Gastrointestinal microbiota may be involved in
associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential ...dysbiosis arising from
infection.
Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-
treatment, relative to 49
negative subjects.
In
positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in
positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between
and
,
,
,
,
were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased
after successful
eradication and more upregulated drug-resistant functional orthologs after failed treatment.
infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful
eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in ...patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 x 10.sup.6 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced greater than or equal to 1 adverse events (AEs). Grade greater than or equal to 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade greater than or equal to 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285. Keywords: Multiple myeloma, Chimeric antigen receptor therapy, B cell maturation antigen, Safety, Efficacy
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background and Aims
Coronavirus disease 2019 (COVID‐19) is a new infectious disease. To reveal the hepatic injury related to this disease and its clinical significance, we conducted a multicenter ...retrospective cohort study that included 5,771 adult patients with COVID‐19 pneumonia in Hubei Province.
Approach and Results
We reported the distributional and temporal patterns of liver injury indicators in these patients and determined their associated factors and death risk. Longitudinal liver function tests were retrospectively analyzed and correlated with the risk factors and death. Liver injury dynamic patterns differed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL). AST elevated first, followed by ALT, in severe patients. ALP modestly increased during hospitalization and largely remained in the normal range. The fluctuation in TBIL levels was mild in the non‐severe and the severe groups. AST abnormality was associated with the highest mortality risk compared with the other indicators of liver injury during hospitalization. Common factors associated with elevated liver injury indicators were lymphocyte count decrease, neutrophil count increase, and male gender.
Conclusion
The dynamic patterns of liver injury indicators and their potential risk factors may provide an important explanation for the COVID‐19‐associated liver injury. Because elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk, our study indicates that these parameters should be monitored during hospitalization.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Understanding the underlying molecular mechanisms of liver fibrosis is important to develop effective therapy. Herein, we show that focal-adhesion-kinse (FAK) plays a key role in promoting hepatic ...stellate cells (HSCs) activation in vitro and liver fibrosis progression in vivo. FAK activation is associated with increased expression of α-smooth muscle actin (α-SMA) and collagen in fibrotic live tissues. Transforming growth factor beta-1 (TGF-β1) induces FAK activation in a time and dose dependent manner. FAK activation precedes the α-SMA expression in HSCs. Inhibition of FAK activation blocks the α-SMA and collagen expression, and inhibits the formation of stress fibers in TGF-β1 treated HSCs. Furthermore, inhibition of FAK activation significantly reduces HSC migration and small GTPase activation, and induces apoptotic signaling in TGF-β1 treated HSCs. Importantly, FAK inhibitor attenuates liver fibrosis in vivo and significantly reduces collagen and α-SMA expression in an animal model of liver fibrosis. These data demonstrate that FAK plays an essential role in HSC activation and liver fibrosis progression, and FAK signaling pathway could be a potential target for liver fibrosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Combination chemotherapy refers to the use of multiple drugs to treat cancer. In this therapy, the optimal ratio of the drugs is essential to achieve drug synergism and the desired therapeutic ...effects. However, most delivery strategies are unable to precisely control the ratio of the drugs during the drug loading and delivery processes, resulting in inefficient synergy and unpredictable efficacy. Herein, a macrocyclic‐amphiphile‐based self‐assembled nanoparticle (MASN) that achieves precise loading and ratiometric delivery of therapeutic combinations is presented. By integrating multiple macrocyclic cavities within a single nanoparticle, the MASN can load multiple drug molecules via the host–guest interaction, and the ratio of the drugs loaded can be predicted with their initial concentrations and characteristic binding affinity. Moreover, MASNs are readily degraded under a hypoxic microenvironment, allowing spontaneous release of the drugs upon reaching tumor tissues. With precise drug loading and controlled release mechanisms, MASNs achieve ratiometric delivery of multiple commercial drugs to tumors, thereby achieving optimal anti‐tumor effects. Since the optimal drug ratio of a therapeutic combination can be quickly determined in vitro, MASNs can translate this optimal ratio to the therapeutic benefits in vivo, providing a potential platform for the rapid development of effective combination cancer therapies involving multiple drugs.
A macrocyclic‐amphiphile‐based self‐assembled nanoparticle (MASN) with the capability of precise loading and ratiometric delivery of different drugs is developed for effective combination chemotherapy. The MASN can quickly convert the optimal drug ratio of a therapeutic combination identified in vitro into therapeutic benefits in vivo, providing a potential platform for the rapid development of effective combinations of cancer therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Fluorescent chemosensors are powerful imaging tools in the fields of life sciences and engineering. Based on the principle of supramolecular chemistry, indicator displacement assay (IDA) provides an ...alternative approach for constructing and optimizing chemosensors, which has the advantages of simplicity, tunability, and modularity. However, the application of IDA in bioimaging continues to face a series of challenges, including interfering signals, background noise, and inconsistent spatial location. Accordingly, we herein report a supramolecular bioimaging strategy of Förster resonance energy transfer (FRET)‐assisted IDA by employing macrocyclic amphiphiles as the operating platform. By merging FRET with IDA, the limitations of IDA in bioimaging were addressed. As a proof of concept, the study achieved mitochondria‐targeted imaging of adenosine triphosphate in live cells with signal amplification. This study opens a non‐covalent avenue for bioimaging with advancements in tunability, generality, and simplicity, apart from the covalent approach.
We present a novel supramolecular strategy for fluorescence imaging via incorporation of Förster resonance energy transfer into indicator displacement assay.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Understanding the role of the oxidation state of the Cu surface and surface-adsorbed intermediate species in electrochemical CO2 reduction is crucial for the development of selective CO2-to-fuel ...electrocatalysts. In this study, the electrochemical CO2 reduction mechanism over the Cu catalysts with various oxidation states was studied by using in situ surface-enhanced infrared absorption spectroscopy (SEIRAS), in situ soft X-ray absorption spectroscopy (Cu L-edge), and online gas chromatography measurements. The atop-adsorbed CO (COatop) intermediate is obtained on the electrodeposited Cu surface which primarily has the oxidation state of Cu(I). COatop is further reduced, followed by the formation of C1 product such as CH4. The residual bridge-adsorbed CO (CObridge) is formed on the as-prepared Cu surface with Cu(0) which inhibits hydrocarbon formation. In contrast, the CV-treated Cu electrode prepared by oxidizing the as-prepared Cu surface contains different amounts of Cu(I) and Cu(0) states. The major theme of this work is that in situ SEIRAS results show the coexistence of COatop and CObridge as the reaction intermediates during CO2 reduction and that the selectivity of CO2-to-ethylene conversion is further enhanced in the CV-treated Cu electrode. The Cu catalysts modulated by the electrochemical method exhibit different oxidation states and reaction intermediates as well as electrocatalytic properties.
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IJS, KILJ, NUK, PNG, UL, UM
In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective ...role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.
•Irisin is highly expressed in mouse hearts.•FNDC5 deletion aggravated and FNDC5 overexpression ameliorated the left ventricle hypertrophy, remodeling, injury and dysfunction induced by pressure overload.•Irisin supplementation attenuated hypertrophy in Ang II– or phenylephrine-induced cardiomyocytes.•Irisin alleviated cardiomyocyte hypertrophy in vivo and in vitro by inducing beneficial autophagy and autophagy influx via AMPK-ULK1 signaling but independent of mTOR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary
Rice (Oryza sativa L.) has two ecotypes, upland and lowland rice, that have been observed to show different tolerance levels under flooding stress. In this study, two rice cultivars, upland ...(Up221, flooding‐intolerant) and lowland (Low88, flooding‐tolerant), were initially used to study their molecular mechanisms in response to flooding germination. We observed that variations in the OsCBL10 promoter sequences in these two cultivars might contribute to this divergence in flooding tolerance. Further analysis using another eight rice cultivars revealed that the OsCBL10 promoter could be classified as either a flooding‐tolerant type (T‐type) or a flooding‐intolerant type (I‐type). The OsCBL10 T‐type promoter only existed in japonica lowland cultivars, whereas the OsCBL10 I‐type promoter existed in japonica upland, indica upland and indica lowland cultivars. Flooding‐tolerant rice cultivars containing the OsCBL10 T‐type promoter have shown lower Ca2+ flow and higher α‐amylase activities in comparison to those in flooding‐intolerant cultivars. Furthermore, the OsCBL10 overexpression lines were sensitive to both flooding and hypoxic treatments during rice germination with enhanced Ca2+ flow in comparison to wild‐type. Subsequent findings also indicate that OsCBL10 may affect OsCIPK15 protein abundance and its downstream pathways. In summary, our results suggest that the adaptation to flooding stress during rice germination is associated with two different OsCBL10 promoters, which in turn affect OsCBL10 expression in different cultivars and negatively affect OsCIPK15 protein accumulation and its downstream cascade.
Significance Statement
This study identifies that OsCBL10 is able to communicate with upstream calcium signaling and downstream flooding responses by affecting OsCIPK15 protein accumulation or stability. The variation in OsCBL10 promoter regions could be a general mechanism in Sub1A‐deficient lowland japonica cultivars in response to flooding germination.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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