% CI: 1.31-6.25, p = 0.008) and severe B-cell reduction (0-10/µL) (OR = 3.22, 95% CI: 1.32-7.88, p = 0.010). Risk factors associated with low anti-S-RBD IgG titer were clinical course of COVID-19 ≤ 7 days (OR = 2.58, 95% CI: 1.59-4.18, p < 0.001) and severe B-cell reduction (0-10/µL) (OR = 2.87, 95% CI: 1.57-5.24, p < 0.001). This study reveals a poor antibody responses to Omicron (BA.5.2.48) infection in HM patients and identified risk factors for poor responders. Highlights that HM patients, especially those with these risk factors, may be susceptible to SARS-CoV-2 reinfection, and the postinfection vaccination strategies for these patients should be tailored. Clinical trial: ChiCTR2300071830.

Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects.

BACKGROUND AND OBJECTIVE: TG103 is a novel GLP-1/Fc fusion protein, developed for the treatment of type 2 diabetes and obesity. This trial was designed to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles after single ascending dose of TG103 in healthy Chinese subjects. METHOD: In this double-blind, randomized, placebo-controlled phase I study, Chinese healthy subjects were admitted consecutively to TG103 3 mg, 7.5 mg, 15 mg, and 22.5 mg group with 8 subjects per group and randomized in a 3:1 ratio to receive TG103 treatment or placebo. Following a single subcutaneous(s.c.) injections of TG103, safety and tolerability were evaluated and blood samples were collected for PK and PD analysis at the specified time-points. RESULT: Overall, 32 healthy subjects were enrolled and completed the study. During the study, a total of 84 adverse effects (AEs) were reported in 25 subjects, all were mild or moderate and resolved spontaneously without intervention. The most common treatment related AEs in TG103 group were decreased appetite (41.7%), nausea, flatulence, elevated urinary ß2-microglobulin, increased serum total bile acid (20.8% each), decreased high-density lipoprotein (16.7%), abdominal distension (12.5%). After a single s.c. administration of TG103 3-22.5 mg, the median Tmax was 36∼48 h, and mean t1/2 was about 147.16∼184.72 h. The mean Cmax for each group was 94.35±52.19, 337.67±56.71, 757.67±206.99, 1236.33±666.25 ng/mL, with AUC0-t of 14.93±7.67, 59.15±7.39, 91.79±20.41, 163.61±55.99 µg·h/mL, respectively. It showed a linear pharmacokinetic profile in the single dose of TG103 3 mg to 22.5 mg. Compared with placebo, fasting blood glucose decreased in all dose groups, most notably in the 15 mg group, which was consistent with the changes in blood glucose during OGTT, while 2-hour postprandial glucose decreased in all dose groups except 3 mg group. CONCLUSION: TG103 offers a potential option for hypoglycemic therapy with good tolerability and safety. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03990090; registered 18 June 2019.

A Single-center, Open-label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N-oxide in Healthy Chinese and Caucasian Volunteers.

Roflumilast is a phosphodiesterase-4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N-oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 µg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0-t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0-t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N-oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N-oxide, respectively. Total phosphodiesterase-4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N-oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10-fold higher plasma AUC compared to the parent roflumilast and a much longer observed half-life, roflumilast N-oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 µg daily during future clinical trials.

A Wearable Capsule Endoscope Electromagnetic Localization System Based on a Novel WCL Algorithm.

The wearable localization system for wireless capsule endoscopy (WCE) is a potential technology to realize rapid diagnosis and treatment of the gastrointestinal (GI). However, the electromagnetic localization accuracy of WCE still needs to be improved. In this paper, based on RSSI electromagnetic fading model, the accurate fitting parameter values are obtained by Kalman filter and the least square method. A novel weighted centroid localization (WCL) algorithm based on exponential weights is proposed, which can achieve high-accuracy localization by using only sparse reception matrix. The simulation results show that when the standard deviation of the localization data is 7.85, the localization root mean square error (RMSE) is 25.4 mm; when the standard deviation of the localization data is 5.475, the localization RMSE is 2.5 mm. These two localization RMSEs are 38% and 79% less than those of the conventional centroid localization algorithm, respectively. An experimental platform of wearable wireless communication and localization system using 24 array receiving antennas is developed in human phantom environment. The experimental results show that the wearable WCE electromagnetic localization system based on the proposed algorithm achieves a localization RMSE of 36.3 mm, which is 17% lower than that of the conventional centroid localization algorithm and meets the needs of clinical diagnosis.

Clinical characteristics and outcomes of newly diagnosed patients with HIV-associated aggressive B-cell NHL in China.

Little is known about the incidence, clinical characteristics and prognostic factors in HIV associated lymphoma as these are less common than HIV-negative lymphoma in China. Currently, there are no standard guidelines for treatment of these patients. Therefore, we performed a study to analyse the clinical characteristics and outcomes of newly diagnosed HIV-associated aggressive B-cell non-Hodgkin's lymphoma (NHL) patients in Chongqing University Cancer Hospital (CUCH). Totally 86 newly diagnosed HIV-associated aggressive B-cell NHL patients in CUCH, southwest China, from July 2008 to August 2021, were analysed. In the entire cohort, median age was 48 years (range, 23-87 years), and more patients were male (87.2%). Most patients had elevated lactate dehydrogenase (LDH) (82.6%), advanced ann arbor stage (80.2%) and high IPI score (IPI score, 3-5) (62.7%) at diagnosis. Median CD4+ T-cell count at diagnosis was 191/µl (range, 4-1022), 84 patients (97.7%) were on combination antiretroviral therapy (cART) at lymphoma diagnosis. In DLBCL patients, cox multivariate analysis showed that age ≥ 60 (HR = 2.251, 95%CI 1.122-4.516; p = 0.012), elevated LDH (HR = 4.452, 95%CI 1.027-19.297; p = 0.041) and received less than two cycles of chemotherapy (HR = 0.629, 95%CI 0.589-1.071; p = 0.012) were independent risk factors for adverse prognosis based on PFS. Age ≥ 60 (HR = 3.162, 95%CI 1.500-6.665; p = 0.002) and received less than two cycles of chemotherapy (HR = 0.524, 95%CI 0.347-0.791; p = 0.002) were also independent risk factor for adverse prognosis based on OS. In BL patients, cox multivariate analysis showed that elevated LDH and received less than two cycles of chemotherapy were independent risk factors for adverse prognosis. In the DLBCL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 12 months, respectively (p = 0.006). Median OS times were not reached and 36 months, respectively (p = 0.021). In the BL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 4.8 months, respectively (p = 0.046). Median OS times were not reached and 10.1 months, respectively (p = 0.035). Overall, these data indicated that standardized anti-lymphoma therapy and rituximab administration were significantly associated with improved outcomes in patients with HIV-associated DLBCL and BL.

Prediction of the Short-Term Therapeutic Effect of Anti-VEGF Therapy for Diabetic Macular Edema Using a Generative Adversarial Network with OCT Images.

PURPOSE: To generate and evaluate individualized post-therapeutic optical coherence tomography (OCT) images that could predict the short-term response of anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME) based on pre-therapeutic images using generative adversarial network (GAN). METHODS: Real-world imaging data were collected at the Department of Ophthalmology, Qilu Hospital. A total of 561 pairs of pre-therapeutic and post-therapeutic OCT images of patients with DME were retrospectively included in the training set, 71 pre-therapeutic OCT images were included in the validation set, and their corresponding post-therapeutic OCT images were used to evaluate the synthetic images. A pix2pixHD method was adopted to predict post-therapeutic OCT images in DME patients that received anti-VEGF therapy. The quality and similarity of synthetic OCT images were evaluated independently by a screening experiment and an evaluation experiment. RESULTS: The post-therapeutic OCT images generated by the GAN model based on big data were comparable to the actual images, and the response of edema resorption was also close to the ground truth. Most synthetic images (65/71) were difficult to differentiate from the actual OCT images by retinal specialists. The mean absolute error (MAE) of the central macular thickness (CMT) between the synthetic OCT images and the actual images was 24.51 ± 18.56 µm. CONCLUSIONS: The application of GAN can objectively demonstrate the individual short-term response of anti-VEGF therapy one month in advance based on OCT images with high accuracy, which could potentially help to improve treatment compliance of DME patients, identify patients who are not responding well to treatment and optimize the treatment program.

Types and Distribution of Organic Amines in Organic Nitrogen Deposition in Strategic Water Sources.

Organic nitrogen (ON) is an important part of atmospheric nitrogen deposition, but the content and distribution of components other than urea and amino acids are the blind area of current research. The deposition of organic amines (OA) in strategic water sources poses a great public health risk to unspecified populations. In order to further reveal the composition of about 50% soluble organic nitrogen, besides urea and amino acids, five functional sampling points (such as industrial area, agricultural area, urban area, tourism area and forest area) were set in the reservoir area to detect dissolved total nitrogen (DTN), dissolved organic nitrogen (DON) and OA components. The results show that the total nitrogen concentration was 6.42-10.82 mg/m3 and the DON concentration was 2.77-4.99 mg/m3. Ten kinds of OA were detected: dimethylamine (DMA), diethylamine (DEA), propylamine (PA), butylamine (BA), pyrrolidine (PYR), dibutylamine (DBA), N-methylaniline (NMA), 2-ethylaniline (2-ELA), benzylamine (BMA), and 4-ethylaniline (4-ELA). The average concentrations were 7.64, 26.35, 14.51, 14.10, 18.55, 7.92, 10.56, 12.84, 13.46 and 21.00 ng/m3, respectively. The total concentration of ten OA accounted for 2.28-9.81% of DON in the current month, of which the content of DEA was the highest, reaching 0.71%, the content of 4-ELA, PYR, PA and BA was 0.4-0.56%, and the content of DMA, DBA and NMA was 0.2-0.36%. The sources of OA in the reservoir area have significant seasonal differences. The content is the highest in spring, followed by autumn, and lower in summer and winter. The rainfall in spring and autumn is small, the source of road dust is relatively high, and the rainfall in summer is large. After the particles in the air are washed by rain, the concentration of OA in the sample is the lowest. On account of spring and autumn being the time of frequent agricultural activities, the concentration of OA is significantly higher than that in winter and summer.

Safety Enhancement by Optimizing Frequency of Implantable Cardiac Pacemaker Wireless Charging System.

Wireless charging devices for implantable cardiac pacemakers have not been clinically applied. For actual applications, safety assessments of a wireless charging system must be conducted. For systems with a certain power, frequency is one of the important factors that directly affect safety. This paper aims to study the safety evaluation method and optimal operation frequency of a cardiac pacemaker wireless charging system. The wireless power transfer (WPT) model considering the coils' AC resistance is established, which is more in line with the actual situation. The analytical solution to the current in coupling coils is derived, which reveals the effect of the frequency. The currents used in electromagnetic and thermal simulations are calculated or measured for different charging prototypes. A safety evaluation method that comprehensively considers specific absorption rate (SAR), electric field, efficiency, temperature rise and electromagnetic interference (EMI) is proposed. In particular, the temperature rise is an innovative perspective as it has rarely been studied in previous literatures. The optimal frequency of a 3 W wireless charging system for cardiac pacemaker is determined based on the results of safety evaluation. The theoretical temperature rise reaches the minimum at 203 kHz, and the theoretical energy loss reaches the minimum at 260 kHz. The comfort and safe frequency band is approximately from 150 kHz to 370 kHz based on theoretical and experimental results, and the optimal frequency band from 200 kHz to 300 kHz is recommended.

Atmospheric Organic Nitrogen Deposition in Strategic Water Sources of China after COVID-19 Lockdown.

Atmospheric nitrogen deposition (AND) may lead to water acidification and eutrophication. In the five months after December 2019, China took strict isolation and COVID-19 prevention measures, thereby causing lockdowns for approximately 1.4 billion people. The Danjiangkou Reservoir refers to the water source in the middle route of South-to-North Water Diversion Project in China, where the AND has increased significantly; thus, the human activities during the COVID-19 period is a unique case to study the influence of AND to water quality. This work monitored the AND distribution around the Danjiangkou Reservoir, including agricultural, urban, traffic, yard, and forest areas. After lockdown, the DTN, DON, and Urea-N were 1.99 kg · hm-2 · month-1, 0.80 kg · hm-2 · month-1, and 0.15 kg · hm-2 · month-1, respectively. The detected values for DTN, DON, and Urea-N in the lockdown period decreased by 9.6%, 30.4%, and 28.97%, respectively, compared to 2019. The reduction in human activities is the reason for the decrease. The urban travel intensity in Nanyang city reduced from 6 to 1 during the lockdown period; the 3 million population which should normally travel out from city were in isolation at home before May. The fertilization action to wheat and orange were also delayed.

Evaluation of a five-gene signature associated with stromal infiltration for diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin lymphoma. The development of immunotherapy greatly improves the patient prognosis but there are some exceptions. Thus, screening for better biomarkers for prognostic evaluation could contribute to the treatment of DLBCL patients. AIM: To screen the novel mediators involved in the development of DLBCL. METHODS: The GSE60 dataset was applied to identify the differentially expressed genes (DEGs) in DLBCL, and the principal components analysis plot was used to determine the quality of the included samples. The protein-protein interactions were analyzed by the STRING tool. The key hub genes were entered into to the GEPIA database to determine their expressions in DLBCL. Furthermore, these hub gene alterations were analyzed in cBioportal. The UALCAN portal was employed to analyze the expression of the hub genes in different stages of DLBCL. The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Score was conducted to evaluate the correlation between the gene expression and tumor purity. The gene-gene correlation analysis was conducted in the GEPIA. The stromal score analysis was conducted in TIMER to confirm the correlation between the gene expression and infiltrated stromal cells. The correlation between the indicated genes and infiltration level of cancer-associated fibroblasts (CAFs) was also completed in TIMER with two methods, MCP-Counter and Tumor immune dysfunction and exclusion. The correlation between fibronectin (FN1) protein level and secreted protein acidic and cysteine-rich (SPARC) messenger ribonucleic acid expression was confirmed in the cBioportal. RESULTS: The top 20 DEGs in DLBCL were identified, and the principal components analysis plot confirmed the quality of the significant DEGs. The pairwise correlation coefficient analysis among all samples showed that these DEGs have a certain co-expression pattern. The DEGs were subjected to STRING to identify the hub genes, alpha-2-macroglobulin (A2M), cathepsin B (CTSB), FN1, matrix metallopeptidase 9 (MMP9), and SPARC. The five hub genes were confirmed to be overexpressed in DLBCL. The cBioportal portal detected these five hub genes that had gene alteration, including messenger ribonucleic acid high amplification and missense mutation, and the gene alteration percentages of A2M, FN1, CTSB, MMP9, and SPARC were 5%, 8%, 5%, 2.7%, and 5%, respectively. Furthermore, the five hub genes had a potential positive correlation with tumor stage. The correlation analysis between the five genes and tumor purity confirmed that the five genes were overexpressed in DLBCL and had a positive correlation with the development of DLBCL. More interestingly, the five genes had a significant correlation with the stromal infiltration scores. The correlation analysis between the fives genes and CAFs also showed a significant value, among which the top two genes, FN1 and SPARC, had a remarkable co-expression pattern. CONCLUSION: The top DEGs were identified, and the five hub genes were overexpressed in DLBCL. Furthermore, the gene alterations were confirmed and the positive correlation with tumor purity revealed the overexpression of the five genes and close association with the development of DLBCL. More interestingly, the five genes were positively correlated with stromal infiltration, especially in CAFs. The top two genes, FN1 and SPARC, showed a co-expression pattern, which indicates their potential as novel therapeutic targets for DLBCL.

Fano resonance sensing based on coupling of a sub-wavelength grating and an all-dielectric multilayer film under angle modulation.

Based on the diffraction effect of the waveguide grating, a hybrid structure of an all-dielectric multilayer film and a sub-wavelength dielectric grating is proposed. The discrete state provided in the sub-wavelength waveguide grating couples with the continuous state provided in the Fabry-Perot cavity (F-P cavity) containing the photonic crystal to form a Fano resonance. The relationship between the structural parameter and the incident angle is analyzed by numerical simulation. The result shows that the figure of merit (FOM) value is 533.2RIU-1. This structure provides an effective theoretical basis for the realization of Fano resonance in the all-dielectric sensing structure.

miR-744-5p Inhibits Multiple Myeloma Proliferation, Epithelial Mesenchymal Transformation and Glycolysis by Targeting SOX12/Wnt/ß-Catenin Signaling.

PURPOSE: This study investigated the function and molecular mechanisms of miR-744-5p in multiple myeloma (MM). METHODS: miR-744-5p and SRY-related high-mobility-group box 12 (SOX12) expression in clinical tissues and MM cells was monitored by quantitative real-time polymerase chain reactions and Western blot. miR-744-5p expression in MM cells was regulated by transfection. Cell proliferation was researched by cell counting kit-8 assay and plate clone formation experiment. Transwell experiment was utilized for migration and invasion detection. Glycolysis test was conducted for the detection of glucose uptake and lactate production of MM cells. The relationship between miR-744-5p and SOX12 was determined by dual-luciferase reporter gene assay and RNA pull-down experiment. In vivo experiment was conducted using nude mice. RESULTS: miR-744-5p expression was reduced in MM patients (P<0.01). Low miR-744-5p expression was associated with lower 60-month survival in MM patients (P=0.0402). miR-744-5p overexpression inhibited MM cells proliferation, invasion, migration, glucose uptake, lactate production, and epithelial mesenchymal transformation (EMT) (P<0.01). miR-744-5p directly inhibited SOX12 expression. miR-744-5p silencing promoted MM cells proliferation, invasion, migration, glucose uptake, lactate production, and EMT by elevating SOX12 (P<0.01). miR-744-5p inhibited the growth of MM xenograft tumors in vivo (P<0.001). CONCLUSION: miR-744-5p inhibits MM cells proliferation, invasion, migration, EMT, and glycolysis by targeting SOX12/Wnt/ß-catenin.

Sintilimab as salvage treatment in an HIV patient with relapsed/refractory Hodgkin: a case report.

The prognosis of relapsed/refractory classical Hodgkin lymphoma companied with Human immunodeficiency virus (R/R HIV-cHL) is poor due to insufficient effective treatments. Nowadays, immune checkpoint blockade is an important new treatment option for patients with relapsed/refractory classical Hodgkin lymphoma (cHL), but rare cases have been reported in R/R HIV-cHL. We present a case of R/R HIV-cHL young patient, who has been successfully treated with sintilimab without significant side effects. In May 2018, we received an Hodgkin lymphoma companied with Human immunodeficiency virus (HIVcHL) patient. At first, we gave him ABVD regime chemotherapy. In April 2019, after 6 cycles of ABVD and radiation, we evaluated the effect of treatment and found that the disease actually progressed. The patient refused auto stem cell transplant, so the second line GDP regime chemotherapy was administrated. After five cycles of the treatment, in September 2019, a PET-CT examination found a new emerging enlargement lymph node in the retroperitoneum and with an elevated SUV. In October 2019, after obtaining the patient's consent, we gave him PD-1 immune checkpoint treatment. And 9 cycles later, PET-CT showed that the enlargement lymph node found last time in the retroperitoneum had disappeared completely, with no other lesions were found. All the courses of treatment went through smoothly, and no severe toxicity happened. Immune checkpoint blockade is successful in R/R HIV-cHL, the toxicities are mild and accepted.

The Signal Transducer and Activator of Transcription 5B (STAT5B) Gene Promotes Proliferation and Drug Resistance of Human Mantle Cell Lymphoma Cells by Activating the Akt Signaling Pathway.

BACKGROUND Mantle cell lymphoma (MCL) is a high-grade B-cell lymphoma with poor prognosis. Fludarabine is used alone or in combination for relapsed and advanced-stage MCL. The expression of the signal transducer and activator of transcription 5B (STAT5B) gene is associated with tumorigenesis in solid tumors, but its role in MCL remains unknown. The aims of this study were to investigate the role of STAT5B in GRANTA-519 human mantle cell lymphoma cells and drug resistance. MATERIAL AND METHODS GRANTA-519 human mantle cell lymphoma cells were cultured with and without 10 µM fludarabine dephosphorylated 9-ß-D-arabinofuranosyl-2-fluoroadenine, (2-F-araA) or 10 µM 4-hydroperoxycyclophosphamide (4-HC). The MTT assay assessed cell proliferation. Flow cytometry was used to investigate the cell cycle in MCL cells treated with the specific inhibitor of the Akt pathway, LY294002, and assessed cell cycle and cell apoptosis. Western blot was used to detect the expression levels of p-Akt/Akt and STAT5B/p-STAT5B. The gene expression profiles of lymph node (LN)-derived MCL cells were compared with peripheral blood (PB)-derived lymphocytes using bioinformatics and hierarchical cluster analysis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine the expression of the marker of proliferation Ki-67 (MKI67) gene. RESULTS STAT5B was significantly upregulated in LN-derived MCL cells compared with PB lymphocytes. Increased expression of STAT5B was associated with increased MCL cell proliferation and reduced cell apoptosis and was associated with drug resistance and activation of Akt. CONCLUSIONS STAT5B promoted cell proliferation and drug resistance in human MCL cells by activating the Akt signaling pathway.

Long intergenic noncoding RNA-p21 inhibits apoptosis by decreasing PUMA expression in non-small cell lung cancer.

OBJECTIVE: Long noncoding RNAs (lncRNAs) are important mediators in tumor progression. Long intergenic noncoding RNA-p21 (lincRNA-p21) participates in multiple biological processes. This study explored the role of lincRNA-p21 in human non-small cell lung cancer (NSCLC) progression and potential regulatory mechanisms. METHODS: LincRNA-p21 expression in NSCLC tissues and cell lines (A549, H1299, H1650, and NCI-H2087) was determined by quantitative real-time PCR. LincRNA-p21 overexpressing and sh-lincRNA-p21 lentiviral were respectively transfected into H1299 and A549 cells. Flow cytometry was used to measure apoptosis. Microarray analysis and RNA pull-down assay were used to predict the target genes of lincRNA-p21. Finally, PUMA siRNA and overexpressing PUMA were transfected into NSCLC cells, and the extent of cell apoptosis was measured. The protein expression levels of the relative genes were confirmed by western blot analysis. RESULTS: LincRNA-p21 was significantly upregulated in NSCLC tissues and cells. The upregulation of lincRNA-p21 considerably inhibited cell apoptosis while the downregulation of lincRNA-p21 showed the opposite effect. PUMA was a direct target gene of lincRNA-p21 and was negatively correlated with lincRNA-p21 in NSCLC specimens. The anti-apoptotic effect of lincRNA-p21 can be effectively attenuated by the upregulation of PUMA. CONCLUSION: LincRNA-p21 is aberrantly upregulated in NSCLC and inhibits cell apoptosis by decreasing PUMA expression.

Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system.

BACKGROUND: Application of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo. METHODS: Human DC and CIK were generated from peripheral blood mononuclear cells (PBMCs) taken from consenting liver cancer patients. Flow cytometry was used to determine the phenotypes of DC and CIK, and cell proliferation. The tumor growth and anti-tumor activity of these cells were further evaluated using a nude mouse tumor model. RESULTS: We demonstrated that DC and CIK significantly enhanced the apoptosis ratio, depending on DC-CIK cell numbers, by increasing caspase-3 protein expression and reducing proliferating cell nuclear antigen (PCNA) protein expression against LCSC. The in vivo data indicated that DC-CIK exhibited significant LCSC cell-induced tumor growth inhibition in nude mice, which was most significant with LCSC antigen loaded DCs. CONCLUSIONS: The results showed, that DC-CIK cells could inhibit HCC and LCSC growths in vitro and in vivo and the most successful DC triggering of cell cytotoxic activity could be achieved by their LCSC antigen loading.

Effect of Sewage Irrigation on the CT-Measured Soil Pore Characteristics of a Clay Farmland in Northern China.

Sewage irrigation has a strong influence on the physical, chemical, and biological properties of soil. However, the effects of sewage irrigation on the pore characteristics of soil are not well understood. This study compares the effects of sewage irrigation and groundwater irrigation on computed tomography (CT)-measured pore parameters and examines the relationships between CT-measured pore parameters and soil physicochemical and microbial properties. Intact soil cores were collected from S1 irrigated with sewage for 25 years, S2 irrigated with sewage for 52 years, and CK irrigated with groundwater. Various soil pore characteristics were determined, including the total pore number, macropore number (>1 mm diam.), coarse mesopore number (0.264⁻1 mm diam.), total porosity, macroporosity, coarse mesoporosity, and circularity. The results indicated that sewage irrigation significantly affected soil pore number and porosity. Compared with S1 and S2, CK exhibited a higher average total pore number (91), macropore number (40), coarse mesopore number (51), total porosity (2.08%), macroporosity (1.90%), and coarse mesoporosity (0.18%) throughout the 50⁻350 mm layer. At depths of 200⁻350 mm, S2 exhibited the lowest average total pore number (33), macropore number (13), coarse mesopore number (21), total porosity (0.42%), macroporosity (0.35%), and coarse mesoporosity (0.07%) among the three sites. In addition, the average pore numbers and porosity at depths of 200⁻350 mm decreased with increasing sewage irrigation time. There were significant positive correlations between pore features (including pore numbers and porosity) and soil properties (phosphorus content and fungi numbers). Our results suggest that decreased macropore numbers and macroporosity in the sewage-irrigated farmland may strongly intensify the accumulation of metals and nutrients in the upper layer. The findings of this study are useful for understanding the negative effects of sewage irrigation on soil pore structure and are critical for developing sustainable strategies in agriculture.