Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD ...combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared with a maximum tolerated dose (MTD) regimen in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8(+) T-cell responses to tumors as determined by interleukin (IL)-2 and IFN-γ secretion. In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m(2)) as the third- or fourth-line treatment. Serum was collected over the course of treatment, and serial IFN-γ and IL-2 levels were used to determine CD8(+) T-cell activation. Of the four patients with disease control, three had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8(+) T-cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8(+) T-cell response. Because the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.
The continuous emergence of SARS-CoV-2 variants has led to a protracted global COVID-19 pandemic with significant impacts on public health and global economy. While there are currently available ...SARS-CoV-2 vaccines and therapeutics, most of the FDA-approved antiviral agents directly target viral proteins. However, inflammation is the initial immune pathogenesis induced by SARS-CoV-2 infection, there is still a need to find additional agents that can control the virus in the early stages of infection to alleviate disease progression for the next pandemic. Here, we find that both the spike protein and its receptor CD147 are crucial for inducing inflammation by SARS-CoV-2 in THP-1 monocytic cells. Moreover, we find that 3-
-betulin, isolated from
, reduces the level of proinflammatory cytokines induced by SARS-CoV-2, consequently resulting in a decreased viral RNA accumulation and plaque formation. In addition, 3-
-betulin displays a broad-spectrum inhibition of entry of SARS-CoV-2 pseudoviruses, including Alpha (B.1.1.7), Eplison (B.1.429), Gamma (P1), Delta (B.1.617.2) and Omicron (BA.1). Moreover, 3-
-betulin potently inhibits SARS-CoV-2 infection with an EC
of <20 μM in Calu-3 lung epithelial cells. Bioinformatic analysis reveals the chemical interaction between the 3-
-betulin and the spike protein, along with the critical amino acid residues in the spike protein that contribute to the inhibitory activity of 3-
-betulin against virus entry. Taken together, our results suggest that 3-
-betulin exhibits dual effect: it reduces SARS-CoV-2-induced inflammation and inhibits virus entry, positioning it as a potential antiviral agent against SARS-CoV-2.
Kan-Lu-Hsiao-Tu-Tan (KLHTT) is a popular traditional Chinese medicine for treating various inflammatory diseases.
The aim of the present study was to investigate the anti-inflammatory effects of ...KLHTT on human neutrophils and its therapeutic potential in treating imiquimod (IMQ)-induced psoriasis-like skin inflammation.
Spectrophotometry, flow cytometry, and microscopy with immunohistochemical staining were used to evaluate superoxide anion generation, elastase release, CD11b expression, adhesion, and neutrophil extracellular trap (NET) formation in activated human neutrophils. Reactive oxygen species (ROS) and reactive nitrogen species in cell-free systems were measured using a multi-well fluorometer or a spectrophotometer. A psoriasis-like skin inflammation was induced in mice using the IMQ cream.
KLHTT suppressed superoxide anion generation, ROS production, CD11b expression, and adhesion in activated human neutrophils. In contrast, KLHTT failed to alter elastase release in activated human neutrophils. Additionally, KLHTT had an ROS-scavenging effect in the AAPH assay, but it did not scavenge superoxide anions directly in the xanthine/xanthine oxidase assay. Protein kinase C (PKC)-induced NET formation most commonly occurs through ROS-dependent mechanisms. KLHTT significantly inhibited phorbol 12-myristate 13-acetate, a PKC activator, inducing NET formation. Furthermore, topical KLHTT treatment reduced the area affected by psoriasis area and severity index (PASI) score and ameliorated neutrophil infiltration in IMQ-induced psoriasis-like skin inflammation in mice.
Our data show that KLHTT has anti-neutrophilic inflammatory effects in inhibiting ROS generation and cell adhesion. KLHTT also mitigated NET formation, mainly via an ROS-dependent pathway. In addition, KLHTT reduced neutrophil infiltration and improved the severity of IMQ-induced psoriasis-like skin inflammation in mice. Therefore, KLHTT may prove to be a safe and effective psoriasis therapy in the future.
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To date, 1841 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been reported worldwide, with 652 deaths. We used a publically available case line list to explore the ...effect of relevant factors, notably underlying comorbidities, on fatal outcome of Middle East respiratory syndrome (MERS) cases up to the end of October 2016. A Bayesian Weibull proportional hazards regression model was used to assess the effect of comorbidity, age, epidemic period and sex on the fatality rate of MERS cases and its variation across countries. The crude fatality rate of MERS cases was 32.1% (95% credibility interval (CI): 29.9%, 34.3%). Notably, the incremental change of daily death rate was most prominent during the first week since disease onset with an average increase of 13%, but then stabilized in the remaining two weeks when it only increased 3% on average. Neither sex, nor country of infection were found to have a significant impact on fatality rates after taking into account the age and comorbidity status of patients. After adjusting for age, epidemic period, MERS patients with comorbidity had around 4 times the risk for fatal infection than those without (adjusted hazard ratio of 3.74 (95% CI: 2.57, 5.67)).
Familial amyloid polyneuropathy (FAP) caused by a mutation in transthyretin (TTR) gene is an autosomal dominant inherited disorder. The aim of this study is to explore the pathophysiological ...mechanism of FAP. We prospectively recruited 12 pauci-symptomatic carriers, 18 patients who harbor a TTR mutation, p.A97S, and two-age matched control groups. Data of nerve excitability test (NET) from ulnar motor and sensory axons were collected.NET study of ulnar motor axons of patients shows increased threshold and rheobase, reduced threshold elevation during hyperpolarizing threshold electrotonus (TE), and increased refractoriness. In sensory nerve studies, there are increased threshold reduction in depolarizing TE, lower slope of recovery and delayed time to overshoot after hyperpolarizing TE, increased refractoriness and superexcitability in recovery cycle. NET profiles obtained from the ulnar nerve of carriers show the increase of threshold and rheobase, whereas no significant threshold changes in hyperpolarizing TE and superexcitability. The regression models demonstrate that the increase of refractoriness and prolonged relative refractory period are correlated to the disease progression from carriers to patients. The marked increase of refractoriness at short-width stimulus suggests a defect in sodium current which may represent an early, pre-symptomatic pathophysiological change in TTR-FAP. Focal disruption of basal lamina and myelin may further increase the internodal capacity, manifested by the lower slope of recovery and delayed time to overshoot after hyperpolarization TE as well as the increase of superexcitability. NET could therefore make a pragmatic tool for monitoring disease progress from the very early stage of TTR-FAP.
The cardiac manifestations of late-onset hereditary transthyretin amyloidosis with p.A97S variant have not been extensively studied, and the prognostic factors remain unclear.
The clinical profile, ...echocardiography, and ECG of patients diagnosed with ATTR p.A97S polyneuropathy between 2000 and 2016 were retrospectively collected. 67 patients with ATTR p.A97S were collected.
A total of 82% of patients met the criteria for left ventricular (LV) hypertrophy. Reduced global longitudinal strain (GLS) was noted in 42.1% of patients, and 14% of patients had a relative apical sparing pattern. A low voltage pattern in the ECG was observed in 31.3% of patients, while 64.2% presented with a pseudoinfarction pattern. End-systolic LV inner dimension (HR: 2.25 (95% CI: 1.01–5.01), p = 0.048), reduced GLS (HR: 5.26 (1.08–25.0), p = 0.039), relative apical longitudinal strain (RALS>1, HR: 8.57 (1.69–43.3), p = 0.009), increased E/A ratio (HR: 6.51 (1.17–36.4), p = 0.033), and increased QRS duration (HR: 1.02 (1.00–1.04), p = 0.05) were correlated with reduced survival in univariate analysis. Multivariate analysis revealed reduced RALS was significantly correlated with reduced survival (HR: 13.00 (1.81–93.45), p = 0.011).
Our findings reveal that ATTR p.A97S is a cardiomyopathy as well as a polyneuropathic syndrome. Routine use of more contemporary echocardiographic techniques are recommended to identify cardiac amyloidosis and provide prognostic information.
•MERS-CoV S1-Fd induces high levels of neutralizing activity as well as S1-specific IgG and isotypes.•MERS-CoV S1-Fd protects against MERS-CoV challenge and reduces viral loads in lung.•QS-21 but not ...AddaVax adjuvanted MERS-CoV S1-Fd activates long-term cellular immunity.
Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants. We found that sera from immunized wild-type and human DPP4 transgenic mice contained S1-specific antibodies that can neutralize MERS-CoV infection in susceptible cells. Vaccination with S1-Fd protein in combination with a saponin-based QS-21 adjuvant provided long-term humoral as well as cellular immunity in mice. Our findings highlight the significance of the trimeric S1 protein in the development of MERS-CoV vaccines and offer a suitable adjuvant, QS-21, to induce robust and prolonged memory T cell response.
There are few studies demonstrating how the effectiveness of various extents of non-pharmaceutical interventions (NPIs) before and after vaccination periods. The study aimed to demonstrate such an ...effectiveness in the alteration of the epidemic curves from theory to practice.
The empirical data on the daily reported COVID-19 cases were extracted from open source. A computer simulation design in conjunction with the susceptible-exposed-infected-recovered (SEIR) type model was applied to evaluating confinement measures in Italy with adjustment for underreported cases; isolation and quarantine in Taiwan; and NPIs and vaccination in Israel.
In Italy scenario, the extents of confinement measures were 34% before the end of March and then scaled up to 70% after then. Both figures were reduced to 22–69% after adjusting for underreported cases. Approximately 44% of confinement measures were implemented in the second surge of pandemic in Italy.
Fitting the observational data on Taiwan assuming the initial outbreak similar to Wuhan, China, 44% of isolation and quarantine were estimated before March 23rd, 2020. Isolation and quarantine were scaled up to 90% and at least 60% to contain community-acquired outbreaks from March 24th, 2020 onwards. Given 15% monthly vaccination rate from December 2020 in Israel, the effectiveness estimates of reducing the infected toll were 36%, 56%, and 85% for NPIs alone, vaccination alone, and both combined, respectively.
We demonstrated how various NPIs stamp out and delay the epidemic curve of COVID-19. The optimal implementation of these NPIs has to be planned before wide vaccine uptake worldwide.
Large gatherings of people on cruise ships and warships are often at high risk of COVID-19 infections. To assess the transmissibility of SARS-CoV-2 on warships and cruise ships and to quantify the ...effectiveness of the containment measures, the transmission coefficient (β), basic reproductive number (R0), and time to deploy containment measures were estimated by the Bayesian Susceptible-Exposed-Infected-Recovered model. A meta-analysis was conducted to predict vaccine protection with or without non-pharmaceutical interventions (NPIs). The analysis showed that implementing NPIs during voyages could reduce the transmission coefficients of SARS-CoV-2 by 50%. Two weeks into the voyage of a cruise that begins with 1 infected passenger out of a total of 3,711 passengers, we estimate there would be 45 (95% CI:25-71), 33 (95% CI:20-52), 18 (95% CI:11-26), 9 (95% CI:6-12), 4 (95% CI:3-5), and 2 (95% CI:2-2) final cases under 0%, 10%, 30%, 50%, 70%, and 90% vaccine protection, respectively, without NPIs. The timeliness of strict NPIs along with implementing strict quarantine and isolation measures is imperative to contain COVID-19 cases in cruise ships. The spread of COVID-19 on ships was predicted to be limited in scenarios corresponding to at least 70% protection from prior vaccination, across all passengers and crew.
The aims of this study were (1) to compare the effect of robot-assisted gait orthosis (RAGO) plus conventional physiotherapy with the effect of conventional therapy alone on functional outcomes, ...including balance, walking ability, muscle strength, daily activity, and cognition, in chronic stroke patients, and (2) to determine the association of adjustable parameters of RAGO on functional outcomes. Adjustable parameters of RAGO included guidance force, treadmill speed, and body-weight support. This retrospective cohort study enrolled 32 patients with chronic stroke. Of these, 16 patients received RAGO plus conventional physiotherapy (RAGO group), and 16 patients received conventional physiotherapy alone (control group). Balance was assessed using the Berg Balance Scale, walking ability using the Functional Ambulation Category, muscle strength using the Motricity Index, daily activity using the Barthel Index, and cognition using the Mini-Mental State Examination. The scores were assessed before and after training. The Mini–Mental State Examination and the Berg Balance Scale increased significantly in both groups, whereas improvements in the Motricity Index and the Barthel Index were only observed in the RAGO group after intervention. During RAGO training, reducing guidance force and body-weight support assistance was associated with improvements in the Barthel Index, whereas higher treadmill walking speed was associated with improvements in the Berg Balance Scale. Our study found that RAGO combination therapy resulted in improvements in more functional outcomes than did conventional training alone. The adjustable parameters of the RAGO training were partly associated with training outcomes.
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