The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and ...reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains ...elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of patients with lung cancer. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-to-mesenchymal transition regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt coreceptor LRP5/6. Activation of these signaling axes decreased GSK3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. In addition, we generated a chimeric anti-ENO1 mAb (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and support the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer. SIGNIFICANCE: This study shows that ENO1 promotes lung cancer metastasis via HGFR and WNT signaling and introduces a novel anti-ENO1 antibody for potential therapeutic use in lung cancer.
The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community ...has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether ...these findings translate to epidermal growth factor receptor (EGFR)–mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual.
Methods
Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided.
Results
A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial.
Conclusions
As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.
Epithelial cell adhesion molecule (EpCAM) is highly expressed in colon cancers, but its role in cancer progression remains to be elucidated. In this work, we found that the extracellular domain of ...EpCAM (EpEX) activated EGFR and downstream ERK1/2 signaling to promote colon cancer cell migration and proliferation, as well as tumor growth. Mechanistically, we discovered that EpEX-EGFR-ERK1/2 signaling positively regulated intramembrane proteolysis (RIP) of EpCAM and shedding of the intracellular domain (EpICD). Treatment with an EGFR inhibitor ablated the EpEX-induced phosphorylation of ERK1/2 and AKT. Additionally, treatment with inhibitors of either EGFR or MEK decreased EpEX-induced EpICD shedding and further revealed that EpICD is necessary for nuclear accumulation of β-catenin and the induction of HIF1α target gene expression in vitro and in vivo. Moreover, an anti-EpCAM neutralizing monoclonal antibody, EpAb2-6, inhibited the nuclear translocation of EpICD and β-catenin and induced apoptosis in colon cancer cells. Importantly, analysis of colorectal cancer tissues showed that nuclear accumulation of EpICD was highly correlated with metastasis and poor prognosis, suggesting that it may play an important functional role in cancer progression. Thus, we provide novel insights into the mechanisms and functions of EpEX-mediated signaling, which may be considered as a promising target for the treatment of colon cancer.
•EpEX enhances proteolytic cleavage of EpCAM via an EGFR-dependent pathway.•EpICD promotes β-catenin nuclear translocation and hypoxia-related genes expression.•Nuclear EpICD correlates with metastasis and poor prognosis of CRC patients.
Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. ...Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR-199a-5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co-loading of siRNA against cPKM (si-cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co-loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si-cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.
How to enable high-performance task offloading and preserve the trust between participants is imperative yet nontrivial to the Cloud-Edge-Device (CED) computing, mainly because the resources are ...geo-distributed and operated by different parties. Also, the CED participants are highly dynamic and heterogeneous in resource provision and may conflict in interest. This paper proposes BlockChain-empowered CED (BC-CED), a blockchain-empowered collaborative task offloading for CED computing. In BC-CED, blockchain plays a central role in the main functionality of CED, including task offloading, brokerage of resource usage, and incentives. We distinguish the BC-CED from the existing solutions by modifying the blockchain consensus process, enabling the participants to reach an agreement via solving the task offloading problem. For this purpose, we formulate the offloading problem by considering the computation capabilities of candidate nodes and the network performance. BC-CED allows each participant to apply reinforcement learning-based methods to solve this problem and compete for the right of block output by comparing the offloading policy performance and accepting the best policy as the offloading scheme within the next period. We also propose a truthful incentive mechanism to encourage resource contributions in BC-CED and force them to be honest. Extensive tests by implementing our solutions in a commercialized blockchain platform have shown how BC-CED achieves a superior performance in task offloading and blockchain maintenance.
Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights ...indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient‐derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF‐κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC.
Patients with intrahepatic cholangiocarcinoma (ICC) complicated with hepatolithiasis have a poor prognosis. This study reveals that bacteria play a role in this process. Escherichia coli induces cGLIS3 expression and promotes tumor progression in ICC. cGLIS3 triggers the assembly of stress granules, activates the NF‐κB pathway, and causes chemoresistance. Icaritin (ICA) combined with Gemcitabine/Cisplatin (GP) is a promising therapy for ICC.
Background
The current randomized, controlled, multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy (NCT) and estrogen deprivation in patients ...with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
Methods
Eligible patients with AJCC stage IIB to stage IIIC, ER‐positive, HER2‐negative breast cancer were enrolled and randomly assigned to receive NCT with or without estrogen deprivation. The primary endpoint was the objective response rate (ORR).
Results
A total of 249 patients were assigned to either neoadjuvant chemoendocrine therapy (NCET) (125 patients) or the NCT group (124 patients). In the intention‐to‐treat analysis, the ORR was found to be significantly higher in the NCET group compared with the NCT group (84.8% vs 72.6%; odds ratio, 2.11 95% CI, 1.13‐3.95; P = .02). The efficacy of NCET was more prominent in tumors with a higher Ki‐67 index (>20%), with an ORR of 91.2% reported in the NCET group versus 68.7% in the NCT group (P = .001). The pathologic complete response and pathological response rates did not differ significantly between the 2 groups. Although there was no significant difference with regard to progression‐free survival (PFS) between the 2 groups (P = .188), patients with a higher baseline Ki‐67 index appeared to derive a greater PFS benefit from NCET (2‐year PFS rate of 91.5% in the NCET group vs 76.5% in the NCT group; P = .058). Adding endocrine agents to NCT did not result in significant differences in adverse events (grade 3 or 4; graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0) between the 2 groups.
Conclusions
The addition of estrogen deprivation to NCT appears to improve the clinical response in patients with ER‐positive, HER2‐negative breast cancer, especially for those individuals with a higher Ki‐67 index. Patients with a higher Ki‐67 index might derive more PFS benefit from concurrent neoadjuvant treatment.
The findings of the current study indicate that concurrent neoadjuvant chemotherapy and estrogen deprivation could be the preferred neoadjuvant treatment option for patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer, especially for those with higher Ki‐67 levels. These results support concurrent treatment as part of a promising therapeutic strategy for this patient population.
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Developing efficient and stable electrocatalysts with three-dimensional (3D) hierarchical nanostructures is extremely important in practical applications of direct alcohol fuel cells. ...Herein, 3D hierarchical thorn-like multi-metallic PtPdNiCu alloyed nanotripods (PtPdNiCu TNTPs) were efficiently fabricated by a one-pot aqueous method, in which Pluronic F127 performed as the structure-director and dispersing agent. The as-prepared PtPdNiCu TNTPs exhibited distinct electrocatalytic activity for methanol oxidation reaction (MOR) with a mass activity (MA) of 1.465 A mg−1Pd, which is superior to commercial Pt/C (0.925 A mg−1Pd) in 1.0 M KOH solution, along with the greater MA (1.019 A mg−1Pd) for ethanol oxidation reaction (EOR) than Pt/C (0.712 A mg−1Pd). This work would provide an impetus for rationally constructing multimetal nanomaterials to commercial implementation of advanced alcohol fuel cells.
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