BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the...BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.展开更多
Therapies for treating ovarian cancer (OvCa) successfully are largely inadequate. Alternative therapies and diet(s) with preventive potential to debilitated onset, and reduced OvCa tumor burden in situ, have not been ...Therapies for treating ovarian cancer (OvCa) successfully are largely inadequate. Alternative therapies and diet(s) with preventive potential to debilitated onset, and reduced OvCa tumor burden in situ, have not been systematically studied. Preventive role of conjugated linoleic acids (CLAs) has been reported in many other cancers. We report the first systematic in vitro and in vivo study modeling potential preventive mechanism(s) of CLA, an octadecadienolic fatty acid in clear cell OvCa cell line TOV-21G. We demonstrate that a dose and time-dependent down-regulation of cyclin E and A proteins (p 0.05) by CLA (t10,c12) was concomitant with cell cycle arrest of TOV-21G cell lines in S phase. To understand the molecular mechanism underlying CLA (t10,c12) induced S phase arrest, levels of cell cycle regulatory proteins were determined by western blot analyses. Exposure to CLA (t10,c12) increased p21(CIP1/WAF1), and p27(KIP1) protein levels in a time and dose-dependent manner. Interestingly CLA (t10,c12) did not significantly affect protein levels of cyclin-dependent kinase (cdk) 2, and p53, however, hyperphosphorylated form of pRb (p 0.05) was abrogated. Exposure to CLA (c9,t11) indicated a modest increase in p21(CIP1/WAF1) and p27(KIP1) levels, but changes in cyclin A and E levels were statistically insignificant. These results indicate that CLA (t10,c12) mediated p27(KIP1) upregulation and inhibition of hyperphosphorylation of ppRb may be the possible mechanism for the S phase arrest in TOV-21G cell line. Our in vivo data showed that CLA reduced the progression of TOV-21G xenografts by >50%. Together our results provide evidence of CLA exerted preventive effect on OvCa cell and tumor growth. Tumor growth arrest may be resultant from CLA (t10,c12) mediated modulation of cell cycle arrest.展开更多
The S-scheme heterojunction has garnered increasing attention due to its remarkable oxidation capacity and efficient separation of photogenerated carriers.In this study,a one-pot glycerol-assisted hydrothermal process...The S-scheme heterojunction has garnered increasing attention due to its remarkable oxidation capacity and efficient separation of photogenerated carriers.In this study,a one-pot glycerol-assisted hydrothermal process was utilized to successfully synthesize S-scheme heterojunction photocatalysts comprising basic bismuth nitrate(BBN)and bismuth tungstate(BWO).Interestingly,the BBN/BWO heterogeneous photo-catalysts exhibited the highest photocatalytic properties.The optimized product achieved the degradation of sulfamethazine(SMZ)within 1 h,with a kinetic constant(k)value of 0.05818 min^(−1).The degradation process was influenced significantly by·O^(2)−and h^(+)species.To determine the degradation pathway of SMZ in the presence of BBN/BWO-0.6,liquid chromatography-mass spectrometry(LC-MS)analysis was performed,which revealed a decrease in the toxicity of intermediates and products.The enhanced pho-tocatalytic activity can be attributed to the internal electric field(IEF)of the S-scheme heterojunction between BBN and BWO,effectively promoting the separation of photogenerated carriers.This research presents a viable approach for developing S-scheme heterojunctions in SMZ photodegradation and other environmental applications.展开更多
Metal clusters or even single-atoms dispersed and anchored on the photocatalysts'surface can enhance photocatalytic performances on organic pollutant oxidation.Here,a simple photoreduction method was used to creat...Metal clusters or even single-atoms dispersed and anchored on the photocatalysts'surface can enhance photocatalytic performances on organic pollutant oxidation.Here,a simple photoreduction method was used to create atomically dispersed metal single-atoms/clusters(MSCs,M=Cu,Pd,Au and Ag)on P-modulated tubular carbon nitride(TCN).The obtained MSCs@TCN demonstrated excellent photocatalytic performances for the degradation of sulfamethazine(SMZ).In particular,the photocatalyst with 2 wt%Cu loading showed ultrahigh SMZ oxidation efficiency(k=0.06110 min^(-1)),almost three times that of TCN(k=0.02066 min^(-1)).It also shows excellent stability in the 5th-cycle measurements.The improved photocatalytic activity of the CuSCs@TCN is ascribed to the synergistic promotion of photogenerated charge separation by Cu single-atoms/clusters as active sites,accelerated charge transfer from bulk TCN to Cu sites through Cu-N_(x)interaction.Meanwhile,the active sites of Cu single-atoms/clusters could promote the production of·O_(2)^(-),which participates in organic oxidation with strong oxidizing holes(h^(+)).This strategy paves a new avenue for designing high-performance photocatalysts decorated with metal single-atoms and clusters.展开更多
Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes(DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. ...Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes(DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme(E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2.展开更多
Dementia is mainly a neurodegenerative disorder involved in several systems, including central nervous system, endocrinology/metabolism system and circulatory system. Alzheimer’s disease (AD) and dementia with Lewy b...Dementia is mainly a neurodegenerative disorder involved in several systems, including central nervous system, endocrinology/metabolism system and circulatory system. Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common forms of the dementia, accounting for 60% - 80% and 10% - 20% of all cases, respectively. DLB is defined by widespread neocortical, limbic and brainstem Lewy bodies but frequently accompanied by variable levels of AD pathology. This pathological and clinical overlap makes their differential diagnosis complicated. Recent advances in the identification of disease bio-markers now make it possible to detect and distinguish their pathology in the early or preclinical stage of the diseases, even in cognitively normal individuals. In addition to the key biomarkers (amyloid β or Aβ, tau and α-synuclein), neurotrophins such as cocaine- and amphetamine-regulated transcript (CART) have also drawn attention due to their expressions and functions. This article summarizes the progress in the definition, pathology and diagnosis of dementia, with a focus on potential biochemical markers in the cere-brospinal fluid (CSF) in the differential diagnosis of the main forms of dementia. To prediction or early diagnosis of dementia, the role of specific and sensitive CSF biomarkers seems to be crucial in a routine clinical setting. The concerns and challenges in the biomarker field are also discussed.展开更多
Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We d...Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.展开更多
Background:The combined use of anti-programmed cell death protein1(PD-1)/anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4)check-point inhibitors has been effective in various cancer types.The SouthwestOncology ...Background:The combined use of anti-programmed cell death protein1(PD-1)/anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4)check-point inhibitors has been effective in various cancer types.The SouthwestOncology Group(SWOG)Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors(DART)S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers,including small cell carcinoma of the ovary,hypercalcemic type(SCCOHT).The purpose of the study wasto evaluate the potential clinical benefitof ipilimumab and nivolumab in patients with SCCOHT.Methods:DART was a prospective,open-labeled,multicenter(>1,000 US sites),multi-cohort phase II clinical trial of intravenous administration of ipilimumab(1 mg/kg,every 6 weeks)plus nivolumab(240 mg,every 2 weeks).The pri-mary endpoint was overall response rate[ORR,confirmed complete response(CR)and partial response(PR)]per RECIST.Secondary endpoints includedprogression-free survival(PFS),overall survival(OS),clinical benefit rate(CBR;overall response plus stable disease≥6 months),and toxicity.Immune responseswere also evaluated.Results:Six patients(median age,30.5 years;median,2 prior therapies;nopriorimmunotherapy exposure)with advanced/metastatic SCCOHT were evalu-able.ORR and CBR were both 16.7%(1/6)with one patient having a confirmedCR lasting 46.2+months.However,another patient had a confirmed immuneCR(iCR)with immune PFS(iPFS)of 53+months[ORR/iORR,33.3%(2/6)].Notably,the latter patient had a progressing lesion at 24 weeks after initialresponse,but with renewed regression with ongoing therapy,suggesting delayedpseudo-progression.At 12-months,3 patients remained alive.Median PFS was1.4 months(range,0.9 months-not reached);median OS was 14.2 months(2months-not reached).No adverse events caused treatment discontinuation.Conclusion:Two of 6 patients(33.3%)with SCCOHT achieved durable CR/iCRand long-term survival with ipilimumab plus nivolumab.Correlative studies todetermine response and resistance markers are ongoing.展开更多
PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),P...PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),PARPi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to treatment.In this review,we discuss the role of PARPi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and PARP inhibitors.展开更多
The transcription factor c-MYC(MYC thereafter)controls diverse transcription programs and plays a key role in the development of many human cancers.Cells develop multiple mechanisms to ensure that MYC levels and activ...The transcription factor c-MYC(MYC thereafter)controls diverse transcription programs and plays a key role in the development of many human cancers.Cells develop multiple mechanisms to ensure that MYC levels and activity are precisely controlled in normal physiological context.As a short half-lived protein,MYC protein levels are tightly regulated by the ubiquitin proteasome system.Over a dozen of ubiquitin ligases have been found to ubiquitinate MYC whereas a number of deubiquitinating enzymes counteract this process.Recent studies show that SUMOylation and deSUMOylation can also regulate MYC protein stability and activity.Interestingly,evidence suggests an intriguing crosstalk between MYC ubiquitination and SUMOylation.Deregulation of the MYC ubiquitination-SUMOylation regulatory network may contribute to tumorigenesis.This review is intended to provide the current understanding of the complex regulation of the MYC biology by dynamic ubiquitination and SUMOylation and their crosstalk.展开更多
Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge,unbiased chemoproteomi...Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge,unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.展开更多
Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms(MPN);in this pathway,IRS2 is involved in the malignant transformation induced by JAK2^(...Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms(MPN);in this pathway,IRS2 is involved in the malignant transformation induced by JAK2^(V617F),and upregulation of IGF1R signaling induces the MPN phenotype.NT157,a synthetic compound designed as an IGF1R-IRS1/2 inhibitor,has been shown to induce antineoplastic effects in solid tumors.Herein,we aimed to characterize the molecular and cellular effects of NT157 in JAK2^(V617F)positive MPN cell lines(HEL and SET2)and primary patient hematopoietic cells.In JAK2^(V617F)cell lines,NT157 decreased cell viability,clonogenicity,and cell proliferation,resulting in increases in apoptosis and cell cycle arrest in the G2/M phase(p<0.05).NT157 treatment inhibited IRS1/2,JAK2/STAT,and NFκB signaling,and it activated the AP-1 complex,downregulated four oncogenes(CCND1,MYB,WT1,and NFKB1),and upregulated three apoptotic-related genes(CDKN1A,FOS,and JUN)(p<0.05).NT157 induced genotoxic stress in a JAK2/STAT-independent manner.NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients(p<0.05).These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.展开更多
Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metab...Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.展开更多
Immune checkpoint blockade(ICB)therapies exhibit substantial clinical benefit in different cancers,but relatively low response rates in the majority of patients highlight the need to understand mutual relationships am...Immune checkpoint blockade(ICB)therapies exhibit substantial clinical benefit in different cancers,but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune features.Here,we reveal overall positive correlations among immune checkpoints and immune cell populations.Clinically,patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy,suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune response.As proof-of-concept,we demonstrated that the immune activation score(ISD)based on dynamic alteration of interleukins in patient plasma as early as two cycles(4-6 weeks)after starting immunotherapy can accurately predict immunotherapy efficacy.Our results reveal a systematic landscape of associations among immune features and provide a noninvasive,cost-effective,and time-efficient approach based on dynamic profiling of pre-and on-treatment plasma to predict immunotherapy efficacy.展开更多
Cholangiocarcinoma(CCA)is a rare and very aggressive malignancy arising from the biliary tract.Based on the location of the tumor,CCA can be divided in intrahepatic cholangiocarcinoma(iCCA),perihilar cholangiocarcinom...Cholangiocarcinoma(CCA)is a rare and very aggressive malignancy arising from the biliary tract.Based on the location of the tumor,CCA can be divided in intrahepatic cholangiocarcinoma(iCCA),perihilar cholangiocarcinoma(pCCA)and distal cholangiocarcinoma(dCCA).Many other characteristics differentiate these groups,including pathological features,oncological approach and surgical techniques,which in turn influences patient outcomes.展开更多
Fluorescence nanoscopy has become increasingly powerful for biomedical research,but it has historically afforded a small field-ofview(FOV)of around 50μm×50μm at once and more recently up to∼200μm×200μm....Fluorescence nanoscopy has become increasingly powerful for biomedical research,but it has historically afforded a small field-ofview(FOV)of around 50μm×50μm at once and more recently up to∼200μm×200μm.Efforts to further increase the FOV in fluorescence nanoscopy have thus far relied on the use of fabricated waveguide substrates,adding cost and sample constraints to the applications.Here we report PRism-Illumination and Microfluidics-Enhanced DNA-PAINT(PRIME-PAINT)for multiplexed fluorescence nanoscopy across millimeter-scale FOVs.Built upon the well-established prism-type total internal reflection microscopy,PRIME-PAINT achieves robust singlemolecule localization with up to∼520μm×520μm single FOVs and 25−40 nm lateral resolutions.Through stitching,nanoscopic imaging over mm^(2)sample areas can be completed in as little as 40 min per target.An on-stage microfluidics chamber facilitates probe exchange for multiplexing and enhances image quality,particularly for formalin-fixed paraffin-embedded(FFPE)tissue sections.We demonstrate the utility of PRIME-PAINT by analyzing∼106 caveolae structures in∼1,000 cells and imaging entire pancreatic cancer lesions from patient tissue biopsies.By imaging from nanometers to millimeters with multiplexity and broad sample compatibility,PRIMEPAINT will be useful for building multiscale,Google-Earth-like views of biological systems.展开更多
基金Supported by the Oregon Health&Sciences(OHSU)Institutional Review Board,No.STUDY00026428.
文摘BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.
文摘Therapies for treating ovarian cancer (OvCa) successfully are largely inadequate. Alternative therapies and diet(s) with preventive potential to debilitated onset, and reduced OvCa tumor burden in situ, have not been systematically studied. Preventive role of conjugated linoleic acids (CLAs) has been reported in many other cancers. We report the first systematic in vitro and in vivo study modeling potential preventive mechanism(s) of CLA, an octadecadienolic fatty acid in clear cell OvCa cell line TOV-21G. We demonstrate that a dose and time-dependent down-regulation of cyclin E and A proteins (p 0.05) by CLA (t10,c12) was concomitant with cell cycle arrest of TOV-21G cell lines in S phase. To understand the molecular mechanism underlying CLA (t10,c12) induced S phase arrest, levels of cell cycle regulatory proteins were determined by western blot analyses. Exposure to CLA (t10,c12) increased p21(CIP1/WAF1), and p27(KIP1) protein levels in a time and dose-dependent manner. Interestingly CLA (t10,c12) did not significantly affect protein levels of cyclin-dependent kinase (cdk) 2, and p53, however, hyperphosphorylated form of pRb (p 0.05) was abrogated. Exposure to CLA (c9,t11) indicated a modest increase in p21(CIP1/WAF1) and p27(KIP1) levels, but changes in cyclin A and E levels were statistically insignificant. These results indicate that CLA (t10,c12) mediated p27(KIP1) upregulation and inhibition of hyperphosphorylation of ppRb may be the possible mechanism for the S phase arrest in TOV-21G cell line. Our in vivo data showed that CLA reduced the progression of TOV-21G xenografts by >50%. Together our results provide evidence of CLA exerted preventive effect on OvCa cell and tumor growth. Tumor growth arrest may be resultant from CLA (t10,c12) mediated modulation of cell cycle arrest.
基金supported by the National Natural Science Foundation of China(No.22278245)the Young Taishan Scholars Program of Shandong Province(No.tsqn.201909026)+1 种基金the Youth Interdisciplinary Science and Innovative Research Groups of Shandong University supported by the Fundamental Research Funds for the Central Universities(No.2020QNQT014)the Shandong University Future Youth Grant Program(No.61440089964189).
文摘The S-scheme heterojunction has garnered increasing attention due to its remarkable oxidation capacity and efficient separation of photogenerated carriers.In this study,a one-pot glycerol-assisted hydrothermal process was utilized to successfully synthesize S-scheme heterojunction photocatalysts comprising basic bismuth nitrate(BBN)and bismuth tungstate(BWO).Interestingly,the BBN/BWO heterogeneous photo-catalysts exhibited the highest photocatalytic properties.The optimized product achieved the degradation of sulfamethazine(SMZ)within 1 h,with a kinetic constant(k)value of 0.05818 min^(−1).The degradation process was influenced significantly by·O^(2)−and h^(+)species.To determine the degradation pathway of SMZ in the presence of BBN/BWO-0.6,liquid chromatography-mass spectrometry(LC-MS)analysis was performed,which revealed a decrease in the toxicity of intermediates and products.The enhanced pho-tocatalytic activity can be attributed to the internal electric field(IEF)of the S-scheme heterojunction between BBN and BWO,effectively promoting the separation of photogenerated carriers.This research presents a viable approach for developing S-scheme heterojunctions in SMZ photodegradation and other environmental applications.
基金financially supported by the National Natural Science Foundation of China(No.U22B20102)Shandong Provincial Natural Science Foundation(No.ZR2023QE218)+3 种基金the Young Taishan Scholars Program of Shandong Province(No.tsqn201909026)Taishan Scholars Project of Shandong Province(No.tstp20230604)the Future Young Scholars Program of Shandong University(No.61440089964189)the Key Laboratory of Organic Compound Pollution Control Engineering(MOE)Foundation(No.20190202)。
文摘Metal clusters or even single-atoms dispersed and anchored on the photocatalysts'surface can enhance photocatalytic performances on organic pollutant oxidation.Here,a simple photoreduction method was used to create atomically dispersed metal single-atoms/clusters(MSCs,M=Cu,Pd,Au and Ag)on P-modulated tubular carbon nitride(TCN).The obtained MSCs@TCN demonstrated excellent photocatalytic performances for the degradation of sulfamethazine(SMZ).In particular,the photocatalyst with 2 wt%Cu loading showed ultrahigh SMZ oxidation efficiency(k=0.06110 min^(-1)),almost three times that of TCN(k=0.02066 min^(-1)).It also shows excellent stability in the 5th-cycle measurements.The improved photocatalytic activity of the CuSCs@TCN is ascribed to the synergistic promotion of photogenerated charge separation by Cu single-atoms/clusters as active sites,accelerated charge transfer from bulk TCN to Cu sites through Cu-N_(x)interaction.Meanwhile,the active sites of Cu single-atoms/clusters could promote the production of·O_(2)^(-),which participates in organic oxidation with strong oxidizing holes(h^(+)).This strategy paves a new avenue for designing high-performance photocatalysts decorated with metal single-atoms and clusters.
基金Supported by NIH/NCI,No.R00 CA127134 and No.R01CA160474a Department of Defense,No.W81XWH-10-1-1029,to Dai MSA Grant from Medical Research Foundation(MRF)of Oregon,to Sun XX
文摘Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes(DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme(E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2.
文摘Dementia is mainly a neurodegenerative disorder involved in several systems, including central nervous system, endocrinology/metabolism system and circulatory system. Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common forms of the dementia, accounting for 60% - 80% and 10% - 20% of all cases, respectively. DLB is defined by widespread neocortical, limbic and brainstem Lewy bodies but frequently accompanied by variable levels of AD pathology. This pathological and clinical overlap makes their differential diagnosis complicated. Recent advances in the identification of disease bio-markers now make it possible to detect and distinguish their pathology in the early or preclinical stage of the diseases, even in cognitively normal individuals. In addition to the key biomarkers (amyloid β or Aβ, tau and α-synuclein), neurotrophins such as cocaine- and amphetamine-regulated transcript (CART) have also drawn attention due to their expressions and functions. This article summarizes the progress in the definition, pathology and diagnosis of dementia, with a focus on potential biochemical markers in the cere-brospinal fluid (CSF) in the differential diagnosis of the main forms of dementia. To prediction or early diagnosis of dementia, the role of specific and sensitive CSF biomarkers seems to be crucial in a routine clinical setting. The concerns and challenges in the biomarker field are also discussed.
文摘Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.
基金National Institutes of HealthNational Cancer Institute,Grant/Award Numbers:U10CA180888,U10CA180819,UG1CA233320,UG1CA233193,UG1CA233198,UG1CA233340Bristol Myers Squibb Company。
文摘Background:The combined use of anti-programmed cell death protein1(PD-1)/anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4)check-point inhibitors has been effective in various cancer types.The SouthwestOncology Group(SWOG)Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors(DART)S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers,including small cell carcinoma of the ovary,hypercalcemic type(SCCOHT).The purpose of the study wasto evaluate the potential clinical benefitof ipilimumab and nivolumab in patients with SCCOHT.Methods:DART was a prospective,open-labeled,multicenter(>1,000 US sites),multi-cohort phase II clinical trial of intravenous administration of ipilimumab(1 mg/kg,every 6 weeks)plus nivolumab(240 mg,every 2 weeks).The pri-mary endpoint was overall response rate[ORR,confirmed complete response(CR)and partial response(PR)]per RECIST.Secondary endpoints includedprogression-free survival(PFS),overall survival(OS),clinical benefit rate(CBR;overall response plus stable disease≥6 months),and toxicity.Immune responseswere also evaluated.Results:Six patients(median age,30.5 years;median,2 prior therapies;nopriorimmunotherapy exposure)with advanced/metastatic SCCOHT were evalu-able.ORR and CBR were both 16.7%(1/6)with one patient having a confirmedCR lasting 46.2+months.However,another patient had a confirmed immuneCR(iCR)with immune PFS(iPFS)of 53+months[ORR/iORR,33.3%(2/6)].Notably,the latter patient had a progressing lesion at 24 weeks after initialresponse,but with renewed regression with ongoing therapy,suggesting delayedpseudo-progression.At 12-months,3 patients remained alive.Median PFS was1.4 months(range,0.9 months-not reached);median OS was 14.2 months(2months-not reached).No adverse events caused treatment discontinuation.Conclusion:Two of 6 patients(33.3%)with SCCOHT achieved durable CR/iCRand long-term survival with ipilimumab plus nivolumab.Correlative studies todetermine response and resistance markers are ongoing.
文摘PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),PARPi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to treatment.In this review,we discuss the role of PARPi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and PARP inhibitors.
基金We thank members of the Dai and Sears laboratories for active discussion.This work was supported by NIH/NCI grant R01 CA186241 to M-S.D.and R.S.
文摘The transcription factor c-MYC(MYC thereafter)controls diverse transcription programs and plays a key role in the development of many human cancers.Cells develop multiple mechanisms to ensure that MYC levels and activity are precisely controlled in normal physiological context.As a short half-lived protein,MYC protein levels are tightly regulated by the ubiquitin proteasome system.Over a dozen of ubiquitin ligases have been found to ubiquitinate MYC whereas a number of deubiquitinating enzymes counteract this process.Recent studies show that SUMOylation and deSUMOylation can also regulate MYC protein stability and activity.Interestingly,evidence suggests an intriguing crosstalk between MYC ubiquitination and SUMOylation.Deregulation of the MYC ubiquitination-SUMOylation regulatory network may contribute to tumorigenesis.This review is intended to provide the current understanding of the complex regulation of the MYC biology by dynamic ubiquitination and SUMOylation and their crosstalk.
基金partially by the financial supports from the National Institutes of Health R01 CA197513 (XX),R01GM122820 (XX) and R21EB028425 (BXL),USAperformed by the OHSU Proteomics Shared Resource with partial support from NIH core grants P30EY010572,P30CA069533,and S10RR025571,USA。
文摘Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge,unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.
基金supported in part by Sao Paulo Research Foundation(FAPESP),Grants#2015/09324-9,#15/02200-2,#14/50947-7,#13/08135-2support also came in part from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil(CAPES),and support also came in part from the National Counsel of Technological and Scientific Development(CNPq).
文摘Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms(MPN);in this pathway,IRS2 is involved in the malignant transformation induced by JAK2^(V617F),and upregulation of IGF1R signaling induces the MPN phenotype.NT157,a synthetic compound designed as an IGF1R-IRS1/2 inhibitor,has been shown to induce antineoplastic effects in solid tumors.Herein,we aimed to characterize the molecular and cellular effects of NT157 in JAK2^(V617F)positive MPN cell lines(HEL and SET2)and primary patient hematopoietic cells.In JAK2^(V617F)cell lines,NT157 decreased cell viability,clonogenicity,and cell proliferation,resulting in increases in apoptosis and cell cycle arrest in the G2/M phase(p<0.05).NT157 treatment inhibited IRS1/2,JAK2/STAT,and NFκB signaling,and it activated the AP-1 complex,downregulated four oncogenes(CCND1,MYB,WT1,and NFKB1),and upregulated three apoptotic-related genes(CDKN1A,FOS,and JUN)(p<0.05).NT157 induced genotoxic stress in a JAK2/STAT-independent manner.NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients(p<0.05).These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.
基金This study is partially supported by NIH R01CA235622(to MK).
文摘Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.
基金supported by grants from the National Key Research and Development Program of China(no.2019YFA0111600 and no.2019YFE0120800 to H.L.)the National Natural Science Foundation of China(no.82073145 to Y.Y.,no.31800979 to H.L.,no.81902149 to Q.G.,and no.82102891 to X.K.)+5 种基金the Natural Science Foundation of China for outstanding Young Scholars(no.82022060 to H.L.)the Shanghai Pujiang Program(no.20PJ1412800 to Y.Y.)the Natural Science Foundation of Shanghai(no.20ZR1472900 to Y.Y.)the Natural Science Foundation of Hunan Province for outstanding Young Scholars(no.2019JJ30040 to H.L.)the Natural Science Foundation of Hunan Province of China(no.2018SK2082 to H.L.)the Scientific Research Project of Hunan Health and Family Planning Commission(no.B20180855 to H.L.).
文摘Immune checkpoint blockade(ICB)therapies exhibit substantial clinical benefit in different cancers,but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune features.Here,we reveal overall positive correlations among immune checkpoints and immune cell populations.Clinically,patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy,suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune response.As proof-of-concept,we demonstrated that the immune activation score(ISD)based on dynamic alteration of interleukins in patient plasma as early as two cycles(4-6 weeks)after starting immunotherapy can accurately predict immunotherapy efficacy.Our results reveal a systematic landscape of associations among immune features and provide a noninvasive,cost-effective,and time-efficient approach based on dynamic profiling of pre-and on-treatment plasma to predict immunotherapy efficacy.
文摘Cholangiocarcinoma(CCA)is a rare and very aggressive malignancy arising from the biliary tract.Based on the location of the tumor,CCA can be divided in intrahepatic cholangiocarcinoma(iCCA),perihilar cholangiocarcinoma(pCCA)and distal cholangiocarcinoma(dCCA).Many other characteristics differentiate these groups,including pathological features,oncological approach and surgical techniques,which in turn influences patient outcomes.
基金supported by the Cancer Early Detection Advanced Research(CEDAR)Center of the OHSU Knight Cancer Institutesupported in part by the OHSU Knight Cancer Institute,the Damon Runyon Cancer Research Foundation,the Cancer Systems Biology Consortium from the National Cancer Institute(CSBC,grant number U54 CA209988,PI:Joe W.Gray)the National Institute of General Medical Sciences(grant number R01 GM132322,PI:X.N.).
文摘Fluorescence nanoscopy has become increasingly powerful for biomedical research,but it has historically afforded a small field-ofview(FOV)of around 50μm×50μm at once and more recently up to∼200μm×200μm.Efforts to further increase the FOV in fluorescence nanoscopy have thus far relied on the use of fabricated waveguide substrates,adding cost and sample constraints to the applications.Here we report PRism-Illumination and Microfluidics-Enhanced DNA-PAINT(PRIME-PAINT)for multiplexed fluorescence nanoscopy across millimeter-scale FOVs.Built upon the well-established prism-type total internal reflection microscopy,PRIME-PAINT achieves robust singlemolecule localization with up to∼520μm×520μm single FOVs and 25−40 nm lateral resolutions.Through stitching,nanoscopic imaging over mm^(2)sample areas can be completed in as little as 40 min per target.An on-stage microfluidics chamber facilitates probe exchange for multiplexing and enhances image quality,particularly for formalin-fixed paraffin-embedded(FFPE)tissue sections.We demonstrate the utility of PRIME-PAINT by analyzing∼106 caveolae structures in∼1,000 cells and imaging entire pancreatic cancer lesions from patient tissue biopsies.By imaging from nanometers to millimeters with multiplexity and broad sample compatibility,PRIMEPAINT will be useful for building multiscale,Google-Earth-like views of biological systems.
