BACKGROUND A significant proportion of cancer patients experience autonomic dysfunction,and cancer treatments such as chemotherapy and radiation therapy can exacerbate impairments in the cardiac autonomic nervous syst...BACKGROUND A significant proportion of cancer patients experience autonomic dysfunction,and cancer treatments such as chemotherapy and radiation therapy can exacerbate impairments in the cardiac autonomic nervous system.This study sought to investigate the characteristics of heart rate variability(HRV)in individuals with cancer.AIM To evaluate the relationship between HRV and cancer patients,providing insights and references for cancer treatment.METHODS The study included 127 cancer patients with available 24-hour dynamic electrocardiogram data.HRV differences were analyzed using both time domain and frequency domain methods.These findings were then compared to HRV data from reference individuals,sourced from literature that utilized the same HRV computing algorithm.RESULTS Our findings revealed that cancer patients generally exhibited abnormal HRV compared to the reference group.HRV was found to be correlated with age and clinical type(P<0.05),but no significant correlation was observed with tumor site or gender(P>0.05).CONCLUSION This study indicates that cancer patients have significantly abnormal HRV compared to reference individuals,suggesting the presence of a certain level of cardiac autonomic dysfunction in this patient population.展开更多
β-Elemene is an effective anti-cancer ingredient extracted from the genus Curcuma(Zingiberaceae familiy).In the present study,we demonstrated thatβ-elemene inhibited the proliferation of colorectal cancer cells and ...β-Elemene is an effective anti-cancer ingredient extracted from the genus Curcuma(Zingiberaceae familiy).In the present study,we demonstrated thatβ-elemene inhibited the proliferation of colorectal cancer cells and induced cell cycle arrest in the G2/M phase.In addition,β-elemene induced nuclear chromatin condensation and cell membrane phosphatidylserine eversion,decreased cell mitochondrial membrane potential,and promoted the cleavage of caspase-3,caspase-9 and PARP proteins,indicating apoptosis in colorectal cancer cells.At the same time,β-elemene induced autophagy response,and the treated cells showed autophagic vesicle bilayer membrane structure,which was accompanied by up-regulation of the expression of LC3B and SQSTM1.Furthermore,β-elemene increased ROS levels in colorectal cancer cells,promoted phosphorylation of AMPK protein,and inhibited mTOR protein phosphorylation.In the experiments in vivo,β-elemene inhibited the tumor size and induced apoptosis and autophagy in nude mice.In summary,β-elemene inhibited the occurrence and development of colon cancer xenografts in nude mice,and significantly induced apoptosis and autophagy in colorectal cancer cells in vitro.These effects were associated with regulation of the ROS/AMPK/mTOR signaling.We offered a molecular basis for the development ofβ-elemene as a promising anti-tumor drug candidate for colorectal cancer.展开更多
Objective:To investigate the effect of different doses of stereotactic radiotherapy(SBRT)on the recurrence,metastasis and survival of lung cancer patients.Methods:The clinical data of 13 patients with lung cancer who ...Objective:To investigate the effect of different doses of stereotactic radiotherapy(SBRT)on the recurrence,metastasis and survival of lung cancer patients.Methods:The clinical data of 13 patients with lung cancer who were treated in our hospital from May 2016 to June 2020 and were followed up for one year were retrospectively analyzed.The patients treated with low-dose SBRT were divided into the observation group(7 cases)and the patients treated with high-dose SBRT were divided into the control group(6 cases).The clinical efficacy,recurrence,metastasis,survival status and incidence of adverse reactions were compared between the two groups.Results:There were no significant differences in the clinical total effective rate,1-year recurrence rate,metastasis rate and survival rate between the two groups(P>0.05);The incidence of adverse reactions in the observation group was lower than that in the control group,the difference was statistically significant(P<0.05).Conclusion:High dose or low dose SBRT can achieve good curative effect and prognosis in patients with lung cancer,but low dose SBRT has less adverse reactions and higher safety.展开更多
BACKGROUND Infectious diseases are still one of the greatest threats to human health,and the etiology of 20%of cases of clinical fever is unknown;therefore,rapid identification of pathogens is highly important.Traditi...BACKGROUND Infectious diseases are still one of the greatest threats to human health,and the etiology of 20%of cases of clinical fever is unknown;therefore,rapid identification of pathogens is highly important.Traditional culture methods are only able to detect a limited number of pathogens and are time-consuming;serologic detection has window periods,false-positive and false-negative problems;and nucleic acid molecular detection methods can detect several known pathogens only once.Three-generation nanopore sequencing technology provides new options for identifying pathogens.CASE SUMMARY Case 1:The patient was admitted to the hospital with abdominal pain for three days and cessation of defecation for five days,accompanied by cough and sputum.Nanopore sequencing of the drainage fluid revealed the presence of orallike bacteria,leading to a clinical diagnosis of bronchopleural fistula.Cefoperazone sodium sulbactam treatment was effective.Case 2:The patient was admitted to the hospital with fever and headache,and CT revealed lung inflammation.Antibiotic treatment for Streptococcus pneumoniae,identified through nanopore sequencing of cerebrospinal fluid,was effective.Case 3:The patient was admitted to our hospital with intermittent fever and an enlarged neck mass that had persisted for more than six months.Despite antibacterial treatment,her symptoms worsened.The nanopore sequencing results indicate that voriconazole treatment is effective for Aspergillus brookii.The patient was diagnosed with mixed cell type classical Hodgkin's lymphoma with infection.CONCLUSION Three-generation nanopore sequencing technology allows for rapid and accurate detection of pathogens in human infectious diseases.展开更多
Objective:This prospective randomized controlled study was conducted to evaluate the safety and efficacy of the Pringle hepatic hilar occlusion with a bulldog clamp in laparoscopic liver resection.Methods:From March 1...Objective:This prospective randomized controlled study was conducted to evaluate the safety and efficacy of the Pringle hepatic hilar occlusion with a bulldog clamp in laparoscopic liver resection.Methods:From March 1,2020 to July 31,2021,80 patients were enrolled,including 40 undergoing intraperitoneal Pringle maneuver(IPM)and 40 extraperitoneal Pringle maneuver(EPM).The observation indices included basic preoperative clinical characteristics and intraoperative and postoperative liver function indices.Results:There were no significant differences in the basic characteristics or types of hepatectomy,intraoperative blood loss,intraoperative blood transfusion,or hepatectomy time between the IPM and EPM groups.However,the blocking and operation time in the IPM group was shorter than that in the EPM group.There were no significant differences in alanine aminotransferase(ALT)or aspartate aminotransferase(AST)levels on the first day after surgery or in total bilirubin(TBIL)or albumin(ALB)levels on the first,third,or fifth days after surgery.However,C-reactive protein(CRP)levels on the first and third days,ALT and AST levels on the third and fifth days were lower,and hospital stay after surgery was shorter in the IPM group than in the EPM group.Conclusion:IPM using bulldog clamps is simple,safe,and effective.The inflammatory reaction is less severe,the degree of liver function injury is lower,and recovery is faster.展开更多
The application of a thermoluminescent detector(TLD) for dose detection at the liver irradiation site in mice under linear accelerator precision radiotherapy and the use of a single high dose to irradiate the mouse li...The application of a thermoluminescent detector(TLD) for dose detection at the liver irradiation site in mice under linear accelerator precision radiotherapy and the use of a single high dose to irradiate the mouse liver to construct a biological model of a radiation-induced liver injury(RILD) in mice were to determine the feasibility of constructing a precision radiotherapy model in small animals under a linear accelerator. A 360° arc volumetric rotational intensity-modulated radiotherapy(VMAT) plan with a prescribed dose of 2 Gy was developed for the planned target volume(PTV) at the location of the TLD within solid water to compare the difference between the measured dose of TLD and the assessed parameters in the TPS system. The TLD was implanted in the livers of mice, and VMAT was planned based on TLD to compare the measured and prescribed doses. C57BL/6 J mice were randomly divided into control and 25-Gy radiation groups and were examined daily for changes in body weight. They were euthanized at 3 and 10 weeks after radiation, and the levels of liver serum enzymes such as alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) were measured to observe any pathological histological changes in the irradiated areas of the mouse liver. The measured values of solid underwater TLD were within ± 3% of the Dmean value of the evaluation parameter in the TPS system. The mice in the 25-Gy radiation group demonstrated pathological signs of radiation-induced liver injury at the site of liver irradiation. The deviation in the measured and prescribed doses of TLD in the mouse liver ranged from-1.5 to 6%;construction of an accurate model of RILD using the VMAT technique under a linear accelerator is feasible.展开更多
Radiotherapy uses high-energy X-rays or other particles to destroy cancer cells and medical practitioners have used this approach extensively for cancer treatment(Hachadorian et al.,2020).However,it is accompanied by ...Radiotherapy uses high-energy X-rays or other particles to destroy cancer cells and medical practitioners have used this approach extensively for cancer treatment(Hachadorian et al.,2020).However,it is accompanied by risks because it seriously harms normal cells while killing cancer cells.The side effects can lower cancer patients’quality of life and are very unpredictable due to individual differences(Bentzen,2006).展开更多
Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials amon...Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.展开更多
Insulin-producing pancreaticβcell death is the fundamental cause of type 1 diabetes(T1D)and a contributing factor to type 2 diabetes(T2D).Moreover,metabolic disorder is another hallmark of T2D.Mammalian sterile 20-li...Insulin-producing pancreaticβcell death is the fundamental cause of type 1 diabetes(T1D)and a contributing factor to type 2 diabetes(T2D).Moreover,metabolic disorder is another hallmark of T2D.Mammalian sterile 20-like kinase 1(MST1)contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreaticβcell dysfunction.AMP-activated protein kinase(AMPK)is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases.Thus,pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy.Here,we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39,which exhibits anti-apoptosis efficacy and improves the survival of pancreaticβcells under diabetogenic conditions,as well as primary pancreatic islets in an ex vivo disease model.Mechanistically,IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro,combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice.Taken together,IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.展开更多
Dear Editor,Approximately 25%of acute myeloid leukemia(AML)carries FLT3-ITD(internal tandem duplication)oncogenic mutations.Although FLT3 kinase inhibitors have already been successfully used in the clinic for treatin...Dear Editor,Approximately 25%of acute myeloid leukemia(AML)carries FLT3-ITD(internal tandem duplication)oncogenic mutations.Although FLT3 kinase inhibitors have already been successfully used in the clinic for treating FLT3-ITD-positive AML,acquired drug resistance is observed after the prolonged treatment.Therefore,seeking a new therapeutic strategy is still imperative for FLT3-ITD-positive AML.展开更多
microRNAs (miRNAs)are endogenous small non-coding RNAs that bind to mRNAs and target them for cleavage and/or translational repression,leading to gene silencing.We previously developed short tandem target mimic (STTM)...microRNAs (miRNAs)are endogenous small non-coding RNAs that bind to mRNAs and target them for cleavage and/or translational repression,leading to gene silencing.We previously developed short tandem target mimic (STTM)technology to deactivate endogenous miRNAs in Arabidopsis.Here,we created hundreds of STTMs that target both conserved and species-specific miRNAs in Arabidopsis,tomato,rice,and maize,providing a resource for the functional interrogation of miRNAs.We not only revealed the functions of several miRNAs in plant development,but also demonstrated that tissue-specific inactivation of a few miRNAs in rice leads to an increase in grain size without adversely affecting overall plant growth and development.RNA-seq and small RNAseq analyses of STTM156/157 and STTM165/166 transgenic plants revealed the roles of these miRNAs in plant hormone biosynthesis and activation,secondary metabolism,and ion-channel activity-associated electrophysiology,demonstrating that STTM technology is an effective approach for studying miRNA functions.To facilitate the study and application of STTM transgenic plants and to provide a useful platform for storing and sharing of information about miRNA-regulated gene networks,we have established an online Genome Browser (https://blossom.ffr.mtu.edu/designindex2.php) to display the transcriptomic and miRNAomic changes in STTMinduced miRNA knockdown plants.展开更多
Acute myeloid leukemia (AML) is an aggressive hematologicmalignancy characterized by the abnormal differentiation andrapid proliferation of hematopoietic cells. The causes of this typeof blood cancer are multiple, wit...Acute myeloid leukemia (AML) is an aggressive hematologicmalignancy characterized by the abnormal differentiation andrapid proliferation of hematopoietic cells. The causes of this typeof blood cancer are multiple, with approximately 30% of AMLpatients characterized by expression of the internal tandemduplication (ITD) of the Fms-like tyrosine kinase 3 (FLT3) gene.1Despite the availability of effective FLT3 inhibitors, alone orcombined with conventional chemotherapy, for the treatment ofFLT3-ITD AML, there is a risk of leukemia relapse due to drugresistance. Reasons for drug resistance include the evolution ofthe secondary mutations of FLT3 in response to drug treatmentand compensatory activation of survival signaling pathways.2Therefore, the discovery of new drug targets and noveltherapeutic strategies for FLT3-ITD-positive AML is imperativefor overcoming resistance to FLT3 inhibitors.展开更多
Since the dinical approval of imatinib,the discovery of protein kinase downregulators entered a prosperous age.However,challenges still exist in the discovery of kinase downregulator drugs,such as the high failure rat...Since the dinical approval of imatinib,the discovery of protein kinase downregulators entered a prosperous age.However,challenges still exist in the discovery of kinase downregulator drugs,such as the high failure rate during development,side effects,and drug-resistance problems.With the progress made through multidisciplinary efforts,an increasing number of new approaches have bee n applied to solve the above problems duri ng the discovery process of kin ase down regulators.In terms of in vitro and in vivo drug evaluation,progress was also made in cellular and animal model platforms for better and more clinically relevant drug assessme nt.Here,we review the adva nces in drug desig n strategies,drug property evaluatio n tech no logies,and efficacy evaluatio n models and tech no logies.Finally,we discuss the challenges and perspectives in the development of kin ase down regulator drugs.展开更多
Enhancer of zeste homolog 2(EZH2),an enzymatic subunit of PRC2 complex,plays an important role in tumor development and progression through its catalytic and noncatalytic activities.Overexpression or gain-of-function ...Enhancer of zeste homolog 2(EZH2),an enzymatic subunit of PRC2 complex,plays an important role in tumor development and progression through its catalytic and noncatalytic activities.Overexpression or gain-of-function mutations of EZH2 have been significantly associated with tumor cell proliferation of triple-negative breast cancer(TNBC)and diffuse large B-cell lymphoma(DLBCL).As a result,it has gained interest as a potential therapeutic target.The currently available EZH2 inhibitors,such as EPZ6438 and GSK126,are of benefit for clinical using or reached clinical trials.However,certain cancers are resistant to these enzymatic inhibitors due to its noncatalytic or transcriptional activity through modulating nonhistone proteins.Thus,it may be more effective to synergistically degrade EZH2 in addition to enzymatic inhibition.Here,through a rational design and chemical screening,we discovered a new irreversible EZH2 inhibitor,IHMT-337,which covalently bounds to and degrades EZH2 via the E3 ligase CHIP-mediated ubiquitination pathway.Moreover,we revealed that IHMT-337 affects cell cycle progression in TNBC cells through targeting transcriptional regulating of CDK4,a novel PRC2 complex-and enzymatic activity-independent function of EZH2.More significantly,our compound inhibits both DLBCL and TNBC cell proliferation in different preclinical models in vitro and in vivo.Taken together,our findings demonstrate that in addition to enzymatic inhibition,destroying of EZH2 by IHMT-337 could be a promising therapeutic strategy for TNBC and other malignancies that are independent of EZH2 enzymatic activity.展开更多
The two most common inherited forms of colorectal cancer(CRC)are familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.They are caused by germline mutations in the APC and mismatch repair genes,...The two most common inherited forms of colorectal cancer(CRC)are familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.They are caused by germline mutations in the APC and mismatch repair genes,respectively.1 The simultaneous inheritance of both an APC gene mutation and a mismatch repair gene mutation is very rare.In this study,we reported a coinheritance of mutations in the APC and MLH1 genes in a 20-year-old patient with CRC and multiple polyposes.We described for the first time the somatic mutational profile of a colorectal tumor harboring concurrent germline mutations in the APC and MLH1 genes.展开更多
Despite the spread of effective vaccination strategies,cervical cancer remains the second leading cause of cancer death among women aged 20 to 39.1 clinical diagnosis of cervical lesions relies on the P16INK4a(P16)mar...Despite the spread of effective vaccination strategies,cervical cancer remains the second leading cause of cancer death among women aged 20 to 39.1 clinical diagnosis of cervical lesions relies on the P16INK4a(P16)marker,but its sensitivity to low-grade cervical intraepithelial neoplasia(CIN)is limited.Exploring more sensitive and specific molecular markers is still a challenge in cervical lesion screening.In this study,we found that HMGB3 could effectively label pathological cells in different cervical lesions,especially for early CIN.Therefore,HMGB3 has the potential to be used as a novel marker for the early screening of cervical lesions.展开更多
Dear Editor,Bruton’s tyrosine kinase(BTK)plays a crucial role in the B-cell receptor(BCR)signaling which is essential for B-cell proliferation,differentiation,and cell migration.Aberrant BCR activation has been ident...Dear Editor,Bruton’s tyrosine kinase(BTK)plays a crucial role in the B-cell receptor(BCR)signaling which is essential for B-cell proliferation,differentiation,and cell migration.Aberrant BCR activation has been identified as a major pathogenic factor in several B-cell non-Hodgkin lymphoma(B-NHL)subtypes,including diffuse large Bcell lymphoma(DLBCL),mantle cell lymphoma(MCL),follicular lymphoma(FL),and chronic lymphocytic leukemia(CLL).1 Therefore,BTK has been recognized as a validated therapeutic target for B-cell malignancies.Ibrutinib,the first approved BTK inhibitor that binds irreversibly to cysteine residue 481,has shown potent clinical activity in the majority of CD20 positive B-cell malignancies.2 However,due to the inhibition of off-target kinases such as EGFR,ITK,and TXK,which have a cysteine residue at the identical position of Cys481 of BTK,Ibrutinib also results in some adverse events,such as the antagonizing Rituximab-dependent NK-cell-mediated antibody-dependent cell-mediated cytotoxicity(ADCC)due to its irreversible binding to ITK,which is required for FcR-stimulated NK cell function.3 Although several secondary generation inhibitors have shown improved selectivity,4,5 more pharmacologically diverse novel inhibitors are still highly demanded in the clinic.展开更多
基金the Medical Ethics Committee of the Hefei Cancer Hospital,Chinese Academy of Sciences(No.PJ-KY-2024-025).
文摘BACKGROUND A significant proportion of cancer patients experience autonomic dysfunction,and cancer treatments such as chemotherapy and radiation therapy can exacerbate impairments in the cardiac autonomic nervous system.This study sought to investigate the characteristics of heart rate variability(HRV)in individuals with cancer.AIM To evaluate the relationship between HRV and cancer patients,providing insights and references for cancer treatment.METHODS The study included 127 cancer patients with available 24-hour dynamic electrocardiogram data.HRV differences were analyzed using both time domain and frequency domain methods.These findings were then compared to HRV data from reference individuals,sourced from literature that utilized the same HRV computing algorithm.RESULTS Our findings revealed that cancer patients generally exhibited abnormal HRV compared to the reference group.HRV was found to be correlated with age and clinical type(P<0.05),but no significant correlation was observed with tumor site or gender(P>0.05).CONCLUSION This study indicates that cancer patients have significantly abnormal HRV compared to reference individuals,suggesting the presence of a certain level of cardiac autonomic dysfunction in this patient population.
基金the National Natural Science Foundation of China(Nos.81603339 and 81803774)Anhui Key Research and Development Program(No.201904a-07020092)+1 种基金the Fundamental Research Funds for the Central Universities(Nos.WK9110000016 and WK9110000079)China Postdoctoral Science Foundation(No.2019M662207).
文摘β-Elemene is an effective anti-cancer ingredient extracted from the genus Curcuma(Zingiberaceae familiy).In the present study,we demonstrated thatβ-elemene inhibited the proliferation of colorectal cancer cells and induced cell cycle arrest in the G2/M phase.In addition,β-elemene induced nuclear chromatin condensation and cell membrane phosphatidylserine eversion,decreased cell mitochondrial membrane potential,and promoted the cleavage of caspase-3,caspase-9 and PARP proteins,indicating apoptosis in colorectal cancer cells.At the same time,β-elemene induced autophagy response,and the treated cells showed autophagic vesicle bilayer membrane structure,which was accompanied by up-regulation of the expression of LC3B and SQSTM1.Furthermore,β-elemene increased ROS levels in colorectal cancer cells,promoted phosphorylation of AMPK protein,and inhibited mTOR protein phosphorylation.In the experiments in vivo,β-elemene inhibited the tumor size and induced apoptosis and autophagy in nude mice.In summary,β-elemene inhibited the occurrence and development of colon cancer xenografts in nude mice,and significantly induced apoptosis and autophagy in colorectal cancer cells in vitro.These effects were associated with regulation of the ROS/AMPK/mTOR signaling.We offered a molecular basis for the development ofβ-elemene as a promising anti-tumor drug candidate for colorectal cancer.
文摘Objective:To investigate the effect of different doses of stereotactic radiotherapy(SBRT)on the recurrence,metastasis and survival of lung cancer patients.Methods:The clinical data of 13 patients with lung cancer who were treated in our hospital from May 2016 to June 2020 and were followed up for one year were retrospectively analyzed.The patients treated with low-dose SBRT were divided into the observation group(7 cases)and the patients treated with high-dose SBRT were divided into the control group(6 cases).The clinical efficacy,recurrence,metastasis,survival status and incidence of adverse reactions were compared between the two groups.Results:There were no significant differences in the clinical total effective rate,1-year recurrence rate,metastasis rate and survival rate between the two groups(P>0.05);The incidence of adverse reactions in the observation group was lower than that in the control group,the difference was statistically significant(P<0.05).Conclusion:High dose or low dose SBRT can achieve good curative effect and prognosis in patients with lung cancer,but low dose SBRT has less adverse reactions and higher safety.
基金Supported by Research and Development Funding for Medical and Health Institutions,No.2021YL007.
文摘BACKGROUND Infectious diseases are still one of the greatest threats to human health,and the etiology of 20%of cases of clinical fever is unknown;therefore,rapid identification of pathogens is highly important.Traditional culture methods are only able to detect a limited number of pathogens and are time-consuming;serologic detection has window periods,false-positive and false-negative problems;and nucleic acid molecular detection methods can detect several known pathogens only once.Three-generation nanopore sequencing technology provides new options for identifying pathogens.CASE SUMMARY Case 1:The patient was admitted to the hospital with abdominal pain for three days and cessation of defecation for five days,accompanied by cough and sputum.Nanopore sequencing of the drainage fluid revealed the presence of orallike bacteria,leading to a clinical diagnosis of bronchopleural fistula.Cefoperazone sodium sulbactam treatment was effective.Case 2:The patient was admitted to the hospital with fever and headache,and CT revealed lung inflammation.Antibiotic treatment for Streptococcus pneumoniae,identified through nanopore sequencing of cerebrospinal fluid,was effective.Case 3:The patient was admitted to our hospital with intermittent fever and an enlarged neck mass that had persisted for more than six months.Despite antibacterial treatment,her symptoms worsened.The nanopore sequencing results indicate that voriconazole treatment is effective for Aspergillus brookii.The patient was diagnosed with mixed cell type classical Hodgkin's lymphoma with infection.CONCLUSION Three-generation nanopore sequencing technology allows for rapid and accurate detection of pathogens in human infectious diseases.
基金supported by grants from Scientific Research Fund of Anhui Medical University(No.2021xkj034)Clinical Research Cultivation Program of the Second Affiliated Hospital of Anhui Medical University(No.2020LCYB18)Anhui Institute of Translational Medicine(No.2023zhyx-C84).
文摘Objective:This prospective randomized controlled study was conducted to evaluate the safety and efficacy of the Pringle hepatic hilar occlusion with a bulldog clamp in laparoscopic liver resection.Methods:From March 1,2020 to July 31,2021,80 patients were enrolled,including 40 undergoing intraperitoneal Pringle maneuver(IPM)and 40 extraperitoneal Pringle maneuver(EPM).The observation indices included basic preoperative clinical characteristics and intraoperative and postoperative liver function indices.Results:There were no significant differences in the basic characteristics or types of hepatectomy,intraoperative blood loss,intraoperative blood transfusion,or hepatectomy time between the IPM and EPM groups.However,the blocking and operation time in the IPM group was shorter than that in the EPM group.There were no significant differences in alanine aminotransferase(ALT)or aspartate aminotransferase(AST)levels on the first day after surgery or in total bilirubin(TBIL)or albumin(ALB)levels on the first,third,or fifth days after surgery.However,C-reactive protein(CRP)levels on the first and third days,ALT and AST levels on the third and fifth days were lower,and hospital stay after surgery was shorter in the IPM group than in the EPM group.Conclusion:IPM using bulldog clamps is simple,safe,and effective.The inflammatory reaction is less severe,the degree of liver function injury is lower,and recovery is faster.
基金supported by the Natural Science Foundation of Anhui Province (No.2208085MA13)Wu Je Ping Medical Foundation (No.320.6750.2020-10-40)the Key Research and Development Program of Anhui Province (No.202004J07020052)。
文摘The application of a thermoluminescent detector(TLD) for dose detection at the liver irradiation site in mice under linear accelerator precision radiotherapy and the use of a single high dose to irradiate the mouse liver to construct a biological model of a radiation-induced liver injury(RILD) in mice were to determine the feasibility of constructing a precision radiotherapy model in small animals under a linear accelerator. A 360° arc volumetric rotational intensity-modulated radiotherapy(VMAT) plan with a prescribed dose of 2 Gy was developed for the planned target volume(PTV) at the location of the TLD within solid water to compare the difference between the measured dose of TLD and the assessed parameters in the TPS system. The TLD was implanted in the livers of mice, and VMAT was planned based on TLD to compare the measured and prescribed doses. C57BL/6 J mice were randomly divided into control and 25-Gy radiation groups and were examined daily for changes in body weight. They were euthanized at 3 and 10 weeks after radiation, and the levels of liver serum enzymes such as alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) were measured to observe any pathological histological changes in the irradiated areas of the mouse liver. The measured values of solid underwater TLD were within ± 3% of the Dmean value of the evaluation parameter in the TPS system. The mice in the 25-Gy radiation group demonstrated pathological signs of radiation-induced liver injury at the site of liver irradiation. The deviation in the measured and prescribed doses of TLD in the mouse liver ranged from-1.5 to 6%;construction of an accurate model of RILD using the VMAT technique under a linear accelerator is feasible.
基金supported by the National Natural Science Foundation of China(Nos.21876176,21777163,21705152,and 22076190)the Youth Innovation Promotion Association,Chinese Academy of Sciences(No.2019432)+3 种基金the Presidential Foundation of Hefei Institute of Physical Sciences of Chinese Academy of Sciences(No.YZJJZX202009)the Functional Development Program of Instrument and Equipment in Chinese Academy of Sciences(No.Y9BS0C1291)the Anhui Provincial Key R&D Program(No.202104d07020003)the Joint Fund of the Second Affiliated Hospital of Anhui Medical University and the Center of Medical Physics and Technology of Hefei Institute of Physical Sciences of the Chinese Academy of Sciences(No.LHJJ2020006)。
文摘Radiotherapy uses high-energy X-rays or other particles to destroy cancer cells and medical practitioners have used this approach extensively for cancer treatment(Hachadorian et al.,2020).However,it is accompanied by risks because it seriously harms normal cells while killing cancer cells.The side effects can lower cancer patients’quality of life and are very unpredictable due to individual differences(Bentzen,2006).
基金supported by the National Natural Science Foundation of China(Grant Nos.81903650,32171479,82103976)the Natural Science Foundation of Anhui Province(Grant Nos.2008085MH274,2108085QH377,China)+2 种基金the Collaborative Innovation Program of Hefei Science Center,CAS(Grant No.2021HSC-CIP014,China)the CASHIPS Director’s Found(Grant Nos.YZJJZX202011,YZJJ2021QN38,China)supported by the High Magnetic Field Laboratory of Anhui Province。
文摘Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.
基金supported by the National Natural Science Foundation of China (Grant No.32171479)the Natural Science Foundation of Anhui Province (Grant No,2108085QH377,1908085QH345)+2 种基金the Frontier Science Key Research Program of CAS (Grant QYZDB-SSW-SLH037)the Collaborative Innovation Program of Hefei Science Center,CAS (Grant No.2021HSC-CIP014)the CASHIPS Director’s Fund (Grant Nos.YZJJZX202011,YZJJ2021QN38).
文摘Insulin-producing pancreaticβcell death is the fundamental cause of type 1 diabetes(T1D)and a contributing factor to type 2 diabetes(T2D).Moreover,metabolic disorder is another hallmark of T2D.Mammalian sterile 20-like kinase 1(MST1)contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreaticβcell dysfunction.AMP-activated protein kinase(AMPK)is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases.Thus,pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy.Here,we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39,which exhibits anti-apoptosis efficacy and improves the survival of pancreaticβcells under diabetogenic conditions,as well as primary pancreatic islets in an ex vivo disease model.Mechanistically,IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro,combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice.Taken together,IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.
基金supported by the National Key R&D Program of China(2021YFA1600202)the National Natural Science Foundation of China(U2032162,81972191,U1932158,and 81871085)+7 种基金Hefei Institutes of Physical Science Director’s Fund(BJPY2021B06)the Collaborative Innovation Program of Hefei Science Center of CAS(2022HSCCIP013)Anhui Provincial Natural Science Foundation(2208085J10)Hefei Municipal Natural Science Foundation(2021009)the Natural Science Foundation of Shandong Province(ZR2019LZL018)the High Magnetic Field Laboratory of Anhui Province(AHHM-FX-2021-04)the Project of China Postdoctoral Science Foundation(2019M652403)the Project of Postdoctoral Innovation of Shandong Province(202002048)。
基金supported by the National Natural Science Foundation of China(Grant Nos.81903650,81803366,81673469,81773777)the Natural Science Foundation of Anhui Province(Grant Nos.2008085MH274,1808085MH268)+4 种基金the China Postdoctoral Science Foundation(Grant No.2019M652057)the Postdoctoral Science Foundation of Anhui Province(Grant No.2019B300)the Frontier Science Key Research Program of CAS(Grant No.QYZDB-SSW-SLH037)the Collaborative Innovation Program of Hefei Science Center,CAS(Grant No.2019HSC-CIP011)the CASHIPS Director’s Fund(Grant Nos.BJPY2019A03,YZJJZX202011).
文摘Dear Editor,Approximately 25%of acute myeloid leukemia(AML)carries FLT3-ITD(internal tandem duplication)oncogenic mutations.Although FLT3 kinase inhibitors have already been successfully used in the clinic for treating FLT3-ITD-positive AML,acquired drug resistance is observed after the prolonged treatment.Therefore,seeking a new therapeutic strategy is still imperative for FLT3-ITD-positive AML.
基金the National Science Foundation,USA (IOS-1048216 and IOS-1340001)the National Natural Science Foundation of China (31571679,31501292,31871554)+1 种基金the Major Science and Technology Project of Henan Province (141100110600)the Support Plan of Science and Technology Innovation Team in Universities of Henan Province (171RTSTHN015),and the Key Scientific Research Project in Universities of Henan Province (16A210009).G.T.is also supported by the Guangdong Innovation Research Team Fund (2014ZT058078)and the 111 Project (D16014)to Henan University.S.T.was supported by a post-doctoral fellowship from Henan Agricultural University.F.M.was a visiting scholar supported by the China Scholarship Council (CSC).T.P.,Z.Z.,L.S.,and L.T.were visiting PhD students supported by scholarships from Henan Agricultural University.
文摘microRNAs (miRNAs)are endogenous small non-coding RNAs that bind to mRNAs and target them for cleavage and/or translational repression,leading to gene silencing.We previously developed short tandem target mimic (STTM)technology to deactivate endogenous miRNAs in Arabidopsis.Here,we created hundreds of STTMs that target both conserved and species-specific miRNAs in Arabidopsis,tomato,rice,and maize,providing a resource for the functional interrogation of miRNAs.We not only revealed the functions of several miRNAs in plant development,but also demonstrated that tissue-specific inactivation of a few miRNAs in rice leads to an increase in grain size without adversely affecting overall plant growth and development.RNA-seq and small RNAseq analyses of STTM156/157 and STTM165/166 transgenic plants revealed the roles of these miRNAs in plant hormone biosynthesis and activation,secondary metabolism,and ion-channel activity-associated electrophysiology,demonstrating that STTM technology is an effective approach for studying miRNA functions.To facilitate the study and application of STTM transgenic plants and to provide a useful platform for storing and sharing of information about miRNA-regulated gene networks,we have established an online Genome Browser (https://blossom.ffr.mtu.edu/designindex2.php) to display the transcriptomic and miRNAomic changes in STTMinduced miRNA knockdown plants.
基金We thank Dr Sara J.Buhrlage and Dr James D.Griffin at Dana-Farber Cancer Institutc—Harvard Medical School for theirgenerous and valuable scientific support.Our work wassupported and funded by the National Natural ScienceFoundation of China(82104198)Claudia Adams Barr Award,MPN Rescarch Foundation,and Gabrielle's Angel Foundation.Authorship Contributions:JY wrote the manuscript and EWprovided valuable scientific feedback.
文摘Acute myeloid leukemia (AML) is an aggressive hematologicmalignancy characterized by the abnormal differentiation andrapid proliferation of hematopoietic cells. The causes of this typeof blood cancer are multiple, with approximately 30% of AMLpatients characterized by expression of the internal tandemduplication (ITD) of the Fms-like tyrosine kinase 3 (FLT3) gene.1Despite the availability of effective FLT3 inhibitors, alone orcombined with conventional chemotherapy, for the treatment ofFLT3-ITD AML, there is a risk of leukemia relapse due to drugresistance. Reasons for drug resistance include the evolution ofthe secondary mutations of FLT3 in response to drug treatmentand compensatory activation of survival signaling pathways.2Therefore, the discovery of new drug targets and noveltherapeutic strategies for FLT3-ITD-positive AML is imperativefor overcoming resistance to FLT3 inhibitors.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81903650)the Natural Science Foundation of Anhui Province(Grant Nos.1808085MH274 and 2008085MH274)+3 种基金the China Postdoctoral Science Foundation(Grant Nos.2020M671916 and 2019M652057)the Postdoctoral Science Foundation of Anhui Province(Grant Nos.2019B326 and 2019B300)the Frontier Science Key Research Program of CAS(Grant No.QYZDB-SSW-SLH037)the CASHIPS Directors Found(Grant Nos.BJPY2019A03 and YZJJZX202011).
文摘Since the dinical approval of imatinib,the discovery of protein kinase downregulators entered a prosperous age.However,challenges still exist in the discovery of kinase downregulator drugs,such as the high failure rate during development,side effects,and drug-resistance problems.With the progress made through multidisciplinary efforts,an increasing number of new approaches have bee n applied to solve the above problems duri ng the discovery process of kin ase down regulators.In terms of in vitro and in vivo drug evaluation,progress was also made in cellular and animal model platforms for better and more clinically relevant drug assessme nt.Here,we review the adva nces in drug desig n strategies,drug property evaluatio n tech no logies,and efficacy evaluatio n models and tech no logies.Finally,we discuss the challenges and perspectives in the development of kin ase down regulator drugs.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.82104198,32171479,82104239)the Natural Science Foundation of Anhui Province(Grant Nos.2008085MH274,2108085QH377)+4 种基金the China Postdoctoral Science Foundation(Grant No.2020M671916)the Frontier Science Key Research Program of CAS(Grant No.QYZDB-SSW-SLH037)the Collaborative Innovation Program of Hefei Science Center,CAS(Grant No.2021HSC-CIP014)the CASHIPS Director’s Found(Grant Nos.BJPY2019A03,YZJJZX202011,YZJJ2021QN38)We are also grateful for the support of the Youth Innovation Promotion Association of CAS support(No.2019437)for H.W.A portion of this work was supported by the High Magnetic Field Laboratory of Anhui Province.
文摘Enhancer of zeste homolog 2(EZH2),an enzymatic subunit of PRC2 complex,plays an important role in tumor development and progression through its catalytic and noncatalytic activities.Overexpression or gain-of-function mutations of EZH2 have been significantly associated with tumor cell proliferation of triple-negative breast cancer(TNBC)and diffuse large B-cell lymphoma(DLBCL).As a result,it has gained interest as a potential therapeutic target.The currently available EZH2 inhibitors,such as EPZ6438 and GSK126,are of benefit for clinical using or reached clinical trials.However,certain cancers are resistant to these enzymatic inhibitors due to its noncatalytic or transcriptional activity through modulating nonhistone proteins.Thus,it may be more effective to synergistically degrade EZH2 in addition to enzymatic inhibition.Here,through a rational design and chemical screening,we discovered a new irreversible EZH2 inhibitor,IHMT-337,which covalently bounds to and degrades EZH2 via the E3 ligase CHIP-mediated ubiquitination pathway.Moreover,we revealed that IHMT-337 affects cell cycle progression in TNBC cells through targeting transcriptional regulating of CDK4,a novel PRC2 complex-and enzymatic activity-independent function of EZH2.More significantly,our compound inhibits both DLBCL and TNBC cell proliferation in different preclinical models in vitro and in vivo.Taken together,our findings demonstrate that in addition to enzymatic inhibition,destroying of EZH2 by IHMT-337 could be a promising therapeutic strategy for TNBC and other malignancies that are independent of EZH2 enzymatic activity.
基金supported by the Key Research and Development Program of Anhui Province,China(No.2022e07020048)the Clinical Research Incubation Program of The Second Hospital of Anhui Medical University,China(No.2020LCZD07)+2 种基金the National Natural Science Foundation of China(No.81872438)the Program of Research and Development of Key Common Technologies and Engineering of Major Scientific and Technological Achievements in Hefei,China(No.2021YL007)the Collaborative Innovation Program of Hefei Science Center CAS(China)(No.2022HSC-CIP015).
文摘The two most common inherited forms of colorectal cancer(CRC)are familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.They are caused by germline mutations in the APC and mismatch repair genes,respectively.1 The simultaneous inheritance of both an APC gene mutation and a mismatch repair gene mutation is very rare.In this study,we reported a coinheritance of mutations in the APC and MLH1 genes in a 20-year-old patient with CRC and multiple polyposes.We described for the first time the somatic mutational profile of a colorectal tumor harboring concurrent germline mutations in the APC and MLH1 genes.
基金supported by the National Natural Science Foundation of China(No.81872276)the Hefei City Natural Science Foundation(Anhui,China)(No.2022050)the Foundation of Anhui Province Key Laboratory of Medical Physics and Technology(China)(No.LMPT201908).
文摘Despite the spread of effective vaccination strategies,cervical cancer remains the second leading cause of cancer death among women aged 20 to 39.1 clinical diagnosis of cervical lesions relies on the P16INK4a(P16)marker,but its sensitivity to low-grade cervical intraepithelial neoplasia(CIN)is limited.Exploring more sensitive and specific molecular markers is still a challenge in cervical lesion screening.In this study,we found that HMGB3 could effectively label pathological cells in different cervical lesions,especially for early CIN.Therefore,HMGB3 has the potential to be used as a novel marker for the early screening of cervical lesions.
基金supported by the National Natural Science Foundation of China(Grant Nos.81773777,81872748,and 81803366)the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”of China(Grant No.2018ZX09711002)+4 种基金the Natural Science Foundation of Anhui Province(Grant No.1808085MH268)the China Postdoctoral Science Foundation(Grants Nos.2018T110634 and 2018M630720)the Frontier Science Key Research Program of CAS(Grant No.QYZDB-SSW-SLH037)the Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(Grant No.2019HSCCIP011)the CASHIPS Director’s Fund(Grant No.BJPY2019A03)the Key Program of 13th five-year plan of CASHIPS(Grant No.KP-2017-26).
文摘Dear Editor,Bruton’s tyrosine kinase(BTK)plays a crucial role in the B-cell receptor(BCR)signaling which is essential for B-cell proliferation,differentiation,and cell migration.Aberrant BCR activation has been identified as a major pathogenic factor in several B-cell non-Hodgkin lymphoma(B-NHL)subtypes,including diffuse large Bcell lymphoma(DLBCL),mantle cell lymphoma(MCL),follicular lymphoma(FL),and chronic lymphocytic leukemia(CLL).1 Therefore,BTK has been recognized as a validated therapeutic target for B-cell malignancies.Ibrutinib,the first approved BTK inhibitor that binds irreversibly to cysteine residue 481,has shown potent clinical activity in the majority of CD20 positive B-cell malignancies.2 However,due to the inhibition of off-target kinases such as EGFR,ITK,and TXK,which have a cysteine residue at the identical position of Cys481 of BTK,Ibrutinib also results in some adverse events,such as the antagonizing Rituximab-dependent NK-cell-mediated antibody-dependent cell-mediated cytotoxicity(ADCC)due to its irreversible binding to ITK,which is required for FcR-stimulated NK cell function.3 Although several secondary generation inhibitors have shown improved selectivity,4,5 more pharmacologically diverse novel inhibitors are still highly demanded in the clinic.
