Search

Objective: To explore the effect of acupotomy intervention on autophagy of chondrocytes in rabbits with knee osteoarthritis (KOA), and to determine the possible mechanisms of acupotomy to alleviate cartilage degeneration. Methods: The modified Videman method was used to construct a KOA rabbit model. After modeling, 40 rabbits were randomly divided into 4 groups by a random number table: control; KOA (model); KOA + acupotomy (acupotomy), and KOA + sham acupotomy (sham), 10 in each group. After a 3-week treatment course, the knee joint activity was determined by the modified Lequesne MG index. Hematoxylin-eosin staining staining was used to examine the morphological changes of chondrocytes. Autophagy of chondrocytes was observed by transmission electron microscopy. The surface morphology of cartilage tissue was observed by scanning electron microscope. The mRNA and protein levels of AMP kinase/mammalian target of rapamycin/Unc-51 (AMPK/mTOR/ULK1) signal pathway key proteins, autophagy-related factor Beclin-1 and microtubule-associated protein 1A/1B light chain 3 (LC3) in rabbit knee cartilage were assessed by real-time fluorescence quantitative polymerase chain reaction and Western blot, respectively. Results: The modified Lequesne MG score of acupotomy group was significantly lower than that of model group (P<0.05). Pathological results showed that chondrocyte autophagy decreased and cartilage surface was rough in the model group, which recovered after acupotomy treatment. The mRNA expressions of AMPK, ULK1, Beclin-1 and the protein levels of p-AMPK, p-ULK1, Beclin-1, and LC3 II/LC3 I were decreased in the model group, while the mRNA and protein expressions of mTOR were increased (P<0.01). However, acupotomy treatment reversed these abnormal changes (P<0.05). Conclusions: Acupotomy could effectively up-regulate the expressions of AMPK, ULK1 and Beclin1, reduce the expression of mTOR, promote autophagy, and alleviate joint degeneration. Acupotomy is a promising complementary and alternative therapy for KOA. [ABSTRACT FROM AUTHOR]

Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC. [ABSTRACT FROM AUTHOR]

The article discusses the emergence of a novel subvariant of the SARS-CoV-2 Omicron variant, called BA.2.86, which has raised concerns due to its high number of mutations in the spike protein. Studies have shown that BA.2.86 is able to evade immunity induced by vaccines and convalescent plasma. The fusogenicity of BA.2.86 and its sensitivity to fusion and replication inhibitors have not been thoroughly evaluated. The authors conducted experiments to assess the fusion kinetics of BA.2.86 and found that it exhibited increased fusogenicity compared to its ancestor subvariant. They also discovered a mutation in the HR1 region of the spike protein that promoted fusion and stabilized the protein in the prefusion state. The authors developed a prokaryotic expression system to produce a recombinant peptide called reEK1, which showed potent antiviral activity against BA.2.86 and other Omicron subvariants. The study suggests that the prokaryotic reEK1 expression system could be a cost-effective alternative to synthetic peptides for clinical use. [Extracted from the article]

A study published in the journal Cell Discovery investigated the immunological characteristics and pathogenic mechanisms of severe community-acquired pneumonia (Sev-CAP) caused by the low-virulence Omicron variant of the SARS-CoV-2 virus in elderly individuals. The study found that older adults with Sev-CAP had elevated inflammatory and antibody responses but diminished antiviral immunity. They also showed weak antibody neutralization against the Omicron variant. The study revealed impaired functions of innate immune cells and effector T cells in Sev-CAP, as well as an increased proportion of plasmacytes with immunoglobulin hyperproduction. The findings suggest that the Omicron variant can still cause severe outcomes in older adults due to age-related factors and impaired immune responses. [Extracted from the article]

Background and aims: Recompensation between patients with ascites and bleeding was unknown in treatment-naïve HBV-related decompensated cirrhosis. Methods: In this retrospective multi-center study, treatment-naïve HBV-related decompensated patients were enrolled at first decompensating event of ascites and/or variceal bleeding. Further complications and clinical characteristics were collected using standard case report form every 6 months to year-5 of antiviral treatment. Recompensation was defined as maintaining free of decompensation for one year and achieving liver function within Child–Pugh A and/or MELD < 10. Results: Totally, 170 (170/298, 57.0%) patients in ascites group of 298 (298/383, 77.8%) treatment-naïve decompensated patients and 33 (33/85, 38.8%) in bleeding group of 85 (85/383, 22.2%) patients, achieved recompensation. Ascites group had higher 5-year rate of recompensation than bleeding group (63.3% vs. 46.5%, p = 0.012), respectively. Patients achieving recompensation in ascites group maintained lower rate of second decompensation than these in bleeding group (at year-5: 26.7% vs. 43.3%, p = 0.032). Specifically, recompensated patients in ascites group had predominantly 5-year rate of further ascites (24.0%) and lower rate of further bleeding (6.0%), which differed from the pattern of these in bleeding group, with lower rate of further ascites (16.0%, p = 0.599) and significantly higher rate of further bleeding (33.9%, p < 0.001). Both patients had superior long-term prognosis (death/LT rate at year-5: 0.6% vs. 3.0%, p = 0.196). Conclusion: Ascites patients could achieve higher rate of recompensation through antiviral therapy than bleeding patients. Recompensated patients in ascites group had better prognosis in terms of preventing further bleeding. [ABSTRACT FROM AUTHOR]

Purpose: Urinary incontinence is a common condition and reduces the quality of life. The purpose of this study was to assess the association between HPV infection and urinary incontinence among adult women in the USA. Methods: We examined a cross-sectional study using the National Health and Nutrition Examination Survey database. Women who had valid HPV DNA vaginal swab test results and answered the questionnaire about urinary incontinence were selected from six consecutive survey cycles (2005–2006 to 2015–2016). The association between HPV status and urinary incontinence was analyzed using weighted logistic regression. Models adjusted for potential variables were established. Results: In total, 8348 females aged between 20 and 59 years old were enrolled in this study. 47.8% of participants had a history of urinary incontinence and 43.9% of women were HPV DNA positive. After adjusting for all confounders, women with HPV infection were less likely to have urinary incontinence (OR = 0.88, 95%CI 0.78–0.98). Low-risk HPV infection correlated with a lower incidence of incontinence (OR = 0.88, 95%CI 0.77–1.00). For women aged below 40 years, low-risk HPV infection negatively correlated with stress incontinence (20–29ys: OR = 0.67, 95%CI 0.49–0.94; 30–39ys: OR = 0.71, 95%CI 0.54–0.93). However, low-risk HPV infection positively correlated with stress incontinence (OR = 1.40, 95%CI 1.01–1.95) for women 50–59 years old. Conclusion: This study revealed a negative association between HPV infection and urinary incontinence in females. Low-risk HPV correlated with stress urinary incontinence, with the reverse trend for participants of different ages. [ABSTRACT FROM AUTHOR]

Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective vaccine development. To depict the currently elusive antigenic signatures of α-HCoVs S proteins, we isolated a panel of antibodies against the HCoV-229E S protein and characterized their epitopes and neutralizing potential. We found that the N-terminal domain of HCoV-229E S protein is antigenically dominant wherein an antigenic supersite is present and appears conserved in HCoV-NL63, which holds potential to serve as a pan-α-HCoVs epitope. In the receptor binding domain, a neutralizing epitope is captured in the end distal to the receptor binding site, reminiscent of the locations of the SARS-CoV-2 RBD cryptic epitopes. We also identified a neutralizing antibody that recognizes the connector domain, thus representing the first S2-directed neutralizing antibody against α-HCoVs. The unraveled HCoVs S proteins antigenic similarities and variances among genera highlight the challenges faced by pan-HCoV vaccine design while supporting the feasibility of broadly effective vaccine development against a subset of HCoVs. The antigenic landscape of α-HCoVs S proteins is revealed, highlighting the challenges faced by pan-HCoV vaccine design but also revealing opportunities for development of broadly effective vaccines against a subset of HCoVs. [ABSTRACT FROM AUTHOR]

The receptor-binding domain (RBD) in S1 subunit and heptad repeat 1 (HR1) domain in S2 subunit of SARS-CoV-2 spike (S) protein are the targets of neutralizing antibodies (nAbs) and pan-coronavirus (CoV) fusion inhibitory peptides, respectively. However, neither nAb- nor peptide-based drugs can be used orally. In this study, we screened a one-bead-two-compound (OBTC) cyclic γ-AApeptide library against SARS-CoV-2 S protein and identified a hit: S-20 with potent membrane fusion inhibitory activity, but moderate selectivity index (SI). After modification, one derivative, S-20-1, exhibited improved fusion inhibitory activity and SI (>1000). S-20-1 could effectively inhibit infection by pseudotyped and authentic SARS-CoV-2 and pseudotyped variants of concern (VOCs), including B.1.617.2 (Delta) and B.1.1.529 (Omicron), as well as MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. It could also inhibit infection of a pseudotyped SARS-related coronavirus WIV1 (SARSr-CoV-WIV1) from bats. Intranasal application of S-20-1 to mice before or after challenge with HCoV-OC43 or SARS-CoV-2 provided significant protection from infection. Importantly, S-20-1 was highly resistant to proteolytic degradation, had long half-life, and possessed favorable oral bioavailability. Mechanistic studies suggest that S-20-1 binds with high affinity to RBD in S1 and HR1 domain in S2 of SARS-CoV-2 S protein. Thus, with its pan-CoV fusion and entry inhibitory activity by targeting two sites in S protein, desirable half-life, and promising oral bioavailability, S-20-1 is a potential candidate for further development as a novel therapeutic and prophylactic drug against infection by SARS-CoV-2 and its variants, as well as future emerging and reemerging CoVs. [ABSTRACT FROM AUTHOR]

Scale bars, 400 µm. h Western blot analysis of S protein expression in effector cells. i-m Statistical analysis of fusion rates mediated by the WT, D614G, and B.1.1.7 S protein after coculture for 1 h (i), 2 h (j), 3 h (k), 4 h (l), and 12 h (m). However, no appreciable difference in fusion kinetics between the WT, D614G or B.1.1.7 S protein was observed in 293T/ACE2 or 293T/ACE2/TMPRSS2 cells, consistent with previously reported[13] (Supplementary Figs. 1g, h, effector cells (293T/S/GFP) bearing B.1.1.7 S protein fused with Calu-3 cells with an efficacy equal to that of effector cells expressing the equal amounts of WT or D614G mutant S protein after co-incubation for 8 h. Previous studies reported that the B.1.1.7 mutant S protein showed greater receptor-binding affinity than the wild-type (WT) S protein[3]. [Extracted from the article]

Background: The relationship between obstructive sleep apnea (OSA) and the risk of nocturia remains unclear. Therefore, we sought to identify whether or not OSA affects the incidence of nocturia. Methods: A thorough literature search was executed in September 1st 2018 from PubMed, Web of Science database, and Embase. We used DerSimonian and Laird random-effects to calculate the pooled relative ratio (RR). Results: Total of 13 studies met inclusion criteria and in total comprised, 406 patients and 9518 controls. There was a significant association between OSA and the risk of nocturia (RR = 1.41, 95% CI 1.26–1.59). Through subgroup analysis by different severity of OSA, we found patients who had severe OSA were at high risk of nocturia. Through another subgroup analysis, we found a statistically significant association between OSA and risk of nocturia in the men (RR = 1.487, 95% CI 1.087–2.034, P = 0.013). However, there was no significant relationship between OSA and nocturia in the women (RR = 1.537, 95% CI 0.831–2.842, P > 0.05). Subgroup analysis of different diagnostic methods indicated that OSA was significantly associated with the risk of nocturia regardless what method was used to diagnose OSA (P < 0.05). Conclusion: The findings suggest that men with OSA have a high incidence of nocturia. A large multicenter study may be useful to explore the relationship between OSA and nocturia, in order to elucidate its causes. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy (OVT) is a novel form of immunotherapy using natural or genetically modified viruses to selectively replicate in and kill malignant cells. Many genetically modified oncolytic viruses (OVs) with enhanced tumor targeting, antitumor efficacy, and safety have been generated, and some of which have been assessed in clinical trials. Combining OVT with other immunotherapies can remarkably enhance the antitumor efficacy. In this work, we review the use of wild-type viruses in OVT and the strategies for OV genetic modification. We also review and discuss the combinations of OVT with other immunotherapies. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) 16 E6 gene mutation is considered an important genetic change in cervical lesion progression. To explore the possible association of specific HPV16 E6 sequence variations with the development of invasive cervical squamous cell carcinoma (SCC) in young women, we examined the distribution of HPV16 E6 variants in a Chinese cervical SCC population and analyzed the difference between younger patients (≤35 years, n = 50) and older ones (>35ys, n = 71). Human papillomavirus type 16 E6 DNA was amplified by polymerase chain reaction and sequenced by Sanger fluorescent dye dideoxy-termination method. Analysis revealed that the most frequently found variation in this Chinese population was the EV (As) lineage (65.45%). In addition, the EV (As) lineage seems more common and uniform in younger patients than other lineages, and it may be associated with early age at diagnosis of cervical SCC in young women. [ABSTRACT FROM PUBLISHER]