Longitudinal immune kinetics of COVID-19 booster versus primary series vaccination: Insight into the annual vaccination strategy.

Background: Data on the durability of booster dose immunity of COVID-19 vaccines are relatively limited. Methods: Immunogenicity was evaluated for up to 9-12 months after the third dose of vaccination in 94 healthy adults. Results: Following the third dose, the anti-spike immunoglobulin G (IgG) antibody response against the wild-type was boosted markedly, which decreased gradually over time. However, even 9-12 months after the booster dose, both the median and geometric mean of anti-spike IgG antibody levels were higher than those measured 4 weeks after the second dose. Breakthrough infection during the Omicron-dominant period boosted neutralizing antibody titers against Omicron sublineages (BA.1 and BA.5) and the ancestral strain. T-cell immune response was efficiently induced and maintained during the study period. Conclusions: mRNA vaccine booster dose elicited durable humoral immunity for up to 1 year after the third dose and T-cell immunity was sustained during the study period, supporting an annual COVID-19 vaccination strategy.

The anti-tumor effects of AZD4547 on ovarian cancer cells: differential responses based on c-Met and FGF19/FGFR4 expression.

BACKGROUND: The FGF/FGFR signaling pathway plays a critical role in human cancers. We analyzed the anti-tumor effect of AZD4547, an inhibitor targeting the FGF/FGFR pathway, in epithelial ovarian cancer (EOC) and strategies on overcoming AZD4547 resistance. METHODS: The effect of AZD4547 on cell viability/migration was evaluated and in vivo experiments in intraperitoneal xenografts using EOC cells and a patient-derived xenograft (PDX) model were performed. The effect of the combination of AZD4547 with SU11274, a c-Met-specific inhibitor, FGF19-specific siRNA, or an FGFR4 inhibitor was evaluated by MTT assay. RESULTS: AZD4547 significantly decreased cell survival and migration in drug-sensitive EOC cells but not drug-resistant cells. AZD4547 significantly decreased tumor weight in xenograft models of drug-sensitive A2780 and SKOV3ip1 cells and in a PDX with drug sensitivity but not in models with drug-resistant A2780-CP20 and SKOV3-TR cells. Furthermore, c-Met expression was high in SKOV3-TR and HeyA8-MDR cells, and co-administration of SU11274 and AZD4547 synergistically induced cell death. In addition, expressions of FGF19 and FGFR4 were high in A2780-CP20 cells. Combining AZD4547 with FGF19 siRNA or with a selective FGFR4 inhibitor led to significantly reduced cell proliferation in A2780-CP20 cells. CONCLUSIONS: This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

Evolution of neutralizing antibodies through vaccination and breakthrough infections in the era of COVID-19 endemicity.

Despite a high vaccination rate, the COVID-19 pandemic continues with immune-evading Omicron variants. The success of additional antigenic stimulation through breakthrough infection (BI) and updated vaccination in overcoming antigenic imprinting needs to be determined. Participants in a long-term follow-up cohort of healthcare worker (HCW) vaccinee were categorized according to their infection/vaccination status. Anti-SARS-CoV-2 spike/nucleocapsid protein antibodies were measured, and plaque reduction neutralization tests (PRNTs) against wild-type (WT), BA.5, BN.1, and XBB.1.5 were conducted. The neutralization activity of intravenous immunoglobulin (IVIG) products was evaluated to assess the immune status of the general population. Ninety-five HCWs were evaluated and categorized into seven groups. The WT PRNT ND50 value was highest regardless of infection/vaccination status, and groups with recent antigenic stimulation showed high PRNT titers overall. Groups with double Omicron stimulation, either by BI plus BA.4/5 bivalent vaccination or repeated BI, exhibited significantly higher BA.5 and BN.1 PRNT to WT PRNT ratios than those with single Omicron stimulation. Overall group immunity was estimated to be boosted in January 2023, reflecting the effect of the BA.4/5 bivalent booster and additional BIs, but slightly declined in June 2023. A substantial increase in the antibody concentrations of IVIG products was noticed in 2022, and recently produced IVIG products exhibited a substantial level of cross-reactive neutralizing activity against emerging variants. Neutralizing activity against emerging variants could be enhanced by repeated antigenic stimulation via BI and/or updated vaccination. Overall group immunity was elevated accordingly, and IVIG products showed substantial activity against circulating strains.

Clinical utility of quantitative immunoassays and surrogate virus neutralization tests for predicting neutralizing activity against the SARS-CoV-2 Omicron BA.1 and BA.5 variants.

Developing new antibody assays for emerging SARS-CoV-2 variants is challenging. SARS-CoV-2 surrogate virus neutralization tests (sVNT) targeting Omicron BA.1 and BA.5 have been devised, but their performance needs to be validated in comparison with quantitative immunoassays. First, using 1749 PRNT-positive sera, we noticed that log-transformed optical density (OD) ratio of wild-type (WT) sVNT exhibited better titer-correlation with plaque reduction neutralization test (PRNT) than % inhibition value. Second, we tried 798 dilutional titration tests with 103 sera, but nonlinear correlation between OD ratio and antibody concentration limited titration of sVNT. Third, the titer-correlations of two sVNT kits for BA.1 and two quantitative immunoassays for WT were evaluated with BA.1 and BA.5 PRNT. All tested kits exhibited a linear correlation with PRNT titers, but the sVNT kits exhibited high false-negative rates (cPass-BA.1 kit, 45.4% for BA.1 and 44.2% for BA.5; STANDARD F-BA.1 kit, 1.9% for BA.1 and 2.2% for BA.5), while quantitative immunoassays showed 100% sensitivity. Linear mixed-effects model suggested superior titer-correlation with PRNT for quantitative immunoassays compared to sVNT kits. Taken together, the use of quantitative immunoassays for WT, rather than rapid development of new kits, would be practical for predicting neutralizing activities against emerging new variants.

Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator and is used for the treatment of uterine leiomyoma (a benign tumor). Uterine sarcoma which is highly malignant cancer with a poor prognosis is clinically resembled with uterine leiomyoma. There has been no experimental research on the effect of UPA on uterine sarcoma. In this study, we examined the efficacy of UPA in uterine sarcoma with in vitro and in vivo animal models. Cytotoxicity of UPA was determined in uterine sarcoma cell lines (MES-SA, SK-UT-1, and SK-LMS-1). Apoptotic genes and signaling pathways affected by UPA were analyzed by complementary DNA (cDNA) microarray of uterine sarcoma cell lines and western blot, respectively. An in vivo efficacy of UPA was examined with uterine sarcoma cell line- and patient-derived xenograft (PDX) mice models. UPA inhibited cell growth in uterine sarcoma cell lines and primary culture cells from a PDX mouse (PDX-C). cDNA microarray analysis revealed that CCL2 was highly down-regulated by UPA. Phosphorylation and the total expression of STAT3 were inhibited by UPA. UPA also inhibited CCL2 and STAT3 in PDX-C. The inhibitory effect of UPA had not changed in the overexpression of PR and treatment of progesterone. In vivo efficacy studies with cell line-derived xenografts and a PDX model with leiomyosarcoma, a typical uterine sarcoma, demonstrated that UPA significantly decreased tumor growth. UPA had significant anti-tumor effects in uterine sarcoma through the inhibition of STAT3/CCL2 signaling pathway and might be a potential therapeutic agent to treat this disease.

Longitudinal kinetics of neutralizing antibodies against circulating SARS-CoV-2 variants and estimated level of group immunity of booster-vaccinated individuals during omicron-dominated COVID-19 outbreaks in the Republic of Korea, 2022.

The coronavirus disease 2019 pandemic persisted for 3 years and is now transitioning to endemicity. We illustrated the change in group immunity induced by vaccination (monovalent vaccines) and breakthrough infections (BIs) in a healthcare worker (HCW) cohort. Five sampling points were analyzed: before the third dose and 1, 3, 5, and 8 months after the vaccination. The last two points corresponded roughly to 1 and 4 months after omicron BA.1/BA.2 BI. A semi-quantitative anti-spike binding antibody (Sab) assay and plaque reduction neutralization test (PRNT) against circulating variants were conducted. A linear regression model was utilized to deduce correlation equations. Baseline characteristics and antibody titers after the third dose were not different between 106 HCWs with or without BI (54/52). One month after the third dose, BA.1 PRNT increased with wild-type (WT), but 3 months after the third dose, it decreased more rapidly than WT PRNT. After BI, BA.1 PRNT increased robustly and waned slower than WT. A linear equation of waning kinetics was deduced between log10Sab and months, and the slope became gradual after BI. The estimated BA.5 PRNT titers at the beginning of the BA.5 outbreak were significantly higher than the BA.1 PRNT titers of the initial BA.1/BA.2 wave, which might be associated with the smaller size of the BA.5 wave. BA.1/BA.2 BI after the third dose elicited robust and broad neutralizing activity, preferentially maintaining cross-neutralizing longevity against BA.1 and BA.5. The estimated kinetics provide an overview of group immunity through the third vaccination and BA.1/BA.2 BI, correlating with the actual outbreaks. IMPORTANCE This study analyzed changes in group immunity induced by coronavirus disease 2019 (COVID-19) vaccination and BA.1/BA.2 breakthrough infections (BIs) in a healthcare worker cohort. We investigated the longitudinal kinetics of neutralizing antibodies against circulating variants and confirmed that BA.1/BA.2 BIs enhance the magnitude and durability of cross-neutralization against BA.1 and BA.5. Correlation equations between semi-quantitative anti-spike antibody and plaque reduction neutralization test titers were deduced from the measured values using a linear regression model. Based on the equations, group immunity was estimated to last up to 11 months following the third dose of the COVID-19 vaccine. The estimated group immunity suggests that the augmented immunity and flattened waning slope through BI could correlate with the overall outbreak size. Our findings could provide a better understanding to establish public health strategies against future endemicity.

Sedum middendorffianum Maxim Induces Apoptosis and Inhibits the Invasion of Human Ovarian Cancer Cells via Oxidative Stress Regulation.

Sedum middendorffianum Maxim (SMM) is a Korean endemic plant belonging to the Crassulaceae family. This study aimed to investigate the antitumor effects of the SMM extract on human ovarian cancer cells. Among five endemic plants grown in Korea, the SMM extract showed the most potent cytotoxicity in ovarian cancer cells and had little effect on normal ovarian surface epithelial cells. Furthermore, we revealed that the SMM extract dose-dependently induced apoptosis in human ovarian cancer A2780 and SKOV3 cells. The SMM extract markedly stimulated the activation of caspase-3/8, while the broad-spectrum caspase inhibitor and caspase-8 selective inhibitor significantly reversed SMM extract-induced apoptosis. In addition, the SMM extract significantly inhibited cell invasion and the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 in ovarian cancer cells. Notably, the SMM extract increased the generation of intracellular ROS, and pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed SMM-induced cytotoxicity and anti-invasive activity. Moreover, NAC treatment reversed the SMM-induced inhibition of MMP-2/9 expression. Taken together, these data suggest that the SMM extract induces caspase-dependent apoptotic cell death and inhibits MMP-dependent invasion via ROS regulation.

Anticancer Evaluation of Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles Encapsulating Fenbendazole and Rapamycin in Ovarian Cancer.

Purpose: We aimed to inhibit ovarian cancer (OC) development by interfering with microtubule polymerization and inhibiting mTOR signaling. To achieve this, previously developed micelles containing fenbendazole and rapamycin were applied. Methods: Herein, we prepared micelles for drug delivery using fenbendazole and rapamycin at a 1:2 molar ratio and methoxy poly(ethylene glycol)-b-poly(caprolactone)(mPEG-b-PCL) via freeze-drying. We revealed their long-term storage capacity of up to 120 days. Furthermore, a cytotoxicity test was performed on the OC cell line HeyA8, and an orthotopic model was established for evaluating in vivo antitumor efficacy. Results: Fenbendazole/rapamycin-loaded mPEG-b-PCL micelle (M-FR) had an average particle size of 37.2 ± 1.10 nm, a zeta potential of -0.07 ± 0.09 mV, and a polydispersity index of 0.20 ± 0.02. Additionally, the average encapsulation efficiency of fenbendazole was 75.7 ± 4.61% and that of rapamycin was 98.0 ± 1.97%. In the clonogenic assay, M-FR was 6.9 times more effective than that free fenbendazole/rapamycin. The in vitro drug release profile showed slower release in the combination formulation than in the single formulation. Conclusion: There was no toxicity, and tumor growth was suppressed substantially by our formulation compared with that seen with the control. The findings of our study lay a foundation for using fenbendazole and rapamycin for OC treatment.

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer.

OBJECTIVE: Fenbendazole (FZ) has potential anti-cancer effects, but its poor water solubility limits its use for cancer therapy. In this study, we investigated the anti-cancer effect of FZ with different drug delivery methods on epithelial ovarian cancer (EOC) in both in vitro and in vivo models. METHODS: EOC cell lines were treated with FZ and cell proliferation was assessed. The effect of FZ on tumor growth in cell line xenograft mouse model of EOC was examined according to the delivery route, including oral and intraperitoneal administration. To improve the systemic delivery of FZ by converting fat-soluble drugs to hydrophilic, we prepared FZ-encapsulated poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (FZ-PLGA-NPs). We investigated the preclinical efficacy of FZ-PLGA-NPs by analyzing cell proliferation, apoptosis, and in vivo models including cell lines and patient-derived xenograft (PDX) of EOC. RESULTS: FZ significantly decreased cell proliferation of both chemosensitive and chemoresistant EOC cells. However, in cell line xenograft mouse models, there was no effect of oral FZ treatment on tumor reduction. When administered intraperitoneally, FZ was not absorbed but aggregated in the intraperitoneal space. We synthesized FZ-PLGA-NPs to obtain water solubility and enhance drug absorption. FZ-PLGA-NPs significantly decreased cell proliferation in EOC cell lines. Intravenous injection of FZ-PLGA-NP in xenograft mouse models with HeyA8 and HeyA8-MDR significantly reduced tumor weight compared to the control group. FZ-PLGA-NPs showed anti-cancer effects in PDX model as well. CONCLUSION: FZ-incorporated PLGA nanoparticles exerted significant anti-cancer effects in EOC cells and xenograft models including PDX. These results warrant further investigation in clinical trials.

Predictive Value of Reactogenicity for Anti-SARS-CoV-2 Antibody Response in mRNA-1273 Recipients: A Multicenter Prospective Cohort Study.

Messenger RNA (mRNA) vaccination was developed to mitigate the coronavirus disease 2019 pandemic. However, data on antibody kinetics and factors influencing these vaccines' immunogenicity are limited. We conducted a prospective study on healthy young adults who received two doses of the mRNA-1273 vaccine at 28-day intervals. After each dose, adverse events were prospectively evaluated, and blood samples were collected. The correlation between humoral immune response and reactogenicity after vaccination was determined. In 177 participants (19-55 years), the geometric mean titers of anti-S IgG antibody were 178.07 and 4409.61 U/mL, while those of 50% neutralizing titers were 479.95 and 2851.67 U/mL four weeks after the first and second vaccine doses, respectively. Anti-S IgG antibody titers were not associated with local reactogenicity but were higher in participants who experienced systemic adverse events (headache and muscle pain). Antipyretic use was an independent predictive factor of a robust anti-SARS-CoV-2 antibody response after receiving both vaccine doses. Systemic reactogenicity after the first dose influenced antibody response after the second dose. In conclusion, mRNA-1273 induced a robust antibody response in healthy young adults. Antipyretic use did not decrease the anti-SARS-CoV-2 antibody response after mRNA-1273 vaccination.

What explains very poor Yelp reviews of oral and maxillofacial surgeons in private practice?

OBJECTIVE: Websites that maintain online physician ratings, such as Yelp.com, have been growing in popularity throughout the United States. The purpose of this study was to determine which factors increase the risk for very poor reviews (1 out of 5 stars) on Yelp.com for oral and maxillofacial surgeons (OMSs) in private practice. STUDY DESIGN: A retrospective cohort study was conducted using data on OMSs from Yelp.com. Predictor variables included clinician characteristics, practice characteristics, and review characteristics. The primary outcome variable was a very poor review. Logistic regression was used to determine risk factors for a very poor review. RESULTS: The final sample consisted of 3802 reviews. Relative to male clinicians, female clinicians were 2.7 times (P < .01) more likely to receive a very poor review. Clinicians who completed residency during the 1970s were over 4.5 times (P < .01) more likely to receive a very poor review relative to clinicians who completed residency during the 2010s. Relative to clinical reviews, nonclinical reviews were more likely (odds ratio = 2.6, P < .01) to be very poor and clinical and nonclinical reviews were less likely (odds ration = 0.5, P < .01) to be very poor. CONCLUSIONS: Nonclinical reviews were more likely to be very poor relative to clinical reviews. Several clinician factors, including female sex and completing OMS residency during the 1970s, were risk factors for receiving a very poor review.

Kinetics of vaccine-induced neutralizing antibody titers and estimated protective immunity against wild-type SARS-CoV-2 and the Delta variant: A prospective nationwide cohort study comparing three COVID-19 vaccination protocols in South Korea.

Introduction: Despite vaccine development, the COVID-19 pandemic is ongoing due to immunity-escaping variants of concern (VOCs). Estimations of vaccine-induced protective immunity against VOCs are essential for setting proper COVID-19 vaccination policy. Methods: We performed plaque-reduction neutralizing tests (PRNTs) using sera from healthcare workers (HCWs) collected from baseline to six months after COVID-19 vaccination and from convalescent COVID-19 patients. The 20.2% of the mean PRNT titer of convalescent sera was used as 50% protective value, and the percentage of HCWs with protective immunity for each week (percent-week) was compared among vaccination groups. A correlation equation was deduced between a PRNT 50% neutralizing dose (ND50) against wild type (WT) SARS-CoV-2 and that of the Delta variant. Results: We conducted PRNTs on 1,287 serum samples from 297 HCWs (99 HCWs who received homologous ChAdOx1 vaccination (ChAd), 99 from HCWs who received homologous BNT162b2 (BNT), and 99 from HCWs who received heterologous ChAd followed by BNT (ChAd-BNT)). Using 365 serum samples from 116 convalescent COVID-19 patients, PRNT ND50 of 118.25 was derived as 50% protective value. The 6-month cumulative percentage of HCWs with protective immunity against WT SARS-CoV-2 was highest in the BNT group (2297.0 percent-week), followed by the ChAd-BNT (1576.8) and ChAd (1403.0) groups. In the inter-group comparison, protective percentage of the BNT group (median 96.0%, IQR 91.2-99.2%) was comparable to the ChAd-BNT group (median 85.4%, IQR 15.7-100%; P =0.117) and significantly higher than the ChAd group (median 60.1%, IQR 20.0-87.1%; P <0.001). When Delta PRNT was estimated using the correlation equation, protective immunity at the 6-month waning point was markedly decreased (28.3% for ChAd group, 52.5% for BNT, and 66.7% for ChAd-BNT). Conclusion: Decreased vaccine-induced protective immunity at the 6-month waning point and lesser response against the Delta variant may explain the Delta-dominated outbreak of late 2021. Follow-up studies for newly-emerging VOCs would also be needed.

COVID-19 vaccine type-dependent differences in immunogenicity and inflammatory response: BNT162b2 and ChAdOx1 nCoV-19.

Evaluation of the safety and immunogenicity of new vaccine platforms is needed to increase public acceptance of coronavirus disease 2019 (COVID-19) vaccines. Here, we evaluated the association between reactogenicity and immunogenicity in healthy adults following vaccination by analyzing blood samples before and after sequential two-dose vaccinations of BNT162b2 and ChAdOx1 nCoV-19. Outcomes included anti-S IgG antibody and neutralizing antibody responses, adverse events, and proinflammatory cytokine responses. A total of 59 and 57 participants vaccinated with BNT162b2 and ChAdOx1 nCoV-19, respectively, were enrolled. Systemic adverse events were more common after the first ChAdOx1 nCoV-19 dose than after the second. An opposite trend was observed in BNT162b2 recipients. Although the first ChAdOx1 nCoV-19 dose significantly elevated the median proinflammatory cytokine levels, the second dose did not, and neither did either dose of BNT162b2. Grades of systemic adverse events in ChAdOx1 nCoV-19 recipients were significantly associated with IL-6 and IL-1ß levels. Anti-S IgG and neutralizing antibody titers resulting from the second BNT162b2 dose were significantly associated with fever. In conclusion, systemic adverse events resulting from the first ChAdOx1 nCoV-19 dose may be associated with proinflammatory cytokine responses rather than humoral immune responses. Febrile reactions after second BNT162b2 dose were positively correlated with vaccine-induced immune responses rather than with inflammatory responses.

Immunogenicity and Reactogenicity of Ad26.COV2.S in Korean Adults: A Prospective Cohort Study.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) pandemic continues, there are concerns regarding waning immunity and the emergence of viral variants. The immunogenicity of Ad26.COV2.S against wild-type (WT) and variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs to be evaluated. METHOD: This prospective cohort study was conducted between June 2021 and January 2022 at two university hospitals in South Korea. Healthy adults who were scheduled to be vaccinated with Ad26.COV2.S were enrolled in this study. The main outcomes included anti-spike (S) IgG antibody and neutralizing antibody responses, S-specific T-cell responses (interferon-γ enzyme-linked immunospot assay), solicited adverse events (AEs), and serious AEs. RESULTS: Fifty participants aged ≥ 19 years were included in the study. Geometric mean titers (GMTs) of anti-S IgG were 0.4 U/mL at baseline, 5.2 ± 3.0 U/mL at 3-4 weeks, 55.7 ± 2.4 U/mL at 5-8 weeks, and 81.3 ± 2.5 U/mL at 10-12 weeks after vaccination. GMTs of 50% neutralizing dilution (ND50) against WT SARS-CoV-2 were 164.6 ± 4.6 at 3-4 weeks, 313.9 ± 3.6 at 5-8 weeks, and 124.4 ± 2.6 at 10-12 weeks after vaccination. As for the S-specific T-cell responses, the median number of spot-forming units/106 peripheral blood mononuclear cell was 25.0 (5.0-29.2) at baseline, 60.0 (23.3-178.3) at 5-8 weeks, and 35.0 (13.3-71.7) at 10-12 weeks after vaccination. Compared to WT SARS-CoV-2, ND50 against Delta and Omicron variants was attenuated by 3.6-fold and 8.2-fold, respectively. The most frequent AE was injection site pain (82%), followed by myalgia (80%), fatigue (70%), and fever (50%). Most AEs were grade 1-2, and resolved within two days. CONCLUSION: Single-dose Ad26.COV2.S was safe and immunogenic. NAb titer and S-specific T-cell immunity peak at 5-8 weeks and rather decrease at 10-12 weeks after vaccination. Cross-reactive neutralizing activity against the Omicron variant was negligible.

Neutralizing Activity Against SARS-CoV-2 Delta and Omicron Variants Following a Third BNT162b2 Booster Dose According to Three Homologous or Heterologous COVID-19 Vaccination Schedules.

With the emergence and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants, escaping vaccine-induced immunity is a concern. Three vaccination schedules, homologous or heterologous, have been initially applied due to an insufficient supply of vaccines in Korea. We investigated neutralizing activities against Omicron and Delta variants in each schedule. Three schedules using three doses of the BNT162b2 (BNT) or the ChAdOx1 (ChAd) vaccines include ChAd-ChAd-BNT, ChAd-BNT-BNT, and BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild type (WT) SARS-CoV-2, Delta variant, and Omicron variant. A total of 170 sera from 75 participants were tested, and the baseline characteristics of participants were not significantly different between groups. After the 2nd vaccine dose, geometric mean titers of PRNT ND50 against WT, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628). ChAd-BNT-BNT showed a slight increase of PRNT ND50 against WT, Delta, and Omicron (2,757, 1,279, and 230) compared to the 2nd dose. The results suggest that a 3rd BNT booster dose induced strengthened neutralizing activity against Delta and Omicron variants. The waning of cross-reactive neutralizing antibodies after the 3rd dose and the need for additional boosting should be further investigated.

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma.

PURPOSE: To evaluate the anticancer effects of cabozantinib, temozolomide, and their combination in uterine sarcoma cell lines and mouse xenograft models. EXPERIMENTAL DESIGN: Human uterine sarcoma cell lines (SK-LMS-1, SK-UT-1, MES-SA, and SKN) were used to evaluate the anticancer activity of cabozantinib, temozolomide, and their combination. The optimal dose of each drug was determined by MTT assay. Cell proliferation and apoptosis were assessed 48 and 72 hours after the drug treatments. The tumor weights were measured in an SK-LMS-1 xenograft mouse model and a patient-derived xenograft (PDX) model of leiomyosarcoma treated with cabozantinib, temozolomide, or both. RESULTS: Given individually, cabozantinib and temozolomide each significantly decreased the growth and viability of cells. This inhibitory effect was more pronounced when cabozantinib (0.50 µmol/L) and temozolomide (0.25 or 0.50 mmol/L) were co-administered (P < 0.05). The combination of the drugs also significantly increased apoptosis in all cells. Moreover, this effect was consistently observed in patient-derived leiomyosarcoma cells. In vivo studies with SK-LMS-1 cell xenografts and the PDX model with leiomyosarcoma demonstrated that combined treatment with cabozantinib (5 mg/kg/d, per os administration) and temozolomide (5 mg/kg/d, per os administration) synergistically decreased tumor growth (both P < 0.05). CONCLUSIONS: The addition of cabozantinib to temozolomide offers synergistic anticancer effects in uterine sarcoma cell lines and xenograft mouse models, including PDX. These results warrant further investigation in a clinical trial.

Heterologous ChAdOx1 and Bnt162b2 vaccination induces strong neutralizing antibody responses against SARS-CoV-2 including delta variant with tolerable reactogenicity.

OBJECTIVES: We assessed humoral responses and reactogenicity following the heterologous vaccination compared to the homologous vaccination groups. METHODS: We enrolled healthcare workers (HCWs) who were either vaccinated with ChAdOx1 followed by BNT162b2 (heterologous group) or 2 doses of ChAdOx1 (ChAdOx1 group) or BNT162b2 (BNT162b2 group). Immunogenicity was assessed by measuring antibody titers against receptor-binding domain (RBD) of SARS-CoV-2 spike protein in all participants and neutralizing antibody titer in 100 participants per group. Reactogenicity was evaluated by a questionnaire-based survey. RESULTS: We enrolled 499 HCWs (ChAdOx1, n = 199; BNT162b2, n = 200; heterologous ChAdOx1/BNT162b2, n = 100). The geometric mean titer of anti-receptor-binding domain antibody at 14 days after the booster dose was significantly higher in the heterologous group (11 780.55 binding antibody unit (BAU)/mL [95% CI, 10 891.52-12 742.14]) than in the ChAdOx1 (1561.51 [95% CI, 1415.03-1723.15]) or BNT162b2 (2895.90 [95% CI, 2664.01-3147.98]) groups (both p < 0.001). The neutralizing antibody titer of the heterologous group (geometric mean ND50, 2367.74 [95% CI, 1970.03-2845.74]) was comparable to that of the BNT162b2 group (2118.63 [95% CI, 1755.88-2556.32]; p > 0.05) but higher than that of the ChAdOx1 group (391.77 [95% CI, 326.16-470.59]; p < 0.001). Compared with those against wild-type SARS-CoV-2, the geometric mean neutralizing antibody titers against the Delta variant at 14 days after the boosting were reduced by 3.0-fold in the heterologous group (geometric mean ND50, 872.01 [95% CI, 685.33-1109.54]), 4.0-fold in the BNT162b2 group (337.93 [95% CI, 262.78-434.57]), and 3.2-fold in the ChAdOx1 group (206.61 [95% CI, 144.05-296.34]). The local or systemic reactogenicity after the booster dose in the heterologous group was higher than that of the ChAdOx1 group but comparable to that of the BNT162b2 group. DISCUSSION: Heterologous ChAdOx1 followed by BNT162b2 vaccination with a 12-week interval induced a robust humoral immune response against SARS-CoV-2, including the Delta variant, that was comparable to the homologous BNT162b2 vaccination and stronger than the homologous ChAdOx1 vaccination, with a tolerable reactogenicity profile.