Comparative Analysis of Adaptive Changes in Immunoendocrine and Physiological Responses to High-Intensity Sprint Interval Training with Progressive and Nonprogressive Loads in Young Wrestlers.

The objective of this study was to explore the effects of a 7-week short sprint interval training (SSIT) with differing in programming volume-loads including progressive (P-SSIT) and nonprogressive (NP-SSIT) approaches on the immunoendocrine, physical fitness attributes and physiological parameters in male wrestlers during the pre-season. Thirty young freestyle wrestlers at the collegiate national-level were included in the study and were divided into three groups: P-SSIT (n = 10), NP-SSIT (n = 10), and an active control group (n = 10). The wrestlers engaged in their specific wrestling training three days weekly, while the P-SSIT and NP-SSIT groups underwent a 7-week SSIT, with scheduling in either progressed or nonprogressed volume-based overloads, three times per week. Before and after the intervention, various aspects of physical fitness (such as 20-m sprint, 4×9-m shuttle run, and maximal strength) and physiological parameters (including cardiorespiratory fitness and anaerobic power output), as well as immunoendocrine responses (such as immunoglobulin-A, testosterone, and cortisol) were measured. Following the training intervention, the control group did not show any significant changes in the variable measured; however, both the P-SSIT and NP-SSIT groups experienced significant improvements (p = 0.001) in physical fitness attributes and physiological parameters with effect sizes ranging from small to very large, and also more adaptive responses compared with control group (p < 0.05). In addition, there were no statistically significant changes observed among the P-SSIT and NP-SSIT groups in terms of immunoendocrine response to training, and physical fitness, as well as physiological parameters (p > 0.05). In conclusion, neither the progressed nor nonprogressed approaches of SSIT demonstrated superior effects on adaptations compared to one another. Therefore, it is recommended for strength and conditioning coaches in wrestling to incorporate both P-SSIT and NP-SSIT into their annual training plan, especially during the pre-season phase, to maximize the physical fitness and physiological parameters of their wrestlers while minimizing changes in immunoendocrine responses.

Intratumoral immune heterogeneity of prostate cancer characterized by typing and hub genes.

Discordant abundances of different immune cell subtypes is regarded to be an essential feature of tumour tissue. Direct studies in Prostate cancer (PC) of intratumoral immune heterogeneity characterized by immune cell subtype, are still lacking. Using the single sample gene set enrichment analysis (ssGSEA) algorithm, the abundance of 28 immune cells infiltration (ICI) were determined for PC. A NMF was performed to determine tumour-sample clustering based on the abundance of ICI and PFS information. Hub genes of clusters were identified via weighted gene co-expression network analysis (WGCNA). The multivariate dimensionality reduction analysis of hub genes expression matrix was carried out via principal component analysis (PCA) to obtain immune score (IS). We analysed the correlation between clustering, IS and clinical phenotype. We divided the 495 patients into clusterA (n = 193) and clusterB (n = 302) on the basis of ICI and PFS via NMF. The progression-free survival (PFS) were better for clusterA than for clusterB (p < 0.001). Each immune cell subtypes was more abundant in clusterA than in clusterB (p < 0.001). The expression levels of CTAL-4 and PD-L1 were lower in clusterB than in clusterA (p < 0.001 and p = 0.006). We obtained 103 hub genes via WGCNA. In the training and validation cohorts, the prognosis of high IS group was worse than that of the low IS group (p < 0.05). IS had good predictive effect on 5-year PFS. The expression of immune checkpoint genes was higher in the low IS group than in the high IS group (p < 0.01). Patients with low IS and receiving hormone therapy had better prognosis than other groups. The combination of IS and clinical characteristics including lymph node metastasis and gleason score can better differentiate patient outcomes than using it alone. IS was a practical algorithm to predict the prognosis of patients. Advanced PC patients with low IS may be more sensitive to hormone therapy. CXCL10, CXCL5, MMP1, CXCL12, CXCL11, CXCL2, STAT1, IL-6 and TLR2 were hub genes, which may drive the homing of immune cells in tumours and promote immune cell differentiation.

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Dihydroartemisinin ameliorates chronic nonbacterial prostatitis and epithelial cellular inflammation by blocking the E2F7/HIF1α pathway.

OBJECTIVE: Chronic nonbacterial prostatitis (CNP) has remained one of the most prevalent urological diseases, particularly in older men. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the role of DHA in inhibiting CNP inflammation and prostatic epithelial cell proliferation remains largely unknown. MATERIALS AND METHODS: CNP animal model was induced by carrageenan in C57BL/6 mouse. Enzyme linked immunosorbent assay (ELISA), Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to examine inflammatory cytokines and proliferation genes expression. Immunofluorescence and immunochemistry staining were used to detect and E2F7 expression. Human prostatic epithelial cells (HPECs) and RWPE-1 was induced by lipopolysaccharide (LPS) to mimic CNP model in vitro. Cell proliferation was determined using MTS assay. RESULTS: DHA significantly alleviated the rough epithelium and inhibited multilamellar cell formation in the prostatic gland cavity and prostatic index induced by carrageenan. In addition, DHA decreased the expression of TNF-α and IL-6 inflammatory factors in prostatitis tissues and in LPS-induced epithelial cells. Upregulation of transcription factor E2F7, which expression was inhibited by DHA, was found in CNP tissues, human BPH tissues and LPS-induced epithelial cells inflammatory response. Mechanically, we found that depletion of E2F7 by shRNA inhibited epithelial cell proliferation and LPS-induced inflammation while DHA further enhance these effects. Furthermore, HIF1α was transcriptional regulated by E2F7 and involved in E2F7-inhibited CNP and cellular inflammatory response. Interestingly, we found that inhibition of HIF1α blocks E2F7-induced cell inflammatory response but does not obstruct E2F7-promoted cell growth. CONCLUSION: The results revealed that DHA inhibits the CNP and inflammation by blocking the E2F7/HIF1α pathway. Our findings provide new evidence for the mechanism of DHA and its key role in CNP, which may provide an alternative solution for the prevention and treatment of CNP.

MODECP: A Multi-Objective Based Approach for Solving Distributed Controller Placement Problem in Software Defined Network.

Software-Defined Network is an emerging networking paradigm that enables intelligent and flexible network management. Specifically, the design of the control plane is crucial. Therefore, in order to avoid a single point of failure, multiple controllers are deployed constantly in a distributed manner on the control plane. In this paper, we propose a controller placement approach based on multiple objectives (MODECP), including network delay, network security, load-balancing rate, and link occupancy. In the controller placement stage, an improved multi-objective differential evolution algorithm is proposed to search for controllers' positions and assign switches to controllers reasonably. Furthermore, an improved affinity propagation algorithm is proposed to obtain the number of controllers placed in the network partition stage, comprehensively considering the delay, node security, and load. Simulations are performed based on several topologies from Internet Topology Zoo. Extensive results show that the proposed algorithm can realize trade-offs among multiple objectives and improve network performance in delay, security, controller load, and link occupancy compared to the single-objective based approach. Moreover, compared with the genetic algorithm and random placement algorithm, the proposed algorithm performs better with low latency, high security, low load rate, and low link overhead.

Molecular studies on structural changes and oligomerisation of violaxanthin de-epoxidase associated with the pH-dependent activation.

Violaxanthin de-epoxidase (VDE) is a conditionally soluble enzyme located in the thylakoid lumen and catalyses the conversion of violaxanthin to antheraxanthin and zeaxanthin, which are located in the thylakoid membrane. These reactions occur when the plant or algae are exposed to saturating light and the zeaxanthin formed is involved in the process of non-photochemical quenching that protects the photosynthetic machinery during stress. Oversaturation by light results in a reduction of the pH inside the thylakoids, which in turn activates VDE and the de-epoxidation of violaxanthin. To elucidate the structural events responsible for the pH-dependent activation of VDE, full length and truncated forms of VDE were studied at different pH using circular dichroism (CD) spectroscopy, crosslinking and small angle X-ray scattering (SAXS). CD spectroscopy showed the formation of α-helical coiled-coil structure, localised in the C-terminal domain. Chemical crosslinking of VDE showed that oligomers were formed at low pH, and suggested that the position of the N-terminal domain is located near the opening of lipocalin-like barrel, where violaxanthin has been predicted to bind. SAXS was used to generate models of monomeric VDE at high pH and also a presumably dimeric structure of VDE at low pH. For the dimer, the best fit suggests that the interaction is dominated by one of the domains, preferably the C-terminal domain due to the lost ability to oligomerise at low pH, shown in earlier studies, and the predicted formation of coiled-coil structure.

Functional and structural characterization of domain truncated violaxanthin de-epoxidase.

Photosynthetic organisms need protection against excessive light. By using non-photochemical quenching, where the excess light is converted into heat, the organism can survive at higher light intensities. This process is partly initiated by the formation of zeaxanthin, which is achieved by the de-epoxidation of violaxanthin and antheraxanthin to zeaxanthin. This reaction is catalyzed by violaxanthin de-epoxidase (VDE). VDE consists of three domains of which the central lipocalin-like domain has been the most characterized. By truncating the domains surrounding the lipocalin-like domain, we show that VDE activity is possible without the C-terminal domain but not without the N-terminal domain. The N-terminal domain shows no VDE activity by itself but when separately expressed domains are mixed, VDE activity is possible. This shows that these domains can be folded separately and could therefore be studied separately. An increase of the hydrodynamic radius of wild-type VDE was observed when pH was lowered toward the pH required for activity, consistent with a pH-dependent oligomerization. The C-terminally truncated VDE did not show such an oligomerization, was relatively more active at higher pH but did not alter the KM for ascorbate. Circular dichroism measurements revealed the presence of α-helical structure in both the N- and C-terminal domains. By measuring the initial formation of the product, VDE was found to convert a large number of violaxanthin molecules to antheraxanthin before producing any zeaxanthin, favoring a model where violaxanthin is bound non-symmetrically in VDE.

Endoscopic decompression of the optic canal for traumatic optic neuropathy.

PURPOSE: Traumatic optic neuropathy (TON) is a serious complication of head trauma with the incidence rate of 0.5%-5%. The aim of this study was to investigate the therapeutic efficacy of endoscopic decompression of the optic canal for optic nerve injuries. METHODS: In this study, 11 patients treated in our hospital from January 2009 to January 2015 with the visual loss resulting from TON were retrospectively reviewed for preoperative vision, visual evoked potential (VEP) scan, surgical approach, postoperative visual acuity, complications, and follow-up results. RESULTS: All these patients received endoscopic decompression of the optic canal. At the 3-month follow- up, the visual acuity improvement rate of the 11 patients was 45.5%. The vision acuity of 2 cases improved from hand movement to 0.08 and 0.3 after operation. Another patient's vision acuity returned to 0.05 compared to light sensation preoperatively. Two cases had finger counting before surgery but they had a vision acuity of 0.4 and light sensation respectively after surgery. However, the other 6 cases' vision did not improve after surgery. CONCLUSION: Endoscopic decompression of the optic canal is an effective way to cure TON. VEP could be used as an important reference for preoperative and prognosis evaluation. Operative time after trauma is only a relative condition that may affect the therapeutic effect of optic canal decompression. Poor results of this procedure may be related to the severity of the optic nerve injury.

Violaxanthin de-epoxidase disulphides and their role in activity and thermal stability.

Violaxanthin de-epoxidase (VDE) catalyses the conversion of violaxanthin to zeaxanthin at the lumen side of the thylakoids during exposure to intense light. VDE consists of a cysteine-rich N-terminal domain, a lipocalin-like domain and a negatively charged C-terminal domain. That the cysteines are important for the activity of VDE is well known, but in what way is less understood. In this study, wild-type spinach VDE was expressed in E. coli as inclusion bodies, refolded and purified to give a highly active and homogenous preparation. The metal content (Fe, Cu, Ni, Mn, Co and Zn) was lower than 1 mol% excluding a metal-binding function of the cysteines. To investigate which of the 13 cysteines that could be important for the function of VDE, we constructed mutants where the cysteines were replaced by serines, one by one. For 12 out of 13 mutants the activity dropped by more than 99.9%. A quantification of free cysteines showed that only the most N-terminal of these cysteines was in reduced form in the native VDE. A disulphide pattern in VDE of C9-C27, C14-C21, C33-C50, C37-C46, C65-C72 and C118-C284 was obtained after digestion of VDE with thermolysin followed by mass spectroscopy analysis of reduced versus non-reduced samples. The residual activity found for the mutants showed a variation that was consistent with the results obtained from mass spectroscopy. Reduction of the disulphides resulted in loss of a rigid structure and a decrease in thermal stability of 15 °C.

Direct comparison of an inactivated subvirion influenza A virus subtype H5N1 vaccine administered by the intradermal and intramuscular routes.

BACKGROUND: Direct comparisons of similar doses of a novel influenza virus antigen administered by the intradermal route and the intramuscular route have not been reported. METHODS: A total of 227 healthy adults aged 18-49 years were randomized to receive 2 doses 1 month apart of a subvirion inactivated influenza A virus subtype H5N1 (rgA/Vietnam/1203/2004) vaccine containing 38.7 µg of H5N1 hemagglutinin (HA), by the intramuscular route or by the intradermal route using the Mantoux technique. Clinical and serologic responses were assessed. RESULTS: Injection site reactions were more frequent in the intradermal group. Immune responses and the geometric mean titer of serum hemagglutination inhibition and neutralizing antibodies 1 month after receipt of the first dose were similar and low but were significantly higher after 2 doses of vaccine in both groups. CONCLUSIONS: Intramuscular and intradermal delivery of vaccine were both well tolerated. Immune responses after 2 doses of this influenza A/H5N1 HA (38.7 µg) were low and not significantly different when given by the intradermal or intramuscular route. Evaluation of higher dosages, alternative intradermal delivery methods, and the addition of adjuvants will be needed to enhance the immunogenicity of inactivated influenza A/H5N1 vaccines by the intradermal route. CLINICAL TRIALS REGISTRATION: NCT00439335.

Dihydroartemisinin ameliorated the inflammatory response and regulated miRNA-mRNA expression profile of chronic nonbacterial prostatitis.

BACKGROUND: Chronic nonbacterial prostatitis (CNP) is a chronic inflammatory disease. Patients often have trouble urinating, experience painful and frequent urination, and pelvic floor pain, which seriously affects their quality of life. Dihydroartemisinin (DHA) is the most important artemisinin derivative with good anti-inflammatory effects. However, the mechanism of DHA for CNP has not been fully elucidated. OBJECTIVES: To examine the protective effect of DHA on CNP in mice model and to explore the potential mechanisms from the perspective of microRNAs (miRNAs). MATERIAL AND METHODS: The CNP mouse model was induced using a prostate protein extract solution and complete Freund's adjuvant. The pain threshold was determined using von Frey filaments. Hematoxylin and eosin (H&E) staining, TUNEL staining, western blot, real-time polymerase chain reaction (PCR), and small RNA sequencing were used to evaluate the effect of DHA on CNP. RESULTS: Dihydroartemisinin significantly alleviated prostate tissue damage in CNP mice, reduced the pain threshold, improved the prostate index, and reduced cell apoptosis. It also reduced the expressions of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage chemoattractant protein-1 (MCP-1). Furthermore, after screening 48 differentially expressed genes, we found 4 miRNAs significantly downregulated and 2 miRNAs upregulated in the model group, which were later significantly reversed by DHA treatment. These results indicate that DHA treatment of CNP involves several signaling pathways. CONCLUSIONS: Dihydroartemisinin can improve the pathological state and inflammatory response in a CNP mouse model, which may be related to the regulation of miRNAs.

Effect of Bushen Huoxue Decoction combined with moxibustion on inflammation and urinary symptoms in patients with prostate cancer.

OBJECTIVE: To investigate the efficacy of Bushen Huoxue Decoction (BSHXD) combined with moxibustion on inflammation and urinary symptoms in prostate cancer (PC) patients. METHODS: A total of 87 patients with PC admitted to the Hebei Provincial Hospital of Traditional Chinese Medicine from 08/2019 to 12/2021 were collected for this retrospective study. There were 42 patients treated with conventional treatment regimens who were regarded as the control group (CG). The remaining 45 patients treated with BSHXD and moxibustion were considered the experimental group (EG). The quality of survival of patients was assessed through the C30 and PR25 subscales of the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ). Patients' urinary symptom changes were evaluated using the International Prostate Symptom Score (IPSS). The levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF)-α were measured by Elisa assay before and after the treatment. The maximum urinary flow rate and residual urine volume of the patients were compared before and after the treatment. Logistic regression was used to analyze the risk factors affecting the progression to castration-resistant prostate cancer (CRPC). RESULTS: There was no statistical difference in the total response rate between the two groups of patients (P>0.05). Patients in the EG had a higher QLQ-C30 and maximum urinary flow rate scores than those in the CG after the treatment. The residual urine volume, IL-6, TNF-α, QLQ-PR25, and IPSS scores in the EG were lower (P<0.05). The multi-factorial regression analysis revealed that the Gleason score and the pre-treatment prostate-specific antigen (PSA) level were independent risk factors for the development of CRPC in patients (P<0.05). We plotted the receiver operating characteristic curves for predicting CRPC based on the indicators of patients. The area under the curve for Gleason score and the pre-treatment PSA level were 0.665 and 0.827, respectively, and 0.935 for the combination. CONCLUSION: BSHXD combined with moxibustion had no effect on patients' progressive values of CRPC and did not enhance their outcomes. It was effective in improving their lower urinary symptoms, inflammation, and quality of life.

Evaluation of age-related differences in the immunogenicity of a G9 H9N2 influenza vaccine.

Avian influenza A/H9N2 viruses can infect people and are viruses considered to be a potential pandemic threat. Prior studies with an inactivated G1 clade H9N2 vaccine reported that persons born before 1968 were more likely to have an immune response than younger subjects. We performed a randomized, double-blind trial to evaluate whether immune responses following immunization with an inactivated, unadjuvanted influenza G9 H9N2 vaccine prepared from A/chicken/Hong Kong/G9/97 virus were more frequent in persons born in 1964 or earlier (44-59 years) than in those born in 1970 or later (18-38 years). One hundred twenty one persons were randomized to receive two doses of either 7.5- or 30-mcg of hemagglutinin intramuscularly. Post-vaccination serum antibody responses as measured by hemagglutination inhibition and microneutralization were either similar in the two age cohorts or greater in the younger age group. Persons born before 1968 were not more likely to respond to a G9 H9N2 influenza vaccine than persons born in 1970 or later.

Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults.

Dosage-sparing strategies, adjuvants and alternative substrates for vaccine production are being explored for influenza vaccine development. We assessed the safety and immunogenicity of a Vero cell culture-grown inactivated whole virus influenza A/H5N1 vaccine with or without aluminum hydroxide adjuvant [Al(OH)(3)] in healthy young adults. Vaccines were well tolerated, but injection site discomfort was more frequent in groups receiving Al(OH)(3). Dose-related increases in serum antibody levels were observed. Neutralizing antibody titers varied significantly when tested by two different laboratories. Al(OH)(3) did not enhance HAI or neutralizing antibody responses, and contributed to increased injection site pain. Because influenza antibody titers vary significantly between different laboratories, international standardization of assays is warranted.

Safety and immunogenicity of a subvirion inactivated influenza A/H5N1 vaccine with or without aluminum hydroxide among healthy elderly adults.

A total of 600 healthy adults > or =65 years were randomized to receive 2 vaccinations 1 month apart of a subvirion avian influenza A/H5N1 vaccine containing 3.75, 7.5, 15, or 45microg of hemagglutinin (HA) with or without aluminum hydroxide (AlOH). All formulations were safe. Groups given the vaccine with AlOH had more injection site discomfort. Dose-related increases in antibody responses were noted after the second vaccination. Antibody responses to the vaccine were not enhanced by AlOH at any HA dose level. A microneutralization titer > or =40 was observed in 36% and 40% of subjects who received 45microg of HA with or without AlOH, respectively.