Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting 1 in 5000–8000 individuals. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is the most common HHT and ...manifests as diverse vascular malformations ranging from mild symptoms such as epistaxis and mucosal and cutaneous telangiectases to severe arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is caused by heterozygous mutations in the ENG gene, which encodes endoglin, the TGFβ homodimeric co‐receptor. It was previously shown that some endoglin HHT1‐causing variants failed to traffic to the plasma membrane due to their retention in the endoplasmic reticulum (ER) and consequent degradation by ER‐associated degradation (ERAD). Endoglin is a homodimer formed in the ER, and we therefore hypothesized that mixed heterodimers might form between ER‐retained variants and WT protein, thus hampering its maturation and trafficking to the plasma membrane causing dominant negative effects. Indeed, HA‐tagged ER‐retained mutants formed heterodimers with Myc‐tagged WT endoglin. Moreover, variants L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking of WT endoglin by reducing its maturation and plasma membrane localization. These results strongly suggest dominant negative effects exerted by these ER‐retained variants aggravating endoglin loss of function in patients expressing them in the heterozygous state with the WT allele. Moreover, this study may help explain some of the variability observed among HHT1 patients due to the additional loss of function exerted by the dominant negative effects in addition to that due to haploinsufficiency. These findings might also have implications for some of the many conditions impacted by ERAD.
The formation of heterodimers between ER‐retained endoglin mutants and WT endoglin impairs WT maturation and trafficking to the plasma membrane.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
With the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some ...cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2-based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.
Objectives: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of ...breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals.
Methods: PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays.
Results: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression.
Conclusion: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression.
BiVO4 is a promising photoanode for photoelectrochemical (PEC) water splitting. Nevertheless, the sluggish water oxidation on its surface causes severe charge carriers recombination and thus reduces ...the overall efficiency. To overcome these imperfections, BiVO4 photoanodes were prepared and modified with transition metal-based oxygen evolution electrocatalysts, namely, NiFe, CoNi, and CoFe–layered double hydroxides (LDHs) oxygen evolution catalysts (OECs). The kinetics of charge transfer and recombination in the prepared photoanodes were studied by transient photocurrent and intensity-modulated photocurrent spectroscopy (IMPS). The rate constants of charge transfer and recombination were determined and correlated with the generated photocurrent to disclose the function of each electrocatalyst. It was concluded that the three investigated LDHs exhibit a comparable electrocatalytic activity at low applied potential, but CoNi–LDH has a superior passivation effect. Contrary to CoFe and NiFe–LDHs, CoNi–LDH passivates the surface states and unpins the Fermi level as proved by IMPS and photovoltage measurements. This study provides a systematic pathway to disclose the role of LDH OECs on BiVO4 surface which is an essential step for the rational design of efficient photoanodes.
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•Pristine BiVO4 films were synthesized using Bi2O3 and vanadium precursors.•They were modified with transition metal-based layered double hydroxides (LDHs).•The lifetime and the rate constants of charge transfer and recombination were determined.•NiFe, CoNi, and CoFe–LDHs showed comparable electrocatalytic activity at low bias.•CoNi–LDH exhibits the highest passivation capability and unpins the Fermi level.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The endoplasmic reticulum (ER) employs stringent quality control mechanisms to ensure the integrity of protein folding, allowing only properly folded, processed and assembled proteins to exit the ER ...and reach their functional destinations. Mutant proteins unable to attain their correct tertiary conformation or form complexes with their partners are retained in the ER and subsequently degraded through ER-associated protein degradation (ERAD) and associated mechanisms. ER retention contributes to a spectrum of monogenic diseases with diverse modes of inheritance and molecular mechanisms. In autosomal dominant diseases, when mutant proteins get retained in the ER, they can interact with their wild-type counterparts. This interaction may lead to the formation of mixed dimers or aberrant complexes, disrupting their normal trafficking and function in a dominant-negative manner. The combination of ER retention and dominant-negative effects has been frequently documented to cause a significant loss of functional proteins, thereby exacerbating disease severity. This review aims to examine existing literature and provide insights into the impact of dominant-negative effects exerted by mutant proteins retained in the ER in a range of autosomal dominant diseases including skeletal and connective tissue disorders, vascular disorders, neurological disorders, eye disorders and serpinopathies. Most crucially, we aim to emphasize the importance of this area of research, offering substantial potential for understanding the factors influencing phenotypic variability associated with genetic variants. Furthermore, we highlight current and prospective therapeutic approaches targeted at ameliorating the effects of mutations exhibiting dominant-negative effects. These approaches encompass experimental studies exploring treatments and their translation into clinical practice.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The oxidative modification of the major cholesterol carrying lipoprotein, oxLDL, is a biomarker as well as a pathological factor in cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), ...obesity and other metabolic diseases. Perturbed cellular homeostasis due to physiological, pathological and pharmacological factors hinder the proper functioning of the endoplasmic reticulum (ER), which is the major hub for protein folding and processing, lipid biosynthesis and calcium storage, thereby leading to ER stress. The cellular response to ER stress is marked by a defensive mechanism called unfolded protein response (UPR), wherein the cell adapts strategies that favor survival. Under conditions of excessive ER stress, when the survival mechanisms fail to restore balance, UPR switches to apoptosis and eliminates the defective cells. ER stress is a major hallmark in metabolic syndromes such as diabetes, non-alcoholic fatty liver disease (NAFLD), neurological and cardiovascular diseases. Though the pathological link between oxLDL and ER stress in cardiovascular diseases is well-documented, its involvement in other diseases is still largely unexplored. This review provides a deep insight into the common mechanisms in the pathogenicity of diseases involving oxLDL and ER stress as key players. In addition, the potential therapeutic intervention of the targets implicated in the pathogenic processes are also explored.
Introduction: Paclitaxel is a microtubule stabilizer that is currently one of the most utilized chemotherapeutic agents. Its efficacy in breast, uterine, lung and other neoplasms made its safety ...profile enhancement a subject of great interest. Neurotoxicity is the most common paclitaxel-associated toxicities. In addition, hypersensitivity reactions, hematological, gastrointestinal, and cardiac toxicities are all encountered.
Areas covered: The current review explores paclitaxel-induced toxicities mechanisms and risk factors. Studies investigating these toxicities pharmacogenomic biomarkers are reviewed and summarized. There is a limited margin of consistency between the retrieved associations. Variants in genes related to neuro-sensitivity are the most promising candidates for future studies.
Expert opinion: Genome-wide association studies highlighted multiple-candidate biomarkers relevant to neuro-sensitivity. Most of the identified paclitaxel-neurotoxicity candidate genes are derived from congenital neuropathy and diabetic-induced neurotoxicity pathways. Future studies should explore these sets of genes while considering the multifactorial nature of paclitaxel-induced neurotoxicity. In the absence of certain paclitaxel-toxicity biomarkers, future research should avoid earlier studies' caveats. Genes in paclitaxel's pharmacokinetic pathways could not provide consistent results in any of its associated toxicities. There is a need to dig deeper into toxicity-development mechanisms and personal vulnerability factors, rather than targeting only the genes suspected to affect drug exposure.
The postmodification approach allows convenient access to charge-tagged ammonium-functionalized bis(1,2,4-triazolin-5-ylidene)palladium(II) complexes even when the respective azolium salts are ...elusive. Bromo-functionalized 1,2,4-triazolium salts were first metalated to form the respective bromo-functionalized bis(NHC) complexes trans-PdBr2(R-tazy-Br)2 (R = Ph, Cy, 1a,b). Subsequent postcoordinative nucleophilic substitutions converted the bromo into ammonium functions, leading to the water-soluble, charge-tagged complexes trans-PdBr2(R-tazy-NEt3)2Br2 (R = Ph, Cy, 2a,b). The catalytic activities of 2a,b in the aqueous Suzuki–Miyaura reaction were compared to those of their analogues 2c,d bearing more bulky mesityl and diisopropylphenyl substituents, and a detailed stereoelectronic profiling of the NHCs using %V bur, HEP, and DFT calculations was conducted to rationalize their catalytic differences. Although all complexes are active, the more donating and less bulky complexes 2a,b performed significantly better than 2c,d at a very low catalyst loading of 0.001 mol %. 2a was found to be highly active for various aryl and heteroaryl bromides and some aryl chlorides. More importantly, this study discloses that NHCs with N-phenyl and N-cyclohexyl groups exhibit stereoelectronic flexibility, which could be the cause for the greater activities of their complexes.
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IJS, KILJ, NUK, PNG, UL, UM
High expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major ...epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer.
Expressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively.
We first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80-90%), and TIGIT were poorly hypomethylated (20-30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues.
Our data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer.
There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly ...selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer.
We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine–tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine–tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting.
Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3–6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7–8·2) in the fruquintinib group versus 4·8 months (4·0–5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55–0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 14%), asthenia (n=35 8%), and hand-foot syndrome (n=29 6%). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group).
Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population.
HUTCHMED.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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