Multiple myeloma(MM),one of the most common hemato logical neoplasms worldwide,originates from malignant plasma cells in the bone marrow.MM remains an incurable disease,although continued treatment advancements have m...Multiple myeloma(MM),one of the most common hemato logical neoplasms worldwide,originates from malignant plasma cells in the bone marrow.MM remains an incurable disease,although continued treatment advancements have markedly increased overall survival.Many patients with MM eventually experience relapse or become treatment-refractory1.Patients with relapsed or refractory multiple myeloma(RRMM)become progressively more challenging to manage and have poor prognosis2.展开更多
Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclona...Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins(M protein),leading to bone destruction,hypercalcemia,anemia,and renal insufficiency(Alexandrakis et al.,2015;Yang et al.,2018).Since a large number of new drugs,represented by proteasome inhibitors and immunomodulators,have been successfullyused to treat MM.展开更多
Invasive fungal infection （IFI） is a growing cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT）. We retrospectively reviewed the records of 408 pat...Invasive fungal infection （IFI） is a growing cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT）. We retrospectively reviewed the records of 408 patients un- dergoing alIo-HSCTs during the period November 1998 to December 2009, analyzed the incidence and risk factors of IFI, and examined the impact of IFI on overall survival. A total of 92 （22.5%） episodes suffered proven or probable IFI （4 patients were proven, 88 patients were probable）. Candida was the most common pathogen for early IFI, and mold was the most frequent causative organism for late IFI. A prior history of IFI, human leukocyte antigen （HLA） mismatch, long-time neutropenia, and acute graft-versus-host-disease （GVHD） were risk factors for early IFI. A prior history of IFI, corticosteroid therapy, cytomegalovirus （CMV） disease, and chronic GVHD were risk factors for late IFI. IFI-related mortality was 53.26%. The 12-year overall survival （OS） rate for IFI was significantly lower than that of patients without IFI （41.9% vs. 63.6%, P〈0.01）.展开更多
There are well-established chemical and turbidity anomalies in the plumes occurring vicinity of hydrothermal vents, which are used to indicate their existence and locations. We here develop a small, accurate multi-cha...There are well-established chemical and turbidity anomalies in the plumes occurring vicinity of hydrothermal vents, which are used to indicate their existence and locations. We here develop a small, accurate multi-channel chemical sensor to detect such anomalies which can be used in deep-sea at depths of more than 4 000 m. The design allowed five all-solid-state electrodes to be mounted on it and each (apart from one reference electrode) could be changed according to chemicals to be measured. Two experiments were conducted using the chemical sensors. The first was a shallow-sea trial which included sample measurements and in situ monitoring. pH, Eh, CO3^2- and SO4^2- electrodes were utilized to demonstrate that the chemical sensor was accurate and stable outside the laboratory. In the second experiment, the chemical sensor was integrated with pH, Eh, CO3^2- and H2S electrodes, and was used in 29 scans of the seabed along the Southwest Indian Ridge (SWIR) to detect hydrothermal vents, from which 27 sets of valid data were obtained. Hydrothermal vents were identified by analyzing the chemical anomalies, the primary judging criteria were decreasing voltages of Eh and H2S, matched by increasing voltages of pH and CO3^2- . We proposed that simultaneous detection of changes in these parameters will indicate a hydrothermal vent. Amongst the 27 valid sets of data, five potential hydrothermal vents were targeted using the proposed method. We suggest that our sensors could be widely employed by marine scientists.展开更多
CUDC-101,an effective and multi-target inhibitor of epidermal growth factor receptor(EGFR),histone deacetylase(HDAC),and human epidermal growth factor receptor 2(HER2),has been reported to inhibit many kinds of cancer...CUDC-101,an effective and multi-target inhibitor of epidermal growth factor receptor(EGFR),histone deacetylase(HDAC),and human epidermal growth factor receptor 2(HER2),has been reported to inhibit many kinds of cancers,such as acute promyelocytic leukemia and non-Hodgkin's lymphoma.However,no studies have yet investigated whether CUDC-101 is effective against myeloma.Herein,we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma(MM)cell lines and induces cell apoptosis in a time-and dose-dependent manner.Moreover,CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase(PI3K)and HDAC,and regulated the cell cycle G2/M arrest.Moreover,we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug.Bortezomib is one of the important drugs in MM treatment,and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib.The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade.Collectively,our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib,which provides insights into exploring new strategies for MM treatment.展开更多
BACKGROUND Although minimal change disease(MCD)and focal segmental glomerulosclerosis(FSGS)have been described as two separate forms of nephrotic syndrome(NS),they are not completely independent.We report a case of a ...BACKGROUND Although minimal change disease(MCD)and focal segmental glomerulosclerosis(FSGS)have been described as two separate forms of nephrotic syndrome(NS),they are not completely independent.We report a case of a patient transitioning from MCD to FSGS,review the literature,and explore the relationship between the two diseases.CASE SUMMARY A 42-year-old male welder,presenting with lower extremity edema and elevated serum creatinine,was diagnosed with NS and end-stage kidney disease(ESKD)based on laboratory test results.The patient had undergone a kidney biopsy for NS 20 years previously,which indicated MCD,and a second recent kidney biopsy suggested FSGS.The patient was an electric welder with excessive levels of cadmium and lead in his blood.Consequently,we suspect that his aggravated pathology and occurrence of ESKD were related to metal nephrotoxicity.The patient eventually received kidney replacement therapy and quit his job which involved long-term exposure to metals.During the 1-year follow-up period,the patient was negative for metal elements in the blood and urine and recovered partial kidney function.CONCLUSION MCD and FSGS may be different stages of the same disease.The transition from MCD to FSGS in this case indicates disease progression,which may be related to excessive metal contaminants caused by the patient’s occupation.展开更多
Waldenström macroglobulinemia(WM)is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M(IgM)protein(Owen et al.,2003).Common signs and symptoms include fatigue...Waldenström macroglobulinemia(WM)is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M(IgM)protein(Owen et al.,2003).Common signs and symptoms include fatigue due to anemia,lymph node enlargement,hepatosplenomegaly,thrombocytopenia,symptoms related to high viscosity,and peripheral neuropathy,among others.Despite significant advances in WM treatment,this type of indolent lymphoma remains incurable,with a wide array of patient outcomes(Ruan et al.,2020).In recent years,chimeric antigen receptor T(CAR-T)cell therapy targeting cluster of differentiation 19(CD19)has shown unprecedented response rates and durability in the treatment of B-cell malignancies.In this report,we describe a challenging case of WM that involved multiple extramedullary sites,relapsed,and was refractory to chemotherapy,immunotherapy,and targeted therapy.After anti-CD19 CAR-T cell therapy,the tumor burden significantly decreased and the patient’s condition remained stable at the writing of this report.展开更多
The QRS-T angle,as an index of noninvasive cardioelectric vector,is closely related to the change of heart structure and function.There are different methedologies to measure the QRS-T angle,which can be roughly divid...The QRS-T angle,as an index of noninvasive cardioelectric vector,is closely related to the change of heart structure and function.There are different methedologies to measure the QRS-T angle,which can be roughly dividedinto two types:plane angle and space angle.Studies show that the influence factors include two aspects of physiology and pathology of the angle,in pathological ways,the disease such as myocardial hypertrophy,myocardial ischemia,hypertension,ventricular arrhythmia has larger clinical significance.In recent years,the research on the risk stratification of the QRS-T angle on sudden death has made great progress,but there are still some disputes about whether the space angle can be replaced by the plane angle and the range of normal value and so on.展开更多
This consensus on multiple myeloma-related bone diseases(MBDs)underscores the importance of a multidisciplinary approach that encompasses hematology,radiology,orthopedics,and additional specialties to tackle its intri...This consensus on multiple myeloma-related bone diseases(MBDs)underscores the importance of a multidisciplinary approach that encompasses hematology,radiology,orthopedics,and additional specialties to tackle its intricate challenges.MBD,a prevalent and debilitating complication of multiple myeloma,leads to bone pain,fractures,and skeletal-related events(SREs),which profoundly impact patients’quality of life.The guidelines offer a thorough framework for diagnosis,treatment,and continual assessment,emphasizing early detection and consistent monitoring using imaging techniques such as positron emission tomography-computed tomography(PET-CT)and magnetic resonance imaging(MRI).Treatment strategies prioritize the careful application of antimyeloma agents,bisphosphonates,and denosumab to minimize bone loss and decrease SRE risk,complemented by surgical and radiotherapy interventions for structural or pain-related issues.Supportive care measures,including pain management,rehabilitation,nutritional support,and dental evaluations,play a crucial role in enhancing patient outcomes and preserving quality of life.This consensus advocates a standardized,evidencebased approach to managing MBD,ensuring comprehensive and coordinated care for patients.展开更多
Infantile hemangioma is the most common benign vascular tumor of infancy and is characterized by a unique life cycle.Animal models that reflect the histological and biological characteristics of infantile hemangioma a...Infantile hemangioma is the most common benign vascular tumor of infancy and is characterized by a unique life cycle.Animal models that reflect the histological and biological characteristics of infantile hemangioma are critical tools for preclinical studies.Various infantile hemangioma animal models have been developed and improved during the past few decades.However,very few reports have provided practical suggestions for selecting a suitable animal model based on the study purpose.This comprehensive review summarizes the construction methods and application scenarios of different models.The advantages and disadvantages of each model are fully discussed,providing a reference for choosing the most applicable animal model for infantile hemangioma-associated research.展开更多
Gliomas present a significant challenge in oncology due to their often subtle early symptoms and the insidious nature of their growth,which is compounded by the blood-brain barrier.Recent evidence has highlighted the ...Gliomas present a significant challenge in oncology due to their often subtle early symptoms and the insidious nature of their growth,which is compounded by the blood-brain barrier.Recent evidence has highlighted the diagnostic and therapeutic potential of monocytes,macrophages,and microglia in the context of glioma.This review focused on emerging evidence and hypotheses concerning the components and interrelationships within the mononuclear phagocyte system(MPS)in the central nervous system and its role in glioma development and invasion.By summarizing the involvement of the MPS in glioma biology,this paper offers a novel perspective for the integration of liquid biopsy and targeted therapies in oncology.展开更多
Psoriasis patients who are obese tend to have serious clinical manifestations and poor responses to various biological agents in most cases. However, the mechanisms by which obesity exacerbates psoriasis remain enigma...Psoriasis patients who are obese tend to have serious clinical manifestations and poor responses to various biological agents in most cases. However, the mechanisms by which obesity exacerbates psoriasis remain enigmatic. In this study, we found that the abundance of systemic and localized cutaneous neutrophil extracellular traps (NETs) associated with the obesity-induced aggravation of psoriasis was positively correlated with disease severity and that the inhibition of NETs alleviated psoriatic dermatitis in obese mice. Mechanistically, we found that changes in fatty acid composition in obese subjects resulted in the deposition of saturated fatty acids (SFAs), which promoted the release of NETs via the TLR4-MD2/ROS signaling pathway. We further revealed that NETs potentiate IL-17 inflammation, especially γδT17-mediated immune responses, in obesity-exacerbated psoriasis patients. Moreover, SFAs induced a decreased response to anti-IL17A treatment in psoriasis-like mice, whereas the inhibition of NETs improved the beneficial effects of anti-IL17A in psoriasis-like mice with lipid metabolism disorders. Our findings collectively suggest that SFA-induced NETs play a critical role in the exacerbation of obesity-related psoriasis and provide potential new strategies for the clinical treatment of refractory psoriasis patients with lipid metabolism disorders.展开更多
Introduction:Stool DNA testing based on methylated syndecan-2(mSDC2)is a potential novel non-invasive screening test for colorectal cancer(CRC).This study aimed to assess its positive predictive value(PPV)in real-worl...Introduction:Stool DNA testing based on methylated syndecan-2(mSDC2)is a potential novel non-invasive screening test for colorectal cancer(CRC).This study aimed to assess its positive predictive value(PPV)in real-world practice.Methods:This study retrospectively recruited consecutive patients with positive stool DNA-based SDC2 methylation tests from 18 hospitals between November 2016 and July 2021.Included patients were classified into the average-risk equivalent or increased-risk population and the previous-negative-colonoscopy or no-previous-colonoscopy groups.Multivariate logistic regression was conducted to investigate the risk factors that affect the detection of advanced colorectal neoplasia(ACN)in patients with a positive mSDC2 test.The primary outcome was the PPV for ACN.Results:The overall PPVs for ACN,CRC,and colorectal neoplasia were 28.5%,12.8%,and 44.6%,respectively.The PPV for ACN was higher in the no-previous-colonoscopy group than in the previous-negative-colonoscopy group(30.1%vs 18.5%,P=0.008)and higher in the increased-risk population than in the average-risk equivalent population(41.1%vs 21.6%,P<0.001).However,the PPV(18.5%)was still high for patients with a previous negative colonoscopy.For ACN detection in patients with a positive mSDC2 test,old age,increased risk,and smoking history were identified as independent risk factors;previous negative colonoscopy was identified as a protective factor.Conclusions:The mSDC2 test,which has a high PPV for both ACN and CRC,is expected to be an alternative CRC screening strategy.Patients with a positive mSDC2 test might require a colonoscopy as soon as possible,even if the previous colonoscopy was negative.展开更多
Photosynthetic CO2 fixation is the ultimate source of organic carbon on earth and thus is essential for crop production and carbon sequestration, Ribulose-1,5-bis- phosphate carboxylase/oxygenase （Rubisco） catalyzes...Photosynthetic CO2 fixation is the ultimate source of organic carbon on earth and thus is essential for crop production and carbon sequestration, Ribulose-1,5-bis- phosphate carboxylase/oxygenase （Rubisco） catalyzes the first step of photosynthetic CO2 fixation. However, the extreme low carboxylation efficiency of Rubisco makes it the most attractive target for improving pho- tosynthetic efficiency. Extensive studies have focused on re-engineering a more efficient enzyme, but the effort has been impeded by the limited understanding of its structure-function relationships and the lack of an effi- cient selection system towards its activity. To address the unsuccessful molecular engineering of Rubisco, we developed an Escherichia coil-based activity-directed selection system which links the growth of host cell solely to the Rubisco activity therein. A Synechococcus sp. PCC7002 Rubisco mutant with E49V and D82G sub- stitutions in the small subunit was selected from a total of 15,000 mutants by one round of evolution. This mutant showed an 85% increase in specific carboxyla- tion activity and a 45% improvement in catalytic efficiency towards CO2. The small-subunit E49V mutation was speculated to influence holoenzyme catalysis through interaction with the large-subunit Q225. This interaction is conserved among various Rubisco from higher plants and Chlamydomonas reinhardtii. Knowledge of these might provide clues for engineering Rubisco from higher plants, with the potential of increasing the crop yield.展开更多
Tumor metastasis is the dominant cause of death in cancer patients. However, the molecular and cellular mechanisms underlying tumor metastasis are still elusive. The identi?cation of protein molecules with their expre...Tumor metastasis is the dominant cause of death in cancer patients. However, the molecular and cellular mechanisms underlying tumor metastasis are still elusive. The identi?cation of protein molecules with their expressions correlated to the metastatic process would help to understand the metastatic mechanisms and thus facilitate the development of strategies for the therapeutic interventions and clini- cal management of cancer. Proteomics is a systematic research approach aiming to provide the global characterization of protein expression and function under given conditions. Proteomic technology has been widely used in biomarker discovery and pathogenetic studies including tumor metastasis. This article provides a brief review of the application of proteomics in identifying molecular factors in tumor metastasis process. The combination of proteomics with other experimental ap- proaches in biochemistry, cell biology, molecular genetics and chemistry, together with the development of new technologies and improvements in existing method- ologies will continue to extend its application in studying cancer metastasis.展开更多
Recycling of carbon dioxide(CO_2) into fuels and chemicals is a potential approach to reduce CO_2 emission and fossil-fuel consumption. Autotrophic microbes can utilize energy from light, hydrogen, or sulfur to assimi...Recycling of carbon dioxide(CO_2) into fuels and chemicals is a potential approach to reduce CO_2 emission and fossil-fuel consumption. Autotrophic microbes can utilize energy from light, hydrogen, or sulfur to assimilate atmospheric CO_2 into organic compounds at ambient temperature and pressure. This provides a feasible way for biological production of fuels and chemicals from CO_2 under normal conditions. Recently great progress has been made in this research area, and dozens of CO_2-derived fuels and chemicals have been reported to be synthesized by autotrophic microbes. This is accompanied by investigations into natural CO_2-fixation pathways and the rapid development of new technologies in synthetic biology. This review first summarizes the six natural CO_2-fixation pathways reported to date, followed by an overview of recent progress in the design and engineering of CO_2-fixation pathways as well as energy supply patterns using the concept and tools of synthetic biology. Finally, we will discuss future prospects in biological fixation of CO_2.展开更多
Graft-versus-host disease （GVHD） is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 （TLR4）, which is a major receptor for bacterial lipopolys...Graft-versus-host disease （GVHD） is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 （TLR4）, which is a major receptor for bacterial lipopolysaccharides （LPS）, in the development of acute GVHD, we used a TLR4-knockout （TLR4-/-） mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4-/- mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type （TLR4＋/＋） mice. In addition, histopathological analyses revealed that in TLR4-/-→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4＋/＋, TLR4-/- mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4-/- mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 （Th 1） development was obviously attenuated compared with TLR4＋/＋ mice dendritic cells, and the levels of interferon-T （IFN-γ） and IL-IO, Th2-cell specific cytokines, were significantly higher in the serum of TLR4-/-→BALB/c than in TLR4＋/＋→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.展开更多
Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, ...Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.展开更多
Development of controllable hypermutable cells can greatly benefit understanding and harnessing microbial evolution.However,there have not been any similar sys-tems developed for Clostridium,an important bacterial gen...Development of controllable hypermutable cells can greatly benefit understanding and harnessing microbial evolution.However,there have not been any similar sys-tems developed for Clostridium,an important bacterial genus.Here we report a novel two-step strategy for de-veloping controllable hypermutable cells of Clostridium acetobutylicum,an important and representative indus-trial strain.Firstly,the mutS/L operon essential for methyl-directed mismatch repair(MMR)activity was inactivated from the genome of C.acetobutylicum to generate hy-permutable cells with over 250-fold increased mutation rates.Secondly,a proofreading control system carrying an inducibly expressed mutS/L operon was constructed.The hypermutable cells and the proofreading control system were integrated to form a controllable hypermut-able system SMBMutC,of which the mutation rates can be regulated by the concentration of anhydrotetracycline(aTc).Duplication of the miniPthl-tetR module of the proof-reading control system further signifi cantly expanded the regulatory space of the mutation rates,demonstrating hypermutable Clostridium cells with controllable mutation rates are generated.The developed C.acetobutylicum strain SMBMutC2 showed higher survival capacities than the control strain facing butanol-stress,indicating greatly increased evolvability and adaptability of the controllable hypermutable cells under environmental challenges.展开更多
基金supported by grant from the National Natural Science Foundation of China(Grant No.82300231).
文摘Multiple myeloma(MM),one of the most common hemato logical neoplasms worldwide,originates from malignant plasma cells in the bone marrow.MM remains an incurable disease,although continued treatment advancements have markedly increased overall survival.Many patients with MM eventually experience relapse or become treatment-refractory1.Patients with relapsed or refractory multiple myeloma(RRMM)become progressively more challenging to manage and have poor prognosis2.
基金the National Natural Science Foundation of China(Nos.81800201 and 81872322)the Zhejiang Key Research and Development Project(No.2020C03014)the Key Project of Zhejiang Provincial Natural Science Foundation of China(No.LZ22H160009)。
文摘Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins(M protein),leading to bone destruction,hypercalcemia,anemia,and renal insufficiency(Alexandrakis et al.,2015;Yang et al.,2018).Since a large number of new drugs,represented by proteasome inhibitors and immunomodulators,have been successfullyused to treat MM.
基金supported by the National Natural Science Foundation of China(Nos.81170526 and 81270640)
文摘Invasive fungal infection （IFI） is a growing cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT）. We retrospectively reviewed the records of 408 patients un- dergoing alIo-HSCTs during the period November 1998 to December 2009, analyzed the incidence and risk factors of IFI, and examined the impact of IFI on overall survival. A total of 92 （22.5%） episodes suffered proven or probable IFI （4 patients were proven, 88 patients were probable）. Candida was the most common pathogen for early IFI, and mold was the most frequent causative organism for late IFI. A prior history of IFI, human leukocyte antigen （HLA） mismatch, long-time neutropenia, and acute graft-versus-host-disease （GVHD） were risk factors for early IFI. A prior history of IFI, corticosteroid therapy, cytomegalovirus （CMV） disease, and chronic GVHD were risk factors for late IFI. IFI-related mortality was 53.26%. The 12-year overall survival （OS） rate for IFI was significantly lower than that of patients without IFI （41.9% vs. 63.6%, P〈0.01）.
基金The Open Foundation of Laboratory of Marine Ecosystem and Biogeochemistry,SOA under contract No.LMEB201701
文摘There are well-established chemical and turbidity anomalies in the plumes occurring vicinity of hydrothermal vents, which are used to indicate their existence and locations. We here develop a small, accurate multi-channel chemical sensor to detect such anomalies which can be used in deep-sea at depths of more than 4 000 m. The design allowed five all-solid-state electrodes to be mounted on it and each (apart from one reference electrode) could be changed according to chemicals to be measured. Two experiments were conducted using the chemical sensors. The first was a shallow-sea trial which included sample measurements and in situ monitoring. pH, Eh, CO3^2- and SO4^2- electrodes were utilized to demonstrate that the chemical sensor was accurate and stable outside the laboratory. In the second experiment, the chemical sensor was integrated with pH, Eh, CO3^2- and H2S electrodes, and was used in 29 scans of the seabed along the Southwest Indian Ridge (SWIR) to detect hydrothermal vents, from which 27 sets of valid data were obtained. Hydrothermal vents were identified by analyzing the chemical anomalies, the primary judging criteria were decreasing voltages of Eh and H2S, matched by increasing voltages of pH and CO3^2- . We proposed that simultaneous detection of changes in these parameters will indicate a hydrothermal vent. Amongst the 27 valid sets of data, five potential hydrothermal vents were targeted using the proposed method. We suggest that our sensors could be widely employed by marine scientists.
基金supported by the National Natural Science Foundation of China(Nos.81872322,81900209,and 82100213)the Zhejiang Key Research and Development Project(No.2020C03014)。
文摘CUDC-101,an effective and multi-target inhibitor of epidermal growth factor receptor(EGFR),histone deacetylase(HDAC),and human epidermal growth factor receptor 2(HER2),has been reported to inhibit many kinds of cancers,such as acute promyelocytic leukemia and non-Hodgkin's lymphoma.However,no studies have yet investigated whether CUDC-101 is effective against myeloma.Herein,we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma(MM)cell lines and induces cell apoptosis in a time-and dose-dependent manner.Moreover,CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase(PI3K)and HDAC,and regulated the cell cycle G2/M arrest.Moreover,we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug.Bortezomib is one of the important drugs in MM treatment,and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib.The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade.Collectively,our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib,which provides insights into exploring new strategies for MM treatment.
文摘BACKGROUND Although minimal change disease(MCD)and focal segmental glomerulosclerosis(FSGS)have been described as two separate forms of nephrotic syndrome(NS),they are not completely independent.We report a case of a patient transitioning from MCD to FSGS,review the literature,and explore the relationship between the two diseases.CASE SUMMARY A 42-year-old male welder,presenting with lower extremity edema and elevated serum creatinine,was diagnosed with NS and end-stage kidney disease(ESKD)based on laboratory test results.The patient had undergone a kidney biopsy for NS 20 years previously,which indicated MCD,and a second recent kidney biopsy suggested FSGS.The patient was an electric welder with excessive levels of cadmium and lead in his blood.Consequently,we suspect that his aggravated pathology and occurrence of ESKD were related to metal nephrotoxicity.The patient eventually received kidney replacement therapy and quit his job which involved long-term exposure to metals.During the 1-year follow-up period,the patient was negative for metal elements in the blood and urine and recovered partial kidney function.CONCLUSION MCD and FSGS may be different stages of the same disease.The transition from MCD to FSGS in this case indicates disease progression,which may be related to excessive metal contaminants caused by the patient’s occupation.
基金supported by the Zhejiang Key Research and Development Project(No.2020C03014).
文摘Waldenström macroglobulinemia(WM)is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M(IgM)protein(Owen et al.,2003).Common signs and symptoms include fatigue due to anemia,lymph node enlargement,hepatosplenomegaly,thrombocytopenia,symptoms related to high viscosity,and peripheral neuropathy,among others.Despite significant advances in WM treatment,this type of indolent lymphoma remains incurable,with a wide array of patient outcomes(Ruan et al.,2020).In recent years,chimeric antigen receptor T(CAR-T)cell therapy targeting cluster of differentiation 19(CD19)has shown unprecedented response rates and durability in the treatment of B-cell malignancies.In this report,we describe a challenging case of WM that involved multiple extramedullary sites,relapsed,and was refractory to chemotherapy,immunotherapy,and targeted therapy.After anti-CD19 CAR-T cell therapy,the tumor burden significantly decreased and the patient’s condition remained stable at the writing of this report.
文摘The QRS-T angle,as an index of noninvasive cardioelectric vector,is closely related to the change of heart structure and function.There are different methedologies to measure the QRS-T angle,which can be roughly dividedinto two types:plane angle and space angle.Studies show that the influence factors include two aspects of physiology and pathology of the angle,in pathological ways,the disease such as myocardial hypertrophy,myocardial ischemia,hypertension,ventricular arrhythmia has larger clinical significance.In recent years,the research on the risk stratification of the QRS-T angle on sudden death has made great progress,but there are still some disputes about whether the space angle can be replaced by the plane angle and the range of normal value and so on.
文摘This consensus on multiple myeloma-related bone diseases(MBDs)underscores the importance of a multidisciplinary approach that encompasses hematology,radiology,orthopedics,and additional specialties to tackle its intricate challenges.MBD,a prevalent and debilitating complication of multiple myeloma,leads to bone pain,fractures,and skeletal-related events(SREs),which profoundly impact patients’quality of life.The guidelines offer a thorough framework for diagnosis,treatment,and continual assessment,emphasizing early detection and consistent monitoring using imaging techniques such as positron emission tomography-computed tomography(PET-CT)and magnetic resonance imaging(MRI).Treatment strategies prioritize the careful application of antimyeloma agents,bisphosphonates,and denosumab to minimize bone loss and decrease SRE risk,complemented by surgical and radiotherapy interventions for structural or pain-related issues.Supportive care measures,including pain management,rehabilitation,nutritional support,and dental evaluations,play a crucial role in enhancing patient outcomes and preserving quality of life.This consensus advocates a standardized,evidencebased approach to managing MBD,ensuring comprehensive and coordinated care for patients.
基金supported by grants from the National Natural Science Foundation of China(No.82071844).
文摘Infantile hemangioma is the most common benign vascular tumor of infancy and is characterized by a unique life cycle.Animal models that reflect the histological and biological characteristics of infantile hemangioma are critical tools for preclinical studies.Various infantile hemangioma animal models have been developed and improved during the past few decades.However,very few reports have provided practical suggestions for selecting a suitable animal model based on the study purpose.This comprehensive review summarizes the construction methods and application scenarios of different models.The advantages and disadvantages of each model are fully discussed,providing a reference for choosing the most applicable animal model for infantile hemangioma-associated research.
基金supported by the National Science Fund for Distinguished Young Scholars(82025024)the National Natural Science Foundation of China(82302593)+1 种基金the Natural Science Foundation of Guangdong Province(2023A1515012512)Guangdong Provincial Clinical Research Center for Laboratory Medicine(2023B110008).
文摘Gliomas present a significant challenge in oncology due to their often subtle early symptoms and the insidious nature of their growth,which is compounded by the blood-brain barrier.Recent evidence has highlighted the diagnostic and therapeutic potential of monocytes,macrophages,and microglia in the context of glioma.This review focused on emerging evidence and hypotheses concerning the components and interrelationships within the mononuclear phagocyte system(MPS)in the central nervous system and its role in glioma development and invasion.By summarizing the involvement of the MPS in glioma biology,this paper offers a novel perspective for the integration of liquid biopsy and targeted therapies in oncology.
基金supported by the National Natural Science Foundation of China(82130089,82103730,82304022,and 32070894)the Key R&D Program of Hubei Province(YFXM2021000203)+1 种基金the National Key Research and Development Program of China(2020YFA0804400)the Program of HUST Academic Frontier Youth Team(2018QYTD10).
文摘Psoriasis patients who are obese tend to have serious clinical manifestations and poor responses to various biological agents in most cases. However, the mechanisms by which obesity exacerbates psoriasis remain enigmatic. In this study, we found that the abundance of systemic and localized cutaneous neutrophil extracellular traps (NETs) associated with the obesity-induced aggravation of psoriasis was positively correlated with disease severity and that the inhibition of NETs alleviated psoriatic dermatitis in obese mice. Mechanistically, we found that changes in fatty acid composition in obese subjects resulted in the deposition of saturated fatty acids (SFAs), which promoted the release of NETs via the TLR4-MD2/ROS signaling pathway. We further revealed that NETs potentiate IL-17 inflammation, especially γδT17-mediated immune responses, in obesity-exacerbated psoriasis patients. Moreover, SFAs induced a decreased response to anti-IL17A treatment in psoriasis-like mice, whereas the inhibition of NETs improved the beneficial effects of anti-IL17A in psoriasis-like mice with lipid metabolism disorders. Our findings collectively suggest that SFA-induced NETs play a critical role in the exacerbation of obesity-related psoriasis and provide potential new strategies for the clinical treatment of refractory psoriasis patients with lipid metabolism disorders.
基金Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0501600)Changhai Hospital Special Foundation for Clinical Research Program(No.2024LYB05)+5 种基金the China National Postdoctoral Program for Innovative Talents(No.BX20230482)Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission(Grant No.22CGA42)Natural Science Foundation of Shanghai(No.23ZR1478700)Shanghai Sailing Program(No.23YF1458600)Shanghai Eastern Talent Youth Program(QNWS2024108)Changfeng Guhai Project of Changying Youth Seedling Plan of Changhai Hospital.
文摘Introduction:Stool DNA testing based on methylated syndecan-2(mSDC2)is a potential novel non-invasive screening test for colorectal cancer(CRC).This study aimed to assess its positive predictive value(PPV)in real-world practice.Methods:This study retrospectively recruited consecutive patients with positive stool DNA-based SDC2 methylation tests from 18 hospitals between November 2016 and July 2021.Included patients were classified into the average-risk equivalent or increased-risk population and the previous-negative-colonoscopy or no-previous-colonoscopy groups.Multivariate logistic regression was conducted to investigate the risk factors that affect the detection of advanced colorectal neoplasia(ACN)in patients with a positive mSDC2 test.The primary outcome was the PPV for ACN.Results:The overall PPVs for ACN,CRC,and colorectal neoplasia were 28.5%,12.8%,and 44.6%,respectively.The PPV for ACN was higher in the no-previous-colonoscopy group than in the previous-negative-colonoscopy group(30.1%vs 18.5%,P=0.008)and higher in the increased-risk population than in the average-risk equivalent population(41.1%vs 21.6%,P<0.001).However,the PPV(18.5%)was still high for patients with a previous negative colonoscopy.For ACN detection in patients with a positive mSDC2 test,old age,increased risk,and smoking history were identified as independent risk factors;previous negative colonoscopy was identified as a protective factor.Conclusions:The mSDC2 test,which has a high PPV for both ACN and CRC,is expected to be an alternative CRC screening strategy.Patients with a positive mSDC2 test might require a colonoscopy as soon as possible,even if the previous colonoscopy was negative.
文摘Photosynthetic CO2 fixation is the ultimate source of organic carbon on earth and thus is essential for crop production and carbon sequestration, Ribulose-1,5-bis- phosphate carboxylase/oxygenase （Rubisco） catalyzes the first step of photosynthetic CO2 fixation. However, the extreme low carboxylation efficiency of Rubisco makes it the most attractive target for improving pho- tosynthetic efficiency. Extensive studies have focused on re-engineering a more efficient enzyme, but the effort has been impeded by the limited understanding of its structure-function relationships and the lack of an effi- cient selection system towards its activity. To address the unsuccessful molecular engineering of Rubisco, we developed an Escherichia coil-based activity-directed selection system which links the growth of host cell solely to the Rubisco activity therein. A Synechococcus sp. PCC7002 Rubisco mutant with E49V and D82G sub- stitutions in the small subunit was selected from a total of 15,000 mutants by one round of evolution. This mutant showed an 85% increase in specific carboxyla- tion activity and a 45% improvement in catalytic efficiency towards CO2. The small-subunit E49V mutation was speculated to influence holoenzyme catalysis through interaction with the large-subunit Q225. This interaction is conserved among various Rubisco from higher plants and Chlamydomonas reinhardtii. Knowledge of these might provide clues for engineering Rubisco from higher plants, with the potential of increasing the crop yield.
基金supported by Hong Kong Research Grants Council Grants HKU 7227/02M(to Q.Y.H.),HKU 7218/02M and HKU 7395/03M(toJ.F.C.)the Department of Chemistry,and the Areasof Excellence scheme of Hong Kong University GrantsCommittee
文摘Tumor metastasis is the dominant cause of death in cancer patients. However, the molecular and cellular mechanisms underlying tumor metastasis are still elusive. The identi?cation of protein molecules with their expressions correlated to the metastatic process would help to understand the metastatic mechanisms and thus facilitate the development of strategies for the therapeutic interventions and clini- cal management of cancer. Proteomics is a systematic research approach aiming to provide the global characterization of protein expression and function under given conditions. Proteomic technology has been widely used in biomarker discovery and pathogenetic studies including tumor metastasis. This article provides a brief review of the application of proteomics in identifying molecular factors in tumor metastasis process. The combination of proteomics with other experimental ap- proaches in biochemistry, cell biology, molecular genetics and chemistry, together with the development of new technologies and improvements in existing method- ologies will continue to extend its application in studying cancer metastasis.
基金supported by the National Basic Research Program of China(31470231)National Natural Science Foundation of China(21106175)
文摘Recycling of carbon dioxide(CO_2) into fuels and chemicals is a potential approach to reduce CO_2 emission and fossil-fuel consumption. Autotrophic microbes can utilize energy from light, hydrogen, or sulfur to assimilate atmospheric CO_2 into organic compounds at ambient temperature and pressure. This provides a feasible way for biological production of fuels and chemicals from CO_2 under normal conditions. Recently great progress has been made in this research area, and dozens of CO_2-derived fuels and chemicals have been reported to be synthesized by autotrophic microbes. This is accompanied by investigations into natural CO_2-fixation pathways and the rapid development of new technologies in synthetic biology. This review first summarizes the six natural CO_2-fixation pathways reported to date, followed by an overview of recent progress in the design and engineering of CO_2-fixation pathways as well as energy supply patterns using the concept and tools of synthetic biology. Finally, we will discuss future prospects in biological fixation of CO_2.
基金We are grateful to Miao Chen, Qiangguo Gao and Yiqi Liu （Second Military Medical University, Shanghai, China） for technical support and offer special thanks to Professor Qing Yi （M.D. Anderson Cancer Center Houston, TX, USA） for helpful guidance in the experiments. We thank Shizuo Akira （Osaka University, Osaka, Japan） for originally providing key mouse strains. This work was supported by grants of the National Natural Science Foundation of China （no. 30772502 and 30973455）, Zhejiang Major Medical and the Health Science and Technology ＆ Ministry of Health of the Chinese Government （no. WKJ2009-2-022）. This work was also supported by the Major Research Plan of the Chinese National Natural Science Foundation （no. 91029740）, Zhejiang Province Science and Technology Department Foundation （no. 2009C03012-2） and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents.
文摘Graft-versus-host disease （GVHD） is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 （TLR4）, which is a major receptor for bacterial lipopolysaccharides （LPS）, in the development of acute GVHD, we used a TLR4-knockout （TLR4-/-） mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4-/- mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type （TLR4＋/＋） mice. In addition, histopathological analyses revealed that in TLR4-/-→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4＋/＋, TLR4-/- mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4-/- mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 （Th 1） development was obviously attenuated compared with TLR4＋/＋ mice dendritic cells, and the levels of interferon-T （IFN-γ） and IL-IO, Th2-cell specific cytokines, were significantly higher in the serum of TLR4-/-→BALB/c than in TLR4＋/＋→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.
文摘Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.
基金the National Natural Science Foundation of China(Grant No.31270107)the National Basic Research Program of China(973 Program)(No.2011CBA00800)+1 种基金the National High Technology Research and Development Program(863 Program)(No.2011AA02A208)the Knowledge Innovation Program of the Chinese Acad-emy of Sciences(No.KSCX2-EW-Q-14).
文摘Development of controllable hypermutable cells can greatly benefit understanding and harnessing microbial evolution.However,there have not been any similar sys-tems developed for Clostridium,an important bacterial genus.Here we report a novel two-step strategy for de-veloping controllable hypermutable cells of Clostridium acetobutylicum,an important and representative indus-trial strain.Firstly,the mutS/L operon essential for methyl-directed mismatch repair(MMR)activity was inactivated from the genome of C.acetobutylicum to generate hy-permutable cells with over 250-fold increased mutation rates.Secondly,a proofreading control system carrying an inducibly expressed mutS/L operon was constructed.The hypermutable cells and the proofreading control system were integrated to form a controllable hypermut-able system SMBMutC,of which the mutation rates can be regulated by the concentration of anhydrotetracycline(aTc).Duplication of the miniPthl-tetR module of the proof-reading control system further signifi cantly expanded the regulatory space of the mutation rates,demonstrating hypermutable Clostridium cells with controllable mutation rates are generated.The developed C.acetobutylicum strain SMBMutC2 showed higher survival capacities than the control strain facing butanol-stress,indicating greatly increased evolvability and adaptability of the controllable hypermutable cells under environmental challenges.
