BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50...BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.展开更多
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known a...B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.展开更多
BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancre...BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.展开更多
Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patien...Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.展开更多
Oncolytic virotherapy(OVT)is a promising option for cancer treatment.OVT involves selective oncolytic virus(OV)replication within cancer cells,which triggers anti-tumor responses and immunostimulation.Despite promisin...Oncolytic virotherapy(OVT)is a promising option for cancer treatment.OVT involves selective oncolytic virus(OV)replication within cancer cells,which triggers anti-tumor responses and immunostimulation.Despite promising potential,OVT faces critical challenges,including insufficient tumor-specific targeting,which results in limited tumor penetration and variability in therapeutic efficacy.These challenges are particularly pronounced in solid tumors with complex microenvironments and heterogeneous vascularization.A comprehensive research program is currently underway to develop and refine innovative delivery methods to address these issues to enhance OVT precision and efficacy.A principal area of investigation is the utilization of cellular carriers to enhance the delivery and distribution of OVs within tumor microenvironments,thereby optimizing immune system activation and maximizing anti-tumor effects.This review offers a comprehensive overview of the current strategies that are being used to enhance the delivery of OVs via cellular carriers with the goal of improving the clinical impact of OVT in cancer therapy.展开更多
BACKGROUND Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize.Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge b...BACKGROUND Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize.Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge been reported prior to the appearance of the primary disease.CASE SUMMARY A patient presented with progressive dysphagia to solids and a persistent earache.Computed tomography of the neck and chest revealed a 3.0 cm×1.8 cm heterogeneous mass originating from the upper third of the esophagus,necrotic cervical and supraclavicular lymphadenopathy,and bilateral pulmonary nodules.She underwent a core needle biopsy of a right cervical node,which suggested a well-differentiated adenocarcinoma of unknown primary.She had an upper endoscopy with biopsy of the esophageal mass suggestive of a welldifferentiated adenocarcinoma.Positron emission tomography imaging revealed increased uptake in the esophageal mass,cervical,and mediastinal lymph nodes.She was started on folinic acid,fluorouracil,and oxaliplatin.Prior to initiation of cycle 8,the patient was found to have a pancreatic body mass that was not present on prior radiographic imaging,confirmed by endoscopic ultrasonography and biopsy to be pancreatic adenocarcinoma.CA19-9 was>10000 U/m L,suggesting a primary pancreaticobiliary origin.CONCLUSION Esophageal metastasis diagnosed before primary pancreatic adenocarcinoma is rare.This case highlights the profound metastatic potential of pancreatic adenocarcinoma.展开更多
Dear Editor,Atovaquone(ATO),a mitochondrial inhibitor,has anti-cancer effects[1].Based on ATO,we developed mitochondria-targeted atovaquone(Mito-ATO)that had even stronger anti-tumor efficacy than ATO[2].We syn-thesiz...Dear Editor,Atovaquone(ATO),a mitochondrial inhibitor,has anti-cancer effects[1].Based on ATO,we developed mitochondria-targeted atovaquone(Mito-ATO)that had even stronger anti-tumor efficacy than ATO[2].We syn-thesized Mito-ATO by attaching the bulky triphenylphos-phonium(TPP)group to ATO via a ten-carbon alkyl chain(Supplementary file of methods;Supplementary Figure S1).展开更多
Spatial statistics are crucial for analyzing clustering patterns in various spaces,such as the distribution of trees in a forest or stars in the sky.Advances in spatial biology,such as single-cell spatial transcriptom...Spatial statistics are crucial for analyzing clustering patterns in various spaces,such as the distribution of trees in a forest or stars in the sky.Advances in spatial biology,such as single-cell spatial transcriptomics,enable researchers to map gene expression patterns within tissues,offering unprecedented insights into cellular functions and disease pathology.Common methods for deriving spatial relationships include density-based methods(quadrat analysis,kernel density estimators)and distance-based methods(nearest-neighbor distance[NND],Ripley’s K function).While density-based methods are effective for visualization,they struggle with quantification due to sensitivity to parameters and complex significance tests.In contrast,distance-based methods offer robust frameworks for hypothesis testing,quantifying spatial clustering or dispersion,and facilitating comparisons with models such as uniform random distributions or Poisson processes[1,2].展开更多
T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained.The objective of this study was to...T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained.The objective of this study was to explore the function of interferon regulatory factor 4(IRF4)in antitumor CD8^(+)T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model.To achieve this,we generated an Irf4^(GFP-DTR) mouse strain and discovered that CD8^(+)tumor-infiltrating lymphocytes(TILs)expressing high levels of IRF4.GFP exhibited a more differentiated PD-1high cell phenotype.By administering diphtheria toxin to tumor-bearing Irf4^(GFP-DTR) mice,we partially depleted IRF4.GFP^(+)TILs and observed an accelerated tumor growth.To specifically explore the function of IRF4 in antitumor CD8^(+)T cells,we conducted 3 adoptive cell therapy(ACT)models.Firstly,depleting IRF4.GFP^(+)CD8^(+)TILs derived from ACT significantly accelerated tumor growth,emphasizing their crucial role in controlling tumor progression.Secondly,deleting the Irf4 gene in antitumor CD8^(+)T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8^(+)TILs,completely abolishing the antitumor effects of ACT.Lastly,we performed a temporal deletion of the Irf4 gene in antitumor CD8^(+)T cells during ACT,starting from 20 days after tumor implantation,which significantly compromised tumor control.Therefore,sustained expression of IRF4 is essential for maintaining CD8^(+)T cell immunity in the melanoma model,and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.展开更多
Adipocytes and immune cells are vital for the development of adipose tissue.Adi-pokines secreted by adipocytes regulate adipogenesis and body metabolism.Chemerin is one of the adipokines.However,the function and mecha...Adipocytes and immune cells are vital for the development of adipose tissue.Adi-pokines secreted by adipocytes regulate adipogenesis and body metabolism.Chemerin is one of the adipokines.However,the function and mechanism of chemerin in adipose tissue are not fully illuminated.Compared with wild type(WT)mice,Rarres2^(-/-)mice gained weight and significantly increased fat distribution in subcutaneous adipose tissue(SAT),rather than visceral adipose tissue(VAT)on high fat diet(HFD).PPARg and C/EBPa,the master regulators of adipogenesis,were up-regulated in SAT and down-regulated in VAT in Rarres2^(-/-)mice comparing with WT mice.Inspite of chemerin deficiency or not,the ratio of adipocyte-progenitors to total cells and the differentiation capacity of adipocyte-progenitors were similar in SAT and VAT,but macrophage infiltration in VAT was more severe than in SAT in Rarres2^(-/-)mice.Furthermore,CD45þimmune cells supernatant from Rarres2^(-/-)SAT pro-moted the differentiation of adipocyte-progenitors and 3T3-L1 cells.Adipokine array assay of CD45þimmune cells supernatant revealed that metalloproteinase inhibitor 1(TIMP1),an in-hibitor of adipogenesis,was reduced in Rarres2^(-/-)SAT,but increased in Rarres2^(-/-)VAT.As we specifically knocked down chemerin in SAT,TIMP1 was down-regulated and adipogenesis was promoted with reducing infiltration of macrophages.The present study demonstrates that the effects of chemerin on adipose tissue is depot different,and specific knock down chemerin in SAT promote adipogenesis and improve glucose tolerance test(GTT)and insulin tolerance test(ITT).This suggests a potential therapeutic target for chemerin in the treatment of obesity related metabolic disorder.展开更多
Alzheimer’s disease and related dementias(AD/ADRD)affects more than 50 million people worldwide but there is no clear therapeutic option affordable for the general patient population.Recently,drug repositioning studi...Alzheimer’s disease and related dementias(AD/ADRD)affects more than 50 million people worldwide but there is no clear therapeutic option affordable for the general patient population.Recently,drug repositioning studies featuring collaborations between academic institutes,medical centers,and hospitals are generating novel therapeutics candidates against these devastating diseases and filling in an important area for healthcare that is poorly represented by pharmaceutical companies.Such drug repositioning studies converge expertise from bioinformatics,chemical informatics,medical informatics,artificial intelligence,high throughput and high-content screening and systems biology.They also take advantage of multi-scale,multi-modality datasets,ranging from transcriptomic and proteomic data,electronical medical records,and medical imaging to social media information of patient behaviors and emotions and epidemiology profiles of disease populations,in order to gain comprehensive understanding of disease mechanisms and drug effects.We proposed a recursive drug repositioning paradigm involving the iteration of three processing steps of modeling,prediction,and validation to identify known drugs and bioactive compounds for AD/ADRD.This recursive paradigm has the potential of quickly obtaining a panel of robust novel drug candidates for AD/ADRD and gaining in-depth understanding of disease mechanisms from those repositioned drug candidates,subsequently improving the success rate of predicting novel hits.展开更多
文摘BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.
文摘B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
文摘BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.
基金Supported by Houston Methodist Cancer Center Innovation Award。
文摘Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.
基金supported by the National Cancer Institute(1R37CA251318-01,1R01CA248111-01A1,R01CA258477-01,R01CA278911,and R01CA288403)the CPRIT Scholar Award(RR210067).
文摘Oncolytic virotherapy(OVT)is a promising option for cancer treatment.OVT involves selective oncolytic virus(OV)replication within cancer cells,which triggers anti-tumor responses and immunostimulation.Despite promising potential,OVT faces critical challenges,including insufficient tumor-specific targeting,which results in limited tumor penetration and variability in therapeutic efficacy.These challenges are particularly pronounced in solid tumors with complex microenvironments and heterogeneous vascularization.A comprehensive research program is currently underway to develop and refine innovative delivery methods to address these issues to enhance OVT precision and efficacy.A principal area of investigation is the utilization of cellular carriers to enhance the delivery and distribution of OVs within tumor microenvironments,thereby optimizing immune system activation and maximizing anti-tumor effects.This review offers a comprehensive overview of the current strategies that are being used to enhance the delivery of OVs via cellular carriers with the goal of improving the clinical impact of OVT in cancer therapy.
文摘BACKGROUND Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize.Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge been reported prior to the appearance of the primary disease.CASE SUMMARY A patient presented with progressive dysphagia to solids and a persistent earache.Computed tomography of the neck and chest revealed a 3.0 cm×1.8 cm heterogeneous mass originating from the upper third of the esophagus,necrotic cervical and supraclavicular lymphadenopathy,and bilateral pulmonary nodules.She underwent a core needle biopsy of a right cervical node,which suggested a well-differentiated adenocarcinoma of unknown primary.She had an upper endoscopy with biopsy of the esophageal mass suggestive of a welldifferentiated adenocarcinoma.Positron emission tomography imaging revealed increased uptake in the esophageal mass,cervical,and mediastinal lymph nodes.She was started on folinic acid,fluorouracil,and oxaliplatin.Prior to initiation of cycle 8,the patient was found to have a pancreatic body mass that was not present on prior radiographic imaging,confirmed by endoscopic ultrasonography and biopsy to be pancreatic adenocarcinoma.CA19-9 was>10000 U/m L,suggesting a primary pancreaticobiliary origin.CONCLUSION Esophageal metastasis diagnosed before primary pancreatic adenocarcinoma is rare.This case highlights the profound metastatic potential of pancreatic adenocarcinoma.
基金This research was supported by National Insti-tutes of Health(NIH):R01CA223804,R01CA232433,R01CA205633,and R01CA280746.
文摘Dear Editor,Atovaquone(ATO),a mitochondrial inhibitor,has anti-cancer effects[1].Based on ATO,we developed mitochondria-targeted atovaquone(Mito-ATO)that had even stronger anti-tumor efficacy than ATO[2].We syn-thesized Mito-ATO by attaching the bulky triphenylphos-phonium(TPP)group to ATO via a ten-carbon alkyl chain(Supplementary file of methods;Supplementary Figure S1).
基金Daniel Shafiee Kermany,Ju Young Ahn,Matthew Vasquez,Lin Wang,Kai Liu,Raksha Raghunathan,Jianting Sheng,Hong Zhao,and Stephen Tin Chi Wong are supported by NCI U01CA252553,NCI R01CA238727,NCI R01CA177909,NCI R01CA244413John S.Dunn Research Foundation,and Ting Tsung and Wei Fong Chao Foundation+3 种基金Xiang Hong-Fei Zhang,Zhan Xu,Xiaoxin Hao,Weijie Zhang are supported by US Department of Defense DAMD W81XWH-16-1-0073(Era of Hope Scholarship)NCI R01CA183878,NCI R01CA251950,NCI U01CA252553,DAMD W81XWH-20-1-0375Breast Cancer Research Foundation,and McNair Medical Institute.Vahid Afshar-Kharghan,Min Soon Cho,Wendolyn Carlos-AlcaldeHani Lee are supported by NCI R01CA177909,NCI R01CA016672,NCI R01CA275762,and NCI P50CA217685.
文摘Spatial statistics are crucial for analyzing clustering patterns in various spaces,such as the distribution of trees in a forest or stars in the sky.Advances in spatial biology,such as single-cell spatial transcriptomics,enable researchers to map gene expression patterns within tissues,offering unprecedented insights into cellular functions and disease pathology.Common methods for deriving spatial relationships include density-based methods(quadrat analysis,kernel density estimators)and distance-based methods(nearest-neighbor distance[NND],Ripley’s K function).While density-based methods are effective for visualization,they struggle with quantification due to sensitivity to parameters and complex significance tests.In contrast,distance-based methods offer robust frameworks for hypothesis testing,quantifying spatial clustering or dispersion,and facilitating comparisons with models such as uniform random distributions or Poisson processes[1,2].
基金The research received support from internal fund provided by the Houston Methodist Research Institute to W.C.
文摘T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained.The objective of this study was to explore the function of interferon regulatory factor 4(IRF4)in antitumor CD8^(+)T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model.To achieve this,we generated an Irf4^(GFP-DTR) mouse strain and discovered that CD8^(+)tumor-infiltrating lymphocytes(TILs)expressing high levels of IRF4.GFP exhibited a more differentiated PD-1high cell phenotype.By administering diphtheria toxin to tumor-bearing Irf4^(GFP-DTR) mice,we partially depleted IRF4.GFP^(+)TILs and observed an accelerated tumor growth.To specifically explore the function of IRF4 in antitumor CD8^(+)T cells,we conducted 3 adoptive cell therapy(ACT)models.Firstly,depleting IRF4.GFP^(+)CD8^(+)TILs derived from ACT significantly accelerated tumor growth,emphasizing their crucial role in controlling tumor progression.Secondly,deleting the Irf4 gene in antitumor CD8^(+)T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8^(+)TILs,completely abolishing the antitumor effects of ACT.Lastly,we performed a temporal deletion of the Irf4 gene in antitumor CD8^(+)T cells during ACT,starting from 20 days after tumor implantation,which significantly compromised tumor control.Therefore,sustained expression of IRF4 is essential for maintaining CD8^(+)T cell immunity in the melanoma model,and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.
基金Fund from Joint International Research Laboratory of Reproduction and Development,Institute of Life Science,Chongqing Medical University.National Key R&D Program of China[grant numbers 2018YFA0800401 to X.Li]National Natural Science Foundation of China[grant numbers 81770861 and 31571401 to X.Li]+3 种基金Chongqing Science and Technology Foundation[grant number cstc2018jcy-jAX0232]Science and Technology Research Program of Chongqing Municipal Education Commission[grant number KJZD-K201800402]The Outstanding Talent Fund of Chongqing Medical University[grant number BJRC201707]Chongqing education committee[grant number CYB17105].
文摘Adipocytes and immune cells are vital for the development of adipose tissue.Adi-pokines secreted by adipocytes regulate adipogenesis and body metabolism.Chemerin is one of the adipokines.However,the function and mechanism of chemerin in adipose tissue are not fully illuminated.Compared with wild type(WT)mice,Rarres2^(-/-)mice gained weight and significantly increased fat distribution in subcutaneous adipose tissue(SAT),rather than visceral adipose tissue(VAT)on high fat diet(HFD).PPARg and C/EBPa,the master regulators of adipogenesis,were up-regulated in SAT and down-regulated in VAT in Rarres2^(-/-)mice comparing with WT mice.Inspite of chemerin deficiency or not,the ratio of adipocyte-progenitors to total cells and the differentiation capacity of adipocyte-progenitors were similar in SAT and VAT,but macrophage infiltration in VAT was more severe than in SAT in Rarres2^(-/-)mice.Furthermore,CD45þimmune cells supernatant from Rarres2^(-/-)SAT pro-moted the differentiation of adipocyte-progenitors and 3T3-L1 cells.Adipokine array assay of CD45þimmune cells supernatant revealed that metalloproteinase inhibitor 1(TIMP1),an in-hibitor of adipogenesis,was reduced in Rarres2^(-/-)SAT,but increased in Rarres2^(-/-)VAT.As we specifically knocked down chemerin in SAT,TIMP1 was down-regulated and adipogenesis was promoted with reducing infiltration of macrophages.The present study demonstrates that the effects of chemerin on adipose tissue is depot different,and specific knock down chemerin in SAT promote adipogenesis and improve glucose tolerance test(GTT)and insulin tolerance test(ITT).This suggests a potential therapeutic target for chemerin in the treatment of obesity related metabolic disorder.
基金Ting Tsung and Wei Fong Chao Foundation,John S.Dunn Research Foundation,Cure Alzheimer’s Fund,NIA R01AG057635,NIA R01AG071496NIA R01ES024165-S to STCW.
文摘Alzheimer’s disease and related dementias(AD/ADRD)affects more than 50 million people worldwide but there is no clear therapeutic option affordable for the general patient population.Recently,drug repositioning studies featuring collaborations between academic institutes,medical centers,and hospitals are generating novel therapeutics candidates against these devastating diseases and filling in an important area for healthcare that is poorly represented by pharmaceutical companies.Such drug repositioning studies converge expertise from bioinformatics,chemical informatics,medical informatics,artificial intelligence,high throughput and high-content screening and systems biology.They also take advantage of multi-scale,multi-modality datasets,ranging from transcriptomic and proteomic data,electronical medical records,and medical imaging to social media information of patient behaviors and emotions and epidemiology profiles of disease populations,in order to gain comprehensive understanding of disease mechanisms and drug effects.We proposed a recursive drug repositioning paradigm involving the iteration of three processing steps of modeling,prediction,and validation to identify known drugs and bioactive compounds for AD/ADRD.This recursive paradigm has the potential of quickly obtaining a panel of robust novel drug candidates for AD/ADRD and gaining in-depth understanding of disease mechanisms from those repositioned drug candidates,subsequently improving the success rate of predicting novel hits.
