A dual-responsive hydrogel (pH/temperature) was developed from a thermos-responsive polymer, pluronic F-127 (PF127), and pH-responsive polymers, N,N,N-trimethyl chitosan (TMC) and polyethylene ...glycolated hyaluronic acid (PEG-HA). Gallic acid, the principal component of the traditional Chinese drug Cortex Moutan was loaded into the hydrogel (PF127/TMC/PEG-HA) for possible application in textile-based transdermal therapy as Cortex Moutan has been proven to be an effective drug for the treatment of atopic dermatitis (AD). TMC and PEG-HA were synthesized, characterized (
H-NMR and FTIR), and added to the formulations to enhance drug release from the hydrogels, and increase the drug targeting of the carriers. The thermo-responsive properties of the hydrogel were assessed by dynamic viscosity analysis and the tube inversion method, and the pH-responsiveness of the formulation was determined by changing the pH of the external media. Rheology study of the hydrogels showed that complex viscosity and storage/loss moduli for PF127/TMC/PEG-HA hydrogel formulation are higher than PF127 hydrogel. The microstructure analysis by reflection SAXS indicated similar type of frozen inhomogeneity of hydrogel formulations. Various characterizations such as FTIR, SEM, TEM, zeta potential, and degradation of the hydrogel formulation indicated that the PF127/TMC/PEG-HA hydrogel showed better physico-chemical properties and morphology than did the PF127 hydrogel, and drug release was also higher for the PF127/TMC/PEG-HA hydrogel than for PF127. The drug release from hydrogels followed more closely first-order rate model than other rate models.
Alteration of tissue mechanical properties is a physical hallmark of solid tumors including gliomas. How tumor cells sense and regulate tissue mechanics is largely unknown. Here, we show that ...mechanosensitive ion channel Piezo regulates mitosis and tissue stiffness of Drosophila gliomas, but not non-transformed brains. PIEZO1 is overexpressed in aggressive human gliomas and its expression inversely correlates with patient survival. Deleting PIEZO1 suppresses the growth of glioblastoma stem cells, inhibits tumor development, and prolongs mouse survival. Focal mechanical force activates prominent PIEZO1-dependent currents from glioma cell processes, but not soma. PIEZO1 localizes at focal adhesions to activate integrin-FAK signaling, regulate extracellular matrix, and reinforce tissue stiffening. In turn, a stiffer mechanical microenvironment elevates PIEZO1 expression to promote glioma aggression. Therefore, glioma cells are mechanosensory in a PIEZO1-dependent manner, and targeting PIEZO1 represents a strategy to break the reciprocal, disease-aggravating feedforward circuit between tumor cell mechanotransduction and the aberrant tissue mechanics.
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•Drosophila Piezo regulates cell proliferation and tissue stiffening of gliomas•Human PIEZO1 is overexpressed in aggressive gliomas and predicts poor survival•Piezo/PIEZO1 interacts with integrin-FAK signaling to regulate tumor stiffness•PIEZO1 co-opts aberrant tissue mechanics to promote glioma aggression
PIEZO1 is an ion channel that converts mechanical stimuli into cellular signaling. Here, Chen et al. perform multi-species studies to define a feedforward circuit mediated by PIEZO1 and tumor tissue mechanics to promote glioma growth.
Despite the recognition that the gut microbiota acts a clinically significant role in cancer chemotherapy, both mechanistic understanding and translational research are still limited. Maximizing drug ...efficacy requires an in‐depth understanding of how the microbiota contributes to therapeutic responses, while microbiota modulation is hindered by the complexity of the human body. To address this issue, a 3D experimental model named engineered microbiota (EM) is reported for bridging microbiota‐drug interaction research and therapeutic decision‐making. EM can be manipulated in vitro and faithfully recapitulate the human gut microbiota at the genus/species level while allowing co‐culture with cells, organoids, and isolated tissues for testing drug responses. Examination of various clinical and experimental drugs by EM reveales that the gut microbiota affects drug efficacy through three pathways: immunological effects, bioaccumulation, and drug metabolism. Guided by discovered mechanisms, custom‐tailored strategies are adopted to maximize the therapeutic efficacy of drugs on orthotopic tumor models with patient‐derived gut microbiota. These strategies include immune synergy, nanoparticle encapsulation, and host–guest complex formation, respectively. Given the important role of the gut microbiota in influencing drug efficacy, EM will likely become an indispensable tool to guide drug translation and clinical decision‐making.
A gradient hydrogel‐based microbial community is presented to simulate the real intestinal microbiome for bridging microbiome‐drug interaction research and treatment decision. This model reveals three mechanisms of drug‐microbiota interaction: immunological effect, bio‐accumulation, and drug metabolism, which provide innovative regulatory approaches for improving the anti‐cancer effect of drugs.
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life‐threatening cutaneous conditions. However, studies of pediatric SJS/TEN are limited. To investigate the causes, clinical ...course, outcomes and complications of SJS and TEN in children. This retrospective study included 47 pediatric patients (aged < 18 years) with SJS, SJS/TEN, or TEN treated at Chang Gung Memorial Hospital, Taiwan, between January 2009 and December 2019. ALDEN scores and serological tests were used to assess causes and SCORTEN scores were applied to evaluate disease severity. Forty‐seven patients, including 30 with SJS, 6 with SJS/TEN, and 11 with TEN were included. Median age was 8 years (range 1–17 years); 51.1% were male. Thirty‐three cases (70.2%) were caused by drugs and infectious pathogens were suspected in 14 cases (29.8%). Oxcarbazepine (5/47, 10.6%) and amoxicillin (5/47, 10.6%) were the most often‐implicated drugs, and Mycoplasma infection (9/47, 19.1%) was the predominant infectious cause. Only one TENS patient died (mortality rate 1/47, 2.1%) due to septic shock with ARDS, acute renal failure and cardiopulmonary shock. Median hospital stay was 15.5 (3–42) days. Pulmonary involvement (2/39, 5.1%), including pneumonia and ARDS, was noted in acute stage. Long‐term sequelae were ocular involvement (6/39, 15.4%), nail dystrophy (4/39, 10.3%) and post‐inflammatory hypo‐/hyperpigmentation (3/39, 7.7%). In the present study, pediatric patients with SJS, SJS/TEN, or TEN have good outcomes with few long‐term complications and low mortality. Mycoplasma is the most common infectious cause in pediatric SJS/TEN. Ocular discomfort, nail dystrophy and skin dyschromia are common long‐term sequelae requiring regular follow‐up.
Background
Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) ...reactivation when treated with biologic or targeted synthetic (b/ts) disease‐modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population.
Methods
From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg−/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed.
Results
During 2845 person‐years of follow‐up, 27 of 416 (6.5%,9.5 per 1000 person‐years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9–186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person‐years), followed by abatacept (incidence rate: 24.0 per 1000 person‐years). In multivariate analysis, rituximab (adjusted hazard ratio aHR: 15.77, 95% confidence interval CI: 4.12–60.32, p = .001), abatacept (aHR: 9.30, 1.83–47.19, p = .007), adalimumab (aHR: 3.86, 1.05–14.26, p = .04) and negative baseline HBV surface antibody (anti‐HBs, <10 mIU/mL) (aHR: 3.89, 1.70–8.92, p < .001) were independent risk factors for HBV reactivation.
Conclusion
HBsAg−/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti‐HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti‐HBs titre and type of therapy.
Patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have high mortality rates. Disseminated intravascular coagulation has been reported in SJS/TEN patients. The influence of ...this lethal complication in patients with SJS/TEN is not well known.
This study aimed to investigate the risk and outcomes of disseminated intravascular coagulation in patients with SJS/TEN.
We analyzed the disseminated intravascular coagulation profiles of patients receiving a diagnosis of SJS/TEN between 2010 and 2019.
We analyzed 150 patients with SJS/TEN (75 with SJS, 22 with overlapping SJS/TEN, and 53 with TEN) and their complete disseminated intravascular coagulation profiles. Disseminated intravascular coagulation was diagnosed in 32 patients (21.3%), primarily those with TEN. It was significantly associated with systemic complications, including gastrointestinal bleeding, respiratory failure, renal failure, liver failure, infection, and bacteremia. Additionally, SJS/TEN patients with disseminated intravascular coagulation had elevated procalcitonin levels. Among patients with SJS/TEN, disseminated intravascular coagulation was associated with a greater than 10-fold increase in mortality (78.1% vs 7%).
The study limitations include small sample size and a single hospital system.
Disseminated intravascular coagulation is a potential complication of SJS/TEN and associated with higher mortality. Early recognition and appropriate management of this critical complication are important for patients with SJS/TEN.
USP7, one of the most abundant ubiquitin-specific proteases (USP), plays multifaceted roles in many cellular events, including oncogenic pathways. Accumulated studies have suggested that USP7, ...through modulating the MDM2/MDMX-p53 pathway, is a promising target for cancer treatment; however, little is known about the function of USP7 in p53-deficient tumors. Here we report that USP7 regulates the autoregulation of SMAD3, a key regulator of transforming growth factor β (TGFβ) signaling, that represses the cell progression of p53-deficient lung cancer. CRISPR/Cas9-mediated inactivation of USP7 in p53-deficient lung cancer H1299 line resulted in advanced cell proliferation in vitro and in xenograft tumor in vivo. Genome-wide analyses (ChIP-seq and RNA-seq) of USP7 KO H1299 cells reveal a dramatic reduction of SMAD3 autoregulation, including decreased gene expression and blunted function of associated super-enhancer (SE). Furthermore, biochemical assays show that SMAD3 is conjugated by mono-ubiquitin, which negatively regulates the DNA-binding function of SMAD3, in USP7 KO cells. In addition, cell-free and cell-based analyses further demonstrate that the deubiquitinase activity of USP7 mediates the removal of mono-ubiquitin from SMAD3 and facilitates the DNA-binding of SMAD3-SMAD4 dimer at SMAD3 locus, and thus enhance the autoregulation of SMAD3. Collectively, our study identified a novel mechanism by which USP7, through catalyzing the SMAD3 de-monoubiquitination, facilitates the positive autoregulation of SMAD3, and represses the cancer progression of p53-deficient lung cancer.
Development of mammalian auditory epithelium, the organ of Corti, requires precise control of both cell cycle withdrawal and differentiation. Sensory progenitors (prosensory cells) in the cochlear ...apex exit the cell cycle first but differentiate last. Sonic hedgehog (Shh) signaling is required for the spatiotemporal regulation of prosensory cell differentiation, but the underlying mechanisms remain unclear. Here, we show that suppressor of fused (Sufu), a negative regulator of Shh signaling, is essential for controlling the timing and progression of hair cell (HC) differentiation. Removal of
leads to abnormal Atoh1 expression and a severe delay of HC differentiation due to elevated
mRNA expression. Later in development, HC differentiation defects are restored in the
mutant by the action of speckle-type PDZ protein (Spop), which promotes Gli2 protein degradation. Deletion of both
and
results in robust Gli2 activation, exacerbating HC differentiation defects. We further demonstrate that Gli2 inhibits HC differentiation through maintaining the progenitor state of Sox2
prosensory cells. Along the basal-apical axis of the developing cochlea, the Sox2 expression level is higher in the progenitor cells than in differentiating cells and is down-regulated from base to apex as differentiation proceeds. The dynamic spatiotemporal change of Sox2 expression levels is controlled by Shh signaling through Gli2. Together, our results reveal key functions of Gli2 in sustaining the progenitor state, thereby preventing HC differentiation and in turn governing the basal-apical progression of HC differentiation in the cochlea.
Bacteria and fungi secrete many natural products that inhibit each other's growth and development. The dynamic changes in secreted metabolites that occur during interactions between bacteria and ...fungi are complicated. Pyochelin is a siderophore produced by many Pseudomonas and Burkholderia species that induces systemic resistance in plants and has been identified as an antifungal agent. Through imaging mass spectrometry and metabolomics analysis, we found that Phellinus noxius, a plant pathogen, can modify pyochelin and ent-pyochelin to an esterification product, resulting in reduced iron-chelation and loss of antifungal activity. We also observed that dehydroergosterol peroxide, the fungal metabolite, is only accumulated in the presence of pyochelin produced through bacteria-fungi interactions. For the first time, we show the fungal transformation of pyochelin in the microbial interaction. Our findings highlight the importance of understanding the dynamic changes of metabolites in microbial interactions and their influences on microbial communities.
Current research has widely applied heteroatom doping for the promotion of catalyst activity in peroxymonosulfate (PMS) systems; however, the relationship between heteroatom doping and stimulated ...activation mechanism transformation is not fully understood. Herein, we introduce nitrogen and sulfur doping into a Co@rGO material for PMS activation to degrade tetracycline (TC) and systematically investigate how heteroatom doping transformed the activation mechanism of the original Co@rGO/PMS system. N was homogeneously inserted into the reduced graphene oxide (rGO) matrix of Co@rGO, inducing a significant increase in the degradation efficiency without affecting the activation mechanism transformation. Additionally, S doping converted Co3O4 to Co4S3 in Co@rGO and transformed the cooperative oxidation pathway into a single non-radical pathway with stronger intensity, which led to a higher stability against environmental interferences. Notably, based on density functional theory (DFT) calculations, we demonstrated that Co4S3 had a higher energy barrier for PMS adsorption and cleavage than Co3O4, and therefore, the radical pathway was not easily stimulated by Co4S3. Overall, this study not only illustrated the improvement due to the heteroatom doping of Co@rGO for TC degradation in a PMS system but also bridged the knowledge gap between the catalyst structure and degradation performance through activation mechanism transformation drawn from theoretical and experimental analyses.
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