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BioRxiv : the Preprint Server For... Jun 2024SARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a...
UNLABELLED
SARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a key line of defense for unvaccinated or immunocompromised individuals. However, these mAbs are now ineffective against current SARS-CoV-2 variants. Here, we tested three aspects of αSARS-CoV-2 therapeutics. First, we tested whether Fc engagement is necessary for clearance of SARS-CoV-2. Secondly, we tested bi-specific killer engagers (BiKEs) that simultaneously engage SARS-CoV-2 and a specific Fc receptor. Benefits of these engagers include the ease of manufacturing, stability, more cell-specific targeting, and high affinity binding to Fc receptors. Using both mAbs and BiKEs, we found that both neutralization and Fc receptor engagement were necessary for effective SARS-CoV-2 clearance. Thirdly, due to ACE2 being necessary for viral entry, ACE2 will maintain binding to SARS-CoV-2 despite viral evolution. Therefore, we used an ACE2 decoy Fc-fusion or BiKE, instead of an anti-SARS-CoV-2 antibody sequence, as a potential therapeutic that would withstand viral evolution. We found that the ACE2 decoy approach also required Fc receptor engagement and, unlike traditional neutralizing antibodies against specific variants, enabled the clearance of two distinct SARS-CoV-2 variants. These data show the importance of Fc engagement for mAbs, the utility of BiKEs as therapies for infectious disease, and the effectiveness of the ACE2 decoy approach. With further studies, we predict combining neutralization, the cellular response, and this ACE2 decoy approach will benefit individuals with ineffective antibody levels.
ABBREVIATIONS
ACE2, scFv, mAb, BiKE, COVID-19, Fc, CD16, CD32b, CD64, d.p.i.
KEY POINTS
With equal dosing, both neutralization and Fc engagement are necessary for the optimal efficacy of antibodies and bi-specific killer engagers (BiKEs) against SARS-CoV-2. BiKEs can clear SARS-CoV-2 virus and protect against severe infection in the hACE2-K18 mouse model. ACE2 decoys as part of Fc-fusions or BiKEs provide clearance of two disparate SARS-CoV-2 variants.
PubMed: 38948747
DOI: 10.1101/2024.06.20.599956 -
BioRxiv : the Preprint Server For... Jun 2024Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of...
UNLABELLED
Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNFα-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro- inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair.
SUMMARY STATEMENT
TNFR1 signaling drives cells towards senesce and muted inflammatory response in painful intervertebral disc degeneration, while limited TNFR2 signaling may limit disc cell repair responses.
PubMed: 38948728
DOI: 10.1101/2024.02.22.581620 -
Postepy Psychiatrii Neurologii Mar 2024Scleroderma is a multisystemic disorder characterised by inflammatory and vascular anomalies, and excess fibrosis. Progressive systemic sclerosis (PSS) mainly progresses...
PURPOSE
Scleroderma is a multisystemic disorder characterised by inflammatory and vascular anomalies, and excess fibrosis. Progressive systemic sclerosis (PSS) mainly progresses with skin, joint, lung, heart, and kidney involvement. Involvement of cerebral vessels is rare in both localised scleroderma and PSS. Transient ischemic attack and stroke are rare complications of scleroderma.
CASE DESCRIPTION
We present a 60-year-old stroke patient with localised scleroderma presenting with impaired speech, forgetting words, and occasional temporary memory loss.
COMMENT
In the case we present, no pathology was found in the clinical and laboratory tests performed in terms of ischemic risk factors. Skin findings included contracture, skin biopsy results, and antibody positivity related to scleroderma. Given the current pathogenesis of scleroderma, the patient was suspected of having a stroke.
PubMed: 38948684
DOI: 10.5114/ppn.2023.134450 -
Cancer Management and Research 2024As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their...
Efficacy and Safety of Chidamide in Combination with PD-1 Inhibitor and Radiotherapy for HER2-Negative Advanced Breast Cancer: Study Protocol of a Single Arm Prospective Study.
PURPOSE
As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer.
PATIENTS AND METHODS
This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored.
CONCLUSION
As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders.
PubMed: 38948681
DOI: 10.2147/CMAR.S464677 -
Journal of Family Medicine and Primary... May 2024COVID-19 is a disease caused by the severe acute respiratory syndrome coronavirus 2 that has appeared as a global pandemic in recent times. Currently, the transmission...
INTRODUCTION
COVID-19 is a disease caused by the severe acute respiratory syndrome coronavirus 2 that has appeared as a global pandemic in recent times. Currently, the transmission rate has slowed down significantly, but the definite pathological reason behind this is still unknown. Therefore, the prevalence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody must be studied to establish the relation between the rate of transmission and antibody presence.
MATERIALS AND METHODS
A clinical assessment was performed to evaluate the seroprevalence of SARS-CoV-2 Immunoglobulin G (IgG) antibodies among 299 healthy volunteers in the period of February to May 2021. Serum samples were analyzed using chemiluminescent microparticle immunoassay (CMIA) technology to detect the presence of IgG antibodies.
RESULT
It was observed that 21% of the participants were seropositive, and 78% of the population was seronegative across the different genders. This confirmed that the generation of antibodies is independent of gender. Simultaneously, a -test was performed that further suggested no statistical correlation between gender and seroprevalence. Moreover, a comprehensive analysis was performed to establish the relation between age and blood group with the seroprevalence. However, there was no statistical relationship found among these parameters.
CONCLUSION
This study assisted in examining the underlying causes of high or low seroprevalence among healthy volunteers.
PubMed: 38948624
DOI: 10.4103/jfmpc.jfmpc_780_23 -
Journal of Family Medicine and Primary... May 2024The Coronavirus disease 2019 (COVID-19) pandemic has been the biggest threat to humankind during the last 3 years. It has caused the loss of more than 6.9 million...
INTRODUCTION
The Coronavirus disease 2019 (COVID-19) pandemic has been the biggest threat to humankind during the last 3 years. It has caused the loss of more than 6.9 million precious lives across the world. The only method by which the massacre could be stopped was by mass vaccination or mass immunization. The patients suffering from autoimmune rheumatic disorders (AIRDs) and treated with immunosuppressants were the high-priority candidates for vaccination. However, the data regarding the efficacy of COVID-19 vaccines in this group of patients are very less. Hence, this study was planned to study the immunogenicity of Covishield in patients with AIRDs attending the rheumatology OPD at DMCH, Ludhiana.
MATERIALS AND METHODS
It was a prospective cohort study and was planned by the Department of Biochemistry and Department of Clinical Immunology and Rheumatology at Dayanand Medical College and Hospital, Ludhiana. Fifty patients with AIRDs attending the DMCH rheumatology OPD and 52 age and sex-matched healthy controls who had received two doses of Covishield vaccine were included in this study. Patients having any other immunosuppressive conditions like uncontrolled diabetes, hepatitis, malignancy or HIV were excluded. Patients who had suffered from previous laboratory-confirmed COVID-19 infection (by RT-PCR) were also excluded. Blood samples were collected following all aseptic precautions from patients and controls on the 28 day after administration of a second dose of Covishield vaccine and total antibodies to the severe acute respiratory syndrome coronavirus 2 spike (S) protein receptor binding domain was measured using Elecsys Anti-SARS-CoV-2 S kit from Roche.
RESULTS
It was observed that no significant difference was there in antibody titre between cases and controls (6213 ± 4418 vs. 8331 ± 7979, = 0.1022). It was also observed that no statistically significant difference in antibody titre in cases without prednisolone and those taking treatment with prednisolone was found ( = 0.7058). A similar observation was found in terms of methotrexate also ( = 0.457). No significant difference in antibody titres was there when compared with controls (for prednisolone, = 0.169, for methotrexate, = 0.078). We found that only the patients receiving mycophenolate mofetil showed a statistically significant decrease in antibody titre in comparison to healthy controls ( = 0.03). Our study showed no statistically significant difference in antibody titres between patients suffering from different AIRDs.
CONCLUSION
Our study supplements the fact that patients with AIRDs in India can receive Covishield as the primary vaccine against COVID-19 without concerns regarding decreased immunogenicity or increased adverse effects.
PubMed: 38948615
DOI: 10.4103/jfmpc.jfmpc_1021_23 -
Journal of Family Medicine and Primary... May 2024The rapid spread and mutation rate of severe acute respiratory syndrome corona virus (SARS-CoV2) demands continuous monitoring in terms of genomic and serosurvival. The...
INTRODUCTION
The rapid spread and mutation rate of severe acute respiratory syndrome corona virus (SARS-CoV2) demands continuous monitoring in terms of genomic and serosurvival. The current study is designed to track the seroprevalence of health care workers (HCWs) postvaccination, as they may be more susceptible to contracting the SARS-CoV-2 infection compared to the general population.
OBJECTIVE
The objective was to identify the seroprevalence rate for SARS-CoV-2 immunoglobulin G (IgG) antibody (N, S1, S2) amongst HCWs of various levels of exposure working in a tertiary care teaching hospital in Puducherry.
MATERIALS AND METHODS
The present study followed a nonprobability consecutive sampling technique, which involved 216 study participants HCWs from the hospital. IgG antibody levels were measured using EUROIMMUNE Anti SARS-COV-2 ELISA KIT (IG g) ELISA at two points: firstly, 2 weeks after the second dose of vaccination, followed by 2 weeks after the booster dose.
RESULTS
Out of the total 216 participants enrolled in the survey, there were 140 males and 76 females, and the maximum number of candidates studied were in the 41-50 age group. Almost 46.7% of the HCWs who participated in the study were seropositive for SARS-CoV-2 in the case of those who were high-risk exposed, while only 30.4% were amongst those who were low-risk exposed. The proportion of study participants who became seropositive increased considerably after the booster dose (65.7%), from 38.0% when tested three months after infection.
CONCLUSION
A significant increase in antibody titres amongst high-risk HCWs postboost vaccination demands continuous monitoring of soluble IgG levels for recommendations of vaccination schedules.
PubMed: 38948592
DOI: 10.4103/jfmpc.jfmpc_1488_23 -
Journal of Family Medicine and Primary... May 2024Corona virus disease (COVID-19) initially appeared to be an exclusively respiratory ailment. While that is true in a vast majority of the cases, its evolution and later...
Corona virus disease (COVID-19) initially appeared to be an exclusively respiratory ailment. While that is true in a vast majority of the cases, its evolution and later evidence have shown that it can afflict virtually any organ system in the human body after first gaining entry through the respiratory tract. The COVID-19 vaccines were one of the turning points in the campaign to control the COVID-19 pandemic. However, after their extensive use all over the world, it has emerged that they can cause some dangerous collateral damage. We, herein, report the case of a 58-year-old woman who presented to us with signs and symptoms of acute intestinal obstruction 4 months after receiving her first dose of Covishield vaccination for COVID-19. Her blood tests showed a high D-dimer and normal platelet count. She was previously admitted to the hospital with an acute abdomen 3 months back. A contrast-enhanced computed tomography (CECT) scan of the abdomen done then had revealed thrombi in the aorta and inferior mesenteric and splenic arteries. She was started on low-molecular-weight heparin and discharged on tablet Warfarin after clinical improvement. CECT abdomen done during her present admission revealed a proximal small bowel stricture with dilated proximal and collapsed distal loops. She underwent a laparoscopic jejuno-ileal resection anastomosis. During the post-operative period, a repeat CECT abdomen done to evaluate multiple episodes of vomiting revealed pulmonary embolism in the lower chest cuts. A venous Doppler revealed extensive deep venous thrombosis of the left lower limb. A thrombophilia profile diagnosed anti-phospholipid antibody syndrome, an exacerbation of which was likely precipitated by the COVID-19 vaccine.
PubMed: 38948557
DOI: 10.4103/jfmpc.jfmpc_1006_23 -
Frontiers in Endocrinology 2024The aim of this study was to evaluate the associations of thyroid autoimmunity (TAI) with the number of oocytes retrieved (NOR), fertilization rate (FR), and embryo...
PURPOSE
The aim of this study was to evaluate the associations of thyroid autoimmunity (TAI) with the number of oocytes retrieved (NOR), fertilization rate (FR), and embryo quality (EQ) in euthyroid women with infertility and diminished ovarian reserve (DOR).
METHODS
This retrospective cohort study involved 1,172 euthyroid women aged 20-40 years with infertility and DOR who underwent an oocyte retrieval cycle. TAI was diagnosed in the presence of serum thyroperoxidase antibody (TPOAb) concentrations higher than 34 IU/ml and/or serum thyroglobulin antibody (TgAb) concentrations exceeding 115.0 IU/ml. Among these women, 147 patients with TAI were classified as the TAI-positive group, while 1,025 patients without TAI were classified as the TAI-negative group. Using generalized linear models (GLMs) adjusted for confounding factors, we evaluated the associations of TAI and the serum TPOAb and TgAb concentrations and NOR, FR, and EQ in this study's subjects. The TPOAb and TGAb values were subjected to log10 transformation to reduce skewness. Logistic regression models were used to estimate the effects of TPOAb and TgAb concentrations on the probabilities of achieving a high NOR (≥7) and high FR (>60%).
RESULTS
For the whole study population, women with TAI had a significantly lower NOR and poorer EQ than women without TAI ( < 0.001 for both). Interestingly, in the TSH ≤2.5 subgroup, the TAI-positive group also had a significantly lower NOR and poorer EQ than the TAI-negative group ( < 0.001 for both). Furthermore, negative associations were observed between log10(TPOAb) concentrations and NOR and the number of high-quality embryos and available embryos ( < 0.05 for all). The log10(TgAb) concentrations were inversely associated with NOR and the number of high-quality embryos ( < 0.05 for all). In the regression analysis, the log10(TPOAb) concentrations had lower probabilities of achieving a high NOR [adjusted odds ratio (aOR): 0.56; 95% confidence interval (95% CI) 0.37, 0.85; = 0.007].
CONCLUSIONS
TAI and higher TPOAb and TgAb concentrations were shown to be associated with reductions in the NOR and EQ in the study population. Our findings provide further evidence to support systematic screening and treatment for TAI in euthyroid women with infertility and DOR.
Topics: Humans; Female; Adult; Infertility, Female; Ovarian Reserve; Retrospective Studies; Autoimmunity; Autoantibodies; Embryonic Development; Young Adult; Pregnancy; Thyroid Gland; Oocyte Retrieval; Fertilization in Vitro; Iodide Peroxidase
PubMed: 38948519
DOI: 10.3389/fendo.2024.1376179 -
Frontiers in Endocrinology 2024To identify the relationship between thyroid autoimmunity and antinuclear antibody (ANA) prevalence in Chinese pregnant women.
OBJECTIVE
To identify the relationship between thyroid autoimmunity and antinuclear antibody (ANA) prevalence in Chinese pregnant women.
METHODS
The study involved 1923 first-trimester women who were measured for thyroid stimulating hormone (TSH) level, thyroid autoantibodies (thyroperoxidase antibody [TPOAb] and thyroglobulin antibody [TgAb]) and ANA titer. Social demographic data were collected through standardized questionnaires.
RESULTS
In this study, 23.3% of pregnant women tested positive for TPOAb and 9.9% tested positive for TgAb. Women with a positive ANA were more likely to be TPOAb-positive or TgAb-positive than women with a negative ANA (adjusted odds ratio [AOR] 1.96, 95% confidence interval [CI] 1.47-2.62 for TPOAb [+]; AOR 3.12, 95% CI 2.18-4.48 for TgAb[+]). In addition, ANA titers were closely associated with thyroid autoimmunity. Women with an ANA titer of >1:320 had a significant higher risk of being TPOAb positive or TgAb positive (AOR 4.49, 95% CI 1.48-13.66 for TPOAb [+]; AOR 5.51, 95% CI 1.65-18.49 for TgAb [+]). The higher the ANA titer, the greater the risk of developing thyroid autoimmunity, especially for those with a high ANA titer.
CONCLUSIONS
ANA positivity is strongly correlated with thyroid autoimmunity. Further study is warranted to clarify the causal relationship between thyroid autoimmunity and ANA in pregnant women.This research is essential to evaluate and predict the risk of co-existing autoimmune disorders,leading to improved care for pregnancy and neonatal health.
Topics: Humans; Female; Pregnancy; Cross-Sectional Studies; Adult; China; Antibodies, Antinuclear; Autoimmunity; Prevalence; Autoantibodies; Pregnancy Complications; Young Adult; Thyroid Gland
PubMed: 38948512
DOI: 10.3389/fendo.2024.1403917