Effect of dental chew on reducing dental plaque, dental calculus and halitosis in beagle dogs.

Periodontosis is the most common clinical disease in adult dogs, which is mainly caused by plaque accumulation and seriously endangers the oral health of dogs and even cause kidney, myocardial, and liver problems in severe cases. The aim of this study was to determine the clinical efficacy of dental chew (Cature Brushing Treats product) with mechanical and chemical properties in beagles. The dogs in the experimental group were fed with a dental chew twice a day after meals; The control group had no treatment. Dental plaque was evaluated on the 14th day and 29th day, respectively. The concentration of volatile sulfur compounds (VSC) in the breath and dental calculus were also evaluated on the 29th day. The results showed that there was no significant difference in the indexes of dental plaque on the 14th day. While they had significantly reduced accumulation of plaque (37.63%), calculus (37.61%), and VSC concentration (81.08%) compared to when receiving no chew on the 29th day.

Effects of COVID-19 vaccination on cervical lymph nodes in patients with thyroid cancer.

Background: Cervical lymph node enlargement caused by coronavirus disease 2019 (COVID-19) vaccination has been reported, but little is known on whether the vaccination would influence preoperative cervical lymph node evaluation and its risk of lymph node metastasis in thyroid cancer. Methods: We retrospectively analyzed data of patients who underwent thyroid cancer surgery in Tangdu Hospital, China, from 1 March 2021 to 30 June 2021. A total of 182 patients were included in the cohort study. All patients with suspected malignant tumors underwent ultrasound (US)-guided fine needle aspiration (FNA) of thyroid lesions before surgery to confirm the diagnosis. Cervical lymph nodes were evaluated by preoperative physical examination and imaging. Wilcoxon rank-sum test and Fisher's exact test were used to evaluate the effect of vaccination on cervical lymph nodes in patients with thyroid cancer. Statistical significance was defined at P<0.05. Results: The patients were divided into two groups according to whether they had been vaccinated or not. Our results showed that there were no significant differences between the two groups in the brand of the vaccine, operation method, and the extent of surgery. Moreover, there was no significant difference in the evaluation of US characteristics of cervical lymph nodes between the two groups regardless of having the vaccination or not. Interestingly, US evaluation found that the experimental group's proportion of cervical lymph node enlargement increased significantly within 14 days after vaccination, which was statistically significant. Conclusions: This study found that vaccination against COVID-19 did not increase the number of cervical lymph node metastases, but inaccurate assessment of cervical lymph nodes in thyroid cancer patients within 14 days of vaccination (due to temporary lymph node enlargement) may lead to more extensive surgery.

Mapping SARS-CoV-2 antigenic relationships and serological responses.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple variants escaping preexisting immunity emerged, causing reinfections of previously exposed individuals. Here, we used antigenic cartography to analyze patterns of cross-reactivity among 21 variants and 15 groups of human sera obtained after primary infection with 10 different variants or after messenger RNA (mRNA)-1273 or mRNA-1273.351 vaccination. We found antigenic differences among pre-Omicron variants caused by substitutions at spike-protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months after a second dose. We found changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine-strain selection.

Clusterin is a biomarker of breast cancer prognosis and correlated with immune microenvironment.

Background: It has been established that clusterin is involved in the invasion of immune cells in the tumor microenvironment, but it remains unknown how it promotes immune invasion in breast cancer. Methods: We used Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to assess the relation between expression of clusterin and immunoinfiltration-related marker genes. TIMER database was used to evaluate the expression of clusterin, and its relation to tumor immune invasion was examined. Based on Kaplan-Meier plotter database, we investigated the association between clusterin expression and prognosis in patients with cancer, and the impact of clinicopathological factors and cancer-related outcomes. Results: Clusterin expression was markedly associated with prognosis of a variety of tumors, specifically breast cancer. Enhanced clusterin expression was markedly associated with molecular typing of breast cancer and expression of multiple markers related to specific immune cell subsets. Conclusions: These results indicate that clusterin is connected to prognosis of breast cancer patients and tumor immune cell infiltration. This demonstrates that clusterin may be a biomarker of immune cell recruitment into breast tumors and an important biomarker for immune cell infiltration; consequently being a valuable prognostic factor in breast cancer patients.

Mapping SARS-CoV-2 antigenic relationships and serological responses.

During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel of 21 variants and 15 groups of human sera obtained following primary infection with 10 different variants or after mRNA-1273 or mRNA-1273.351 vaccination. We find antigenic differences among pre-Omicron variants caused by substitutions at spike protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months post-2nd dose. We find changes in immunodominance of different spike regions depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine strain selection.

Impact of intraoperative frozen section pathology on the treatment outcome of unilateral papillary thyroid microcarcinoma and its influencing factors-a retrospective cohort study.

Background: Most patients with papillary thyroid carcinoma have a good prognosis. Excessive resection of thyroid and cervical lymph nodes is an important reason for affecting the quality of life of patients after surgery. Intraoperative rapid frozen pathological examination is an important step in the development of a surgical plan for thyroid cancer (especially micropapillary carcinoma); however, whether it affects the treatment outcome remains unclear. Methods: The clinicopathological data of papillary thyroid microcarcinoma (PTMC) patients who underwent surgery in our center from 1 January 2021 to 31 December 2021 were retrospectively analyzed. Patients with unilateral low-risk PTMC who underwent radical surgery were selected as the main research subjects. The negative results of intraoperative frozen section of the central lymph node (CLN) of the affected side were the experimental group, and the positive results were the control group. Subjects with lesions larger than 10 mm and those who did not undergo intraoperative frozen section pathological examination were excluded. After excluding other risk factors for recurrence, we calculated the proportion of patients requiring radioactive iodine (RAI) treatment among those with metastases detected by intraoperative rapid frozen section pathology and its influencing factors. Patient data were analysed using SPSS version 20. Continuous variables were presented as means when symmetrical or as medians and ranges when asymmetrical. Categorical variables were presented as proportions. A P value <0.05 was considered significant. Results: A total of 564 PTMC patients were included, among whom 122 patients (21.6%) underwent total thyroidectomy due to the presence of metastases in the ipsilateral CLNs. Compared with the experimental group, the patients with male, young age and tumor located in the middle and lower pole in the control group had higher lymph node metastasis (P<0.05). Conclusions: The proportion of patients requiring postoperative RAI treatment for unilateral low-risk PTMC is relatively low, and the possibility that an intraoperative frozen pathological finding will change the treatment outcome is low. However, the need for postoperative RAI therapy notably increases when the intraoperative frozen pathological analysis reveals ipsilateral CLN metastases, especially in males, younger patients, and/or patients with lesions located in the middle and lower poles.

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker-which quantifies the neutralization potency of antibodies in an individual's serum against an HIV-1 isolate-can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

GDF11 knockdown downregulates SMURF1 to inhibit breast cancer progression by activation of p53 and inactivation of ERα signaling.

Breast cancer (BC) is a prevalent neoplasm that occurs in women all over the world. Growth and differentiation factor 11 (GDF11) plays an essential role in cancer progression. This study focused on investigating the biological role and underlying mechanisms of GDF11 in BC. We detected the expression of GDF11 in 27 patients with BC and BC cell lines. Kaplan-Meier plotter was employed to analyze the relationship between GDF11 expression and overall survival (OS) of BC patients. The proliferative, migratory, invasive, and apoptotic abilities of T47D cells were examined. Correlation analysis of GDF11 with Smad ubiquitination regulatory factor 1 (SMURF1) was conducted. The association between GDF11 and the p53 pathway was analyzed by western blot and PFT-α (a p53 inhibitor)-mediated rescue assays. A brief analysis of the role of estrogen receptor alpha (ERα) signaling in BC progression was performed. The results showed that GDF11 was increased in BC tissues and cell lines, and the high expression of GDF11 was associated with the poor OS of BC patients. GDF11 knockdown inhibited the proliferation, migration, and invasion of T47D cells, but promoted cell apoptosis. Meanwhile, the GDF11 knockdown reduced the SMURF1 expression and invoked the p53 pathway activation. SMURF1 overexpression and PFT-α partially blocked the effects of GDF11 knockdown. In addition, GDF11 knockdown and SMURF1 silencing inhibited the activation of the ERα signaling pathway. In summary, GDF11 was involved in the progression of BC by regulating SMURF1-mediated p53 and ERα pathways, opening up a new way for BC treatment.

Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization.

The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in live virus and pseudovirus assays. Omicron was 41-84-fold less sensitive to neutralization than D614G and 5.3-7.4-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 µg mRNA-1273. A 50 µg boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.

SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral spike vaccines.

All current vaccines for COVID-19 utilize ancestral SARS-CoV-2 spike with the goal of generating protective neutralizing antibodies. The recent emergence and rapid spread of several SARS-CoV-2 variants carrying multiple spike mutations raise concerns about possible immune escape. One variant, first identified in the United Kingdom (B.1.1.7, also called 20I/501Y.V1), contains eight spike mutations with potential to impact antibody therapy, vaccine efficacy, and risk of reinfection. Here, we show that B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (∼sim;2-fold), by serum samples from convalescent individuals and recipients of an mRNA vaccine (mRNA-1273, Moderna) and a protein nanoparticle vaccine (NVX-CoV2373, Novavax). A subset of monoclonal antibodies to the receptor binding domain (RBD) of spike are less effective against the variant, while others are largely unaffected. These findings indicate that variant B.1.1.7 is unlikely to be a major concern for current vaccines or for an increased risk of reinfection.

SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines.

The SARS-CoV-2 Spike glycoprotein mediates virus entry and is a major target for neutralizing antibodies. All current vaccines are based on the ancestral Spike with the goal of generating a protective neutralizing antibody response. Several novel SARS-CoV-2 variants with multiple Spike mutations have emerged, and their rapid spread and potential for immune escape have raised concerns. One of these variants, first identified in the United Kingdom, B.1.1.7 (also called VUI202012/01), contains eight Spike mutations with potential to impact antibody therapy, vaccine efficacy and risk of reinfection. Here we employed a lentivirus-based pseudovirus assay to show that variant B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (~2-fold), by serum samples from convalescent individuals and recipients of two different vaccines based on ancestral Spike: mRNA-1273 (Moderna), and protein nanoparticle NVX-CoV2373 (Novavax). Some monoclonal antibodies to the receptor binding domain (RBD) of Spike were less effective against the variant while others were largely unaffected. These findings indicate that B.1.1.7 is not a neutralization escape variant that would be a major concern for current vaccines, or for an increased risk of reinfection.

The application of the three-dimensional high-definition laparoscope in thyroid microcarcinoma.

BACKGROUND: This study aimed to evaluate the feasibility and safety of the three-dimensional (3D) high-definition (HD) laparoscope via a chest-breast approach in thyroid microcarcinoma. METHODS: In this retrospective study, ten patients with thyroid microcarcinoma who underwent laparoscopic thyroidectomy in the Department of General Surgery of Tangdu Hospital from May 2016 to October 2016 were included. Preoperative thyroid and neck ultrasound in these patients showed a thyroid nodule ≤1 cm, and no significantly enlarged cervical lymph nodes were observed. The patients' thyroid function showed no subclinical hyperthyroidism. Three trocars were used via the chest and breast during the surgery. The main outcome measures included the operation time, intraoperative blood loss, postoperative hospital stay time, postoperative drainage volume, and the incidence of complications. RESULTS: The ten patients were successfully treated using a 3D HD laparoscope. The mean operation time was 70-160 minutes, the average intraoperative blood loss was 10-30 mL, the mean postoperative hospital stay was 4.5 days, and the mean postoperative drainage volume was 10-20 mL. None of the patients needed to receive a traditional open thyroidectomy during the operation. No patient experienced hoarseness, numbness of limbs, or choking or coughing while drinking water. CONCLUSIONS: The 3D endoscopic thyroidectomy operation via the chest-breast approach is a feasible and safe therapeutic method for the treatment of thyroid microcarcinoma.

Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus.

A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional, and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to a higher titer as pseudotyped virions. In infected individuals, G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus and support continuing surveillance of Spike mutations to aid with development of immunological interventions.

Growth factor receptor bound protein-7 regulates proliferation, cell cycle, and mitochondrial apoptosis of thyroid cancer cells via MAPK/ERK signaling.

It is of great significance to explore the molecular mechanism of thyroid cancer (TC) pathogenesis for its improvement and therapy. Growth factor receptor bound protein-7 (GRB7) has been regarded as an important regulatory gene in the developments of various malignant tumors. Our study aimed to illustrate the role of GRB7 in the TC pathology mechanism. Firstly, GRB7 was found to be significantly upregulated in 49 cases of TC tissues and 5 TC cell lines by using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. Silencing GRB7 with siRNA dramatically inhibited proliferation and induced cell cycle arrest in TC cells. Besides, GRB7 silence resulted in the decrease of adenosine triphosphate content, glucose uptake, and lactose production in TC cells and attenuated the activity and expression of mitochondrial respiratory complex. We also demonstrated that GRB7 downregulation increased the levels of Bax and caspase 3, and inhibited the expression of Bcl-2, suggesting the induced mitochondrial apoptosis. More importantly, our study proved that mitogen-activated protein kinase/extracellular-regulated protein kinases (MAPK/ERK) signaling played a crucial role in the regulation of GRB7 on TC cell functions. In general, the present research verified that GRB7 was upregulated during TC development and modulated the proliferation, cell cycle, and mitochondrial apoptosis of TC cells by activating MAPK/ERK pathway. This may provide a novel target for the therapeutic strategy of TC.

Correction: Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.

[This corrects the article DOI: 10.1371/journal.ppat.1008026.].

Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.

Correction: HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies.

[This corrects the article DOI: 10.1371/journal.ppat.1007431.].

MARCH5 overexpression contributes to tumor growth and metastasis and associates with poor survival in breast cancer.

BACKGROUND: Human MARCH5 is a mitochondrial localized E3 ubiquitin-protein ligase that is critical for the regulation of mitochondrial dynamics. A body of evidence has indicated the close links between unbalanced mitochondrial dynamics and cancers. However, the expression, biological functions, and prognostic significance of MARCH5 in breast cancer (BC) have not been determined. MATERIALS AND METHODS: The mRNA and protein expressions of MARCH5 were evaluated by quantitative real-time PCR and Western blot analysis in BC cell lines and tumor tissues. Clinical prognostic significance of MARCH5 was assessed in 65 patients with BC. The biological functions of MARCH5 were determined by in vitro cell proliferation, apoptosis, cell cycle, migration and invasion assays, and in vivo tumor growth and metastasis assays through knockdown or overexpression of MARCH5 in BC cells. In addition, the underlying mechanisms by which MARCH5 regulated BC cell growth and metastasis were explored. RESULTS: MARCH5 was substantially upregulated in BC cells mainly due to the downregulation of miR-30a, which contributed to the poor survival of BC patients. MARCH5 promoted the growth and metastasis of BC cells both in vitro and in vivo by inducing G1-S cell cycle arrest and epithelial-mesenchymal transition. Mechanistic investigations revealed that the oncogenic effect of MARCH5 was mainly mediated by increased mitochondrial fission and subsequent ROS production in BC cells. CONCLUSION: Our findings demonstrate that MARCH5 plays a critical oncogenic role in BC cells, which provides experimental evidence supporting MARCH5 as a potential therapeutic target in BC therapy.