Gallbladder cancer(GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment op...Gallbladder cancer(GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment options. These necessitate development of early prognostic/predictive markers and novel therapeutic interventions. Micro RNAs(mi RNAs) are small, noncoding RNA molecules that play a key role in tumor biology by functioning like tumor suppressor- or oncogenes and their aberrant expression are associated with the pathogenesis of several neoplasms with overwhelming clinical implications. Since mi RNA signature is tissue specific, here, we focused on current data concerning the mi RNAs abberations in GBC pathogenesis. In GBC, mi RNAs with tumor suppressor activity(mi R-135-5p, mi R-335, mi R-34 a, mi R-26 a, mi R-146b-5p, Mir-218-5p, mi R-1, mi R-145, mir-130a) were found downregulated, while those with oncogenic property(mi R-20 a, mi R-182, mir-155) were upregulated. The expression profile of mi RNAs was significantly associated with GBC prognosis and prediction, and forced over-expression/ inhibition of these mi RNAs was shown to affect tumor growth and development. Further, differential expression of mi RNAs in the blood samples of GBC patients suggest mi RNAs as promising noninvasive biomarker. Thus, mi RNAs represent potential candidate for GBC management, though many hurdles need to be overcome before mi RNAs therapy can be clinically applied to GBC prevention and treatment.展开更多
Pancreatic cancer(PC) has been one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment. Recently, there have been important advances in the molecular, pathological and biologica...Pancreatic cancer(PC) has been one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment. Recently, there have been important advances in the molecular, pathological and biological understandingof pancreatic cancer. Even after the emergence of recent new targeted agents and the use of multiple therapeutic combinations, no treatment option is viable in patients with advanced cancer. Developing novel strategies to target progression of PC is of intense interest. A small population of pancreatic cancer stem cells(CSCs) has been found to be resistant to chemotherapy and radiation therapy. CSCs are believed to be responsible for tumor initiation, progression and metastasis. The CSC research has recently achieved much progress in a variety of solid tumors, including pancreatic cancer to some extent. This leads to focus on understanding the role of pancreatic CSCs. The focus on CSCs may offer new targets for prevention and treatment of this deadly cancer. We review the most salient developments in important areas of pancreatic CSCs. Here, we provide a review of current updates and new insights on the role of CSCs in pancreatic tumor progression with special emphasis on Dcl K1 and Lgr5, signaling pathways altered by CSCs, and the role of CSCs in prevention and treatment of PC.展开更多
There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunothe...There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.展开更多
Two novel ultrasound imaging techniques with imaging contrast mechanisms are in the works:X-ray-induced acoustic computed tomography(XACT),and nanoscale photoacoustic tomogra-phy(nPAT).XACT has incredible potential in...Two novel ultrasound imaging techniques with imaging contrast mechanisms are in the works:X-ray-induced acoustic computed tomography(XACT),and nanoscale photoacoustic tomogra-phy(nPAT).XACT has incredible potential in:(1)biomedical imaging,through which a 3D image can be generated using only a single X-ray projection,and(2)radiation dosimetry.nPATas a new alternative of super-resolution microscopy can break through the optical difraction limitand is capable of exploring sub-celular structures without reliance on fuorescence labeling.We expect these new imaging techniques to find widespread applications in both pre-clinical andclinical biomedical research.展开更多
Nasolabial cysts are uncommonly diagnosed non-odontogenic soft tissue lesions occurring close to the nasal alar region of the face. Patients usually present with a slowly enlarging asymptomatic swelling. Diagnosis is ...Nasolabial cysts are uncommonly diagnosed non-odontogenic soft tissue lesions occurring close to the nasal alar region of the face. Patients usually present with a slowly enlarging asymptomatic swelling. Diagnosis is usually made in the early stages because of the esthetic effects. Histologically, the lesion is lined with non-keratinized squamous epithelium or, more frequently, pseudostratified columnar epithelium with goblet cells. These cysts are most often diagnosed in the fourth decade of life. However, we report a case of nasolabial cyst in an 80-year-old woman, and discuss the diagnosis, differential diagnosis, and treatment with reference to the literature.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
Lung cancer is one of the most common cancer in the world.In 2018,there were over 2 million new cases of lung cancer and over 1.7 million deaths were attributed to lung cancer.Targeted therapy has emerged as an import...Lung cancer is one of the most common cancer in the world.In 2018,there were over 2 million new cases of lung cancer and over 1.7 million deaths were attributed to lung cancer.Targeted therapy has emerged as an important mean of the disease management for patients with non-small-cell lung cancer(NSCLC).Herein,we review and analyze recent literature,discuss the targeting pathways and ongoing clinical trials in lung cancer.Chemotherapy is no longer the best available treatment for all patients.Therapeutic decisions should be guided by an understanding of the molecular features of patient’s tumor tissues.The future gains will likely emerge from finding optimal ways of combining targeted therapy,immunotherapy,and chemotherapy.展开更多
Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tum...Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tumor are likely causes for poor outcomes.We previously reported that BMI1,a stem-cell factor is instrumental in regulating chemoresistance.2,3 However,to advance anti-BMI1 therapy from the bench to the bedside,efficacy needs to be tested in patient-derived chemoresistant HGSOC models,which is lacking.展开更多
Neuroblastoma(NB)is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths.This mortality rate has been attributed to the>50%frequency of relapse despite intensive,multimodal...Neuroblastoma(NB)is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths.This mortality rate has been attributed to the>50%frequency of relapse despite intensive,multimodal clinical therapy in patients with progressive NB.Given the disease’s heterogeneity and developed resistance,attaining a cure after relapse of progressive NB is highly challenging.A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells(CSCs).In this review,we present the current understanding of NB-CSCs,their intrinsic role in tumorigenesis,their function in disease progression,and their influence on acquired therapy resistance and tumor evolution.In particular,this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB,the function of pre-existing CSCs in NB progression and therapy response,the formation and influence of induced CSCs(iCSCs)in drug resistance and tumor evolution,and the development of a CSC-targeted therapeutic approach.展开更多
The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in v...The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in various types of cancers at low rates.In the last few years,two potent and selective RET protein tyrosine kinase inhibitors(TKIs),pralsetinib(BLU-667)and selpercatinib(LOXO-292,LY3527723)were developed and received regulatory approval.Although pralsetinib and selpercatinib gave high overall response rates(ORRs),<10%of patients achieved a complete response(CR).The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations,acquired alternative oncogenes,or MET amplification.RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib.Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials.However,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs.Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.展开更多
The rearranged during transfection(RET)gene encodes a protein tyrosine kinase.RET alterations by point mutations and gene fusions were found in diverse cancers.RET fusions allow abnormal expression and activation of t...The rearranged during transfection(RET)gene encodes a protein tyrosine kinase.RET alterations by point mutations and gene fusions were found in diverse cancers.RET fusions allow abnormal expression and activation of the oncogenic kinase,whereas only a few of RET point mutations found in human cancers are known oncogenic drivers.Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors(TKIs)with RET inhibitor activity.These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations.Recently,two potent and selective RET TKIs,pralsetinib(BLU-667)and selpercatinib(LOXO-292),were developed.High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials,demonstrating the RET dependence in human cancers harboring these RET lesions.Pralsetinib and selpercatinib were effective in inhibiting RETV804L/M gatekeeper mutants.However,adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RETG810 residue have been found,pointing to the need for the development of the next-generation of RET TKIs.展开更多
Cancer-associated fibroblasts(CAFs)are a major constituent of the tumor microenvironment(TME)and an important contributor to cancer progression and therapeutic resistance.Regulation of CAF activation is a promising st...Cancer-associated fibroblasts(CAFs)are a major constituent of the tumor microenvironment(TME)and an important contributor to cancer progression and therapeutic resistance.Regulation of CAF activation is a promising strategy to influence cancer outcomes.Here,we report that ovarian cancer cells(OCs)and TME cells promote the activation of ovarian CAFs,whereas gold nanoparticles(GNPs)of 20 nm in diameter inhibit the activation,as demonstrated by the changes in cell morphology,migration,and molecular markers.GNPs exert the effect by altering the levels of multiple fibroblast activation or inactivation proteins,such as TGF-β1,PDGF,uPA and TSP1,secreted by OCs and TME cells.Thus,GNPs represent a potential tool to help understand multicellular communications existing in the TME as well as devise strategies to disrupt the communication.展开更多
Progressive neuroblastomas(pNBs)that defy current intensive multimodal clinical therapy(IMCT)are a significant contributor to overall childhood cancer deaths[l].Neuroblastomas(NBs)that survive first-line IMCT actively...Progressive neuroblastomas(pNBs)that defy current intensive multimodal clinical therapy(IMCT)are a significant contributor to overall childhood cancer deaths[l].Neuroblastomas(NBs)that survive first-line IMCT actively evolve to acquire genetic and molecular rearrangements and display unparalleled plasticity and evolution,which causes frequent relapses in a rapidly accelerating timeline[2-4].展开更多
Neuroblastoma(NB)is the most common extra cranial solid tumor in children and comprises one tenth of all childhood cancer deaths.More than half of infants presented with NB,a designated“cold tumor”with low immune ce...Neuroblastoma(NB)is the most common extra cranial solid tumor in children and comprises one tenth of all childhood cancer deaths.More than half of infants presented with NB,a designated“cold tumor”with low immune cell repertoire in the tumor microenvironment(TME)[1],develop progressive disease(PD).展开更多
Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of ...Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of research that have elucidated the transcriptional regulation,post-translational modifications and functions of Bmi-1 in regulating the DNA damage response,cellular bioenergetics,and pathologies,the entire potential of a protein with such varied functions remains to be realized.This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer.Additionally,since cancer stem cells are emerging as a new paradigm for therapy resistance,the role of Bmi-1 in this perspective is also highlighted.The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy.Nonetheless,new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.展开更多
Coronavirus disease 2019(COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19...Coronavirus disease 2019(COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients(≥18 years old) between January 29,2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups—non-critically ill,critically ill, and death groups—in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol(LDL-C), and high-density lipoproteins cholesterol(HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old(interquartile range(IQR), 52–71). Among the patients enrolled in the study, 2,008(76.6%) were diagnosed as non-critically ill and 615(23.4%) were critically ill patients, including 383(14.6%) critically ill survivors and 232(8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein(LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time(APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients.展开更多
Neuroblastoma(NB),the most common cancer at infancy,is derived from a selective sympathoadrenal lineage of the neural crest cells[1-3].The majority of NB is found in children younger than 5 years(median age:2 years)an...Neuroblastoma(NB),the most common cancer at infancy,is derived from a selective sympathoadrenal lineage of the neural crest cells[1-3].The majority of NB is found in children younger than 5 years(median age:2 years)and is rare in children older than 10 years.Although NB accounts for only 5-6%of the childhood cancers,it heavily contributes(about 15%)to pediatric cancer deaths[4,5].展开更多
Neuroblastoma(NB)deriving from neural crest cells is the most common extra-cranial solid cancer at infancy.NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body.C...Neuroblastoma(NB)deriving from neural crest cells is the most common extra-cranial solid cancer at infancy.NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body.Clinically,NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance.MicroRNAs(miRNAs,miRs)are small(19-22 nt in length)non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling,growth,differentiation,death,stemness,and maintenance.Consequently,the function of miRs in tumorigenesis,progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution,therapy resistance,and poor clinical outcomes.Over the last two decades,much attention has been devoted to understanding the functional roles of miRs in NB biology.This review focuses on highlighting the important implications of miRs within the context of NB disease progression,particularly miRs’influences on NB disease evolution and therapy resistance.In this review,we discuss the functions of both the“oncomiRs”and“tumor suppressor miRs”in NB progression/therapy resistance.These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance.展开更多
Neuroblastoma is the most common extracranial solid tumor in children and comprises one-tenth of all childhood cancer deaths.The current clinical therapy for this deadly disease is multimodal,involving an induction ph...Neuroblastoma is the most common extracranial solid tumor in children and comprises one-tenth of all childhood cancer deaths.The current clinical therapy for this deadly disease is multimodal,involving an induction phase with alternating regimens of high-dose chemotherapeutic drugs and load reduction surgery;a consolidation phase with more intensive chemotherapy,radiotherapy,and stem cell transplant;and a maintenance phase with immunotherapy and immune-activating cytokine treatment.Despite such intensive treatment,children with neuroblastoma have unacceptable life quality and survival,warranting preventive measures to regulate the cellular functions that orchestrate tumor progression,therapy resistance,metastasis,and tumor relapse/recurrence.Globally,active efforts are underway to identify novel chemopreventive agents,define their mechanism(s)of action,and assess their clinical benefit.Some chemoprevention strategies(e.g.,retinoids,difluoromethylornithine)have already been adopted clinically as part of maintenance phase therapy.Several agents are in the pipeline,while many others are in preclinical characterization.Here we review the classes of chemopreventive agents investigated for neuroblastoma,including cellular events targeted,mode(s)of action,and the level of development.Our review:(i)highlights the pressing need for new and improved chemopreventive strategies for progressive neuroblastoma;(ii)lists the emerging classes of chemopreventive agents for neuroblastoma;and(iii)recognizes the relevance of targeting dynamically evolving hallmark functions of tumor evolution(e.g.,survival,differentiation,lineage transformation).With recent gains in the understanding of tumor evolution processes and preclinical and clinical efforts,it is our strong opinion that effective chemopreventive strategies for aggressive neuroblastoma are a near reality.展开更多
文摘Gallbladder cancer(GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment options. These necessitate development of early prognostic/predictive markers and novel therapeutic interventions. Micro RNAs(mi RNAs) are small, noncoding RNA molecules that play a key role in tumor biology by functioning like tumor suppressor- or oncogenes and their aberrant expression are associated with the pathogenesis of several neoplasms with overwhelming clinical implications. Since mi RNA signature is tissue specific, here, we focused on current data concerning the mi RNAs abberations in GBC pathogenesis. In GBC, mi RNAs with tumor suppressor activity(mi R-135-5p, mi R-335, mi R-34 a, mi R-26 a, mi R-146b-5p, Mir-218-5p, mi R-1, mi R-145, mir-130a) were found downregulated, while those with oncogenic property(mi R-20 a, mi R-182, mir-155) were upregulated. The expression profile of mi RNAs was significantly associated with GBC prognosis and prediction, and forced over-expression/ inhibition of these mi RNAs was shown to affect tumor growth and development. Further, differential expression of mi RNAs in the blood samples of GBC patients suggest mi RNAs as promising noninvasive biomarker. Thus, mi RNAs represent potential candidate for GBC management, though many hurdles need to be overcome before mi RNAs therapy can be clinically applied to GBC prevention and treatment.
基金In part by Kerley Cade Endowed Chair(Chinthalapally V Rao),University of Oklahoma Health Sciences Centerin part support from the National Cancer Institute,No.5R03CA181584-02(Altaf Mohammed)
文摘Pancreatic cancer(PC) has been one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment. Recently, there have been important advances in the molecular, pathological and biological understandingof pancreatic cancer. Even after the emergence of recent new targeted agents and the use of multiple therapeutic combinations, no treatment option is viable in patients with advanced cancer. Developing novel strategies to target progression of PC is of intense interest. A small population of pancreatic cancer stem cells(CSCs) has been found to be resistant to chemotherapy and radiation therapy. CSCs are believed to be responsible for tumor initiation, progression and metastasis. The CSC research has recently achieved much progress in a variety of solid tumors, including pancreatic cancer to some extent. This leads to focus on understanding the role of pancreatic CSCs. The focus on CSCs may offer new targets for prevention and treatment of this deadly cancer. We review the most salient developments in important areas of pancreatic CSCs. Here, we provide a review of current updates and new insights on the role of CSCs in pancreatic tumor progression with special emphasis on Dcl K1 and Lgr5, signaling pathways altered by CSCs, and the role of CSCs in prevention and treatment of PC.
文摘There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.
文摘Two novel ultrasound imaging techniques with imaging contrast mechanisms are in the works:X-ray-induced acoustic computed tomography(XACT),and nanoscale photoacoustic tomogra-phy(nPAT).XACT has incredible potential in:(1)biomedical imaging,through which a 3D image can be generated using only a single X-ray projection,and(2)radiation dosimetry.nPATas a new alternative of super-resolution microscopy can break through the optical difraction limitand is capable of exploring sub-celular structures without reliance on fuorescence labeling.We expect these new imaging techniques to find widespread applications in both pre-clinical andclinical biomedical research.
文摘Nasolabial cysts are uncommonly diagnosed non-odontogenic soft tissue lesions occurring close to the nasal alar region of the face. Patients usually present with a slowly enlarging asymptomatic swelling. Diagnosis is usually made in the early stages because of the esthetic effects. Histologically, the lesion is lined with non-keratinized squamous epithelium or, more frequently, pseudostratified columnar epithelium with goblet cells. These cysts are most often diagnosed in the fourth decade of life. However, we report a case of nasolabial cyst in an 80-year-old woman, and discuss the diagnosis, differential diagnosis, and treatment with reference to the literature.
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.
基金The authors would like to acknowledge financial support by grants from the Shenkang Clinical Three-Year Action Plan(no.16CR3072B)the Key Project of Shanghai Health and Family Planning Commission(no.201640020)+6 种基金the Western Medicine Guiding Project of Shanghai Science and Technology Commission(no.17411967300)the Shanghai Municipal Commission of Health and Family Planning Research and Development of New Chinese Medicine and Hospital Preparations(no.2016LP029)the Shanghai Science and Technology Commission,Industry-University-Research Subproject(no.16431903200)the Shanghai Sailing Program(no.19YF1438300)the Pujiang Fostering Program of Shanghai Tenth Peoples'Hospital(no.040118024)the National Natural Science Foundation of China(no.81803090 and 81772905)the Shanghai outstanding academic leader(no.18XD1424000).
文摘Lung cancer is one of the most common cancer in the world.In 2018,there were over 2 million new cases of lung cancer and over 1.7 million deaths were attributed to lung cancer.Targeted therapy has emerged as an important mean of the disease management for patients with non-small-cell lung cancer(NSCLC).Herein,we review and analyze recent literature,discuss the targeting pathways and ongoing clinical trials in lung cancer.Chemotherapy is no longer the best available treatment for all patients.Therapeutic decisions should be guided by an understanding of the molecular features of patient’s tumor tissues.The future gains will likely emerge from finding optimal ways of combining targeted therapy,immunotherapy,and chemotherapy.
基金This study was supported by research awards from the US Department of Defense to RB(No.W81XWH1810073,and W81XWH1810054)Histology and immunohistochemistry service was provided by the Stephenson Cancer Tissue Pathology research core supported by the NIGMS Grant P20GM103639 and NCI Grant P30CA225520 of the NIH.
文摘Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tumor are likely causes for poor outcomes.We previously reported that BMI1,a stem-cell factor is instrumental in regulating chemoresistance.2,3 However,to advance anti-BMI1 therapy from the bench to the bedside,efficacy needs to be tested in patient-derived chemoresistant HGSOC models,which is lacking.
基金The authors are supported by the research funding from the National Institutes of Health(NIH 1P20GM103639-01)from the COBRE Program of NIHOUHSC Department of Radiation Oncology Research Development Funds.
文摘Neuroblastoma(NB)is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths.This mortality rate has been attributed to the>50%frequency of relapse despite intensive,multimodal clinical therapy in patients with progressive NB.Given the disease’s heterogeneity and developed resistance,attaining a cure after relapse of progressive NB is highly challenging.A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells(CSCs).In this review,we present the current understanding of NB-CSCs,their intrinsic role in tumorigenesis,their function in disease progression,and their influence on acquired therapy resistance and tumor evolution.In particular,this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB,the function of pre-existing CSCs in NB progression and therapy response,the formation and influence of induced CSCs(iCSCs)in drug resistance and tumor evolution,and the development of a CSC-targeted therapeutic approach.
基金Cancer research in Jie Wu’s laboratory was supported by NIH grants R01CA242845,R01CA273168,a PHF SEED grantOklahoma Center for the Advancement of Science and Technology(OCAST)grant HR19-026Additional support was provided by the Oklahoma Tobacco Settlement Endowment Trust,and the Peggy and Charles Stephenson Endowment,and NIH grants P30CA225520 and P20GM103639 to the institution.
文摘The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in various types of cancers at low rates.In the last few years,two potent and selective RET protein tyrosine kinase inhibitors(TKIs),pralsetinib(BLU-667)and selpercatinib(LOXO-292,LY3527723)were developed and received regulatory approval.Although pralsetinib and selpercatinib gave high overall response rates(ORRs),<10%of patients achieved a complete response(CR).The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations,acquired alternative oncogenes,or MET amplification.RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib.Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials.However,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs.Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.
文摘The rearranged during transfection(RET)gene encodes a protein tyrosine kinase.RET alterations by point mutations and gene fusions were found in diverse cancers.RET fusions allow abnormal expression and activation of the oncogenic kinase,whereas only a few of RET point mutations found in human cancers are known oncogenic drivers.Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors(TKIs)with RET inhibitor activity.These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations.Recently,two potent and selective RET TKIs,pralsetinib(BLU-667)and selpercatinib(LOXO-292),were developed.High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials,demonstrating the RET dependence in human cancers harboring these RET lesions.Pralsetinib and selpercatinib were effective in inhibiting RETV804L/M gatekeeper mutants.However,adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RETG810 residue have been found,pointing to the need for the development of the next-generation of RET TKIs.
基金This study was supported by National Institutes of Health Grants CA220237,CA136494,CA213278(to P.M.)and HL120585(to both P.M.and R.B.)We thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center for a seed grant and an Institutional Development Award(IDeA)from the National Institute of General Medical Sciences of the NIH under grant number P20 GM103639 for the use of Histology and Immunohistochemistry Core+1 种基金Research reported in this publication was also supported in part by the NCI Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and used the Office of Cancer ResearchThe authors thank Drs.Andy E.Madden,Preston Larson and Julian Sabisch for technical assistance with EDS,XRD and TEM.
文摘Cancer-associated fibroblasts(CAFs)are a major constituent of the tumor microenvironment(TME)and an important contributor to cancer progression and therapeutic resistance.Regulation of CAF activation is a promising strategy to influence cancer outcomes.Here,we report that ovarian cancer cells(OCs)and TME cells promote the activation of ovarian CAFs,whereas gold nanoparticles(GNPs)of 20 nm in diameter inhibit the activation,as demonstrated by the changes in cell morphology,migration,and molecular markers.GNPs exert the effect by altering the levels of multiple fibroblast activation or inactivation proteins,such as TGF-β1,PDGF,uPA and TSP1,secreted by OCs and TME cells.Thus,GNPs represent a potential tool to help understand multicellular communications existing in the TME as well as devise strategies to disrupt the communication.
基金funded by Oklahoma Center for the Advancement of Science and Technology,OCAST-HR19-045Department of Defense,DoD Peer Reviewed Cancer Research Program,CA-210339+2 种基金the National Institutes of Health P20GM103639supported by the National Cancer Institute Cancer Center Support Grant[P30CA225520]a grant from the Oklahoma Tobacco Settlement Endowment Trust[R23-03]both awarded to the OU Health Stephenson Cancer Center.
文摘Progressive neuroblastomas(pNBs)that defy current intensive multimodal clinical therapy(IMCT)are a significant contributor to overall childhood cancer deaths[l].Neuroblastomas(NBs)that survive first-line IMCT actively evolve to acquire genetic and molecular rearrangements and display unparalleled plasticity and evolution,which causes frequent relapses in a rapidly accelerating timeline[2-4].
基金funded by Department of Defense(DoD CA-210339)Oklahoma Center for the Advancement of Science and Technology(OCAST-HR19-045)+2 种基金the National Institutes of Health(P20GM103639)supported by the National Cancer Institute Cancer Center Support Grant(P30CA225520)a grant from the Oklahoma Tobacco Settlement Endowment Trust(R23-03)both awarded to the OU Health Stephenson Cancer Center.
文摘Neuroblastoma(NB)is the most common extra cranial solid tumor in children and comprises one tenth of all childhood cancer deaths.More than half of infants presented with NB,a designated“cold tumor”with low immune cell repertoire in the tumor microenvironment(TME)[1],develop progressive disease(PD).
基金This study was supported by the National Institutes of Health(NIH)CA157481 awarded to RB.
文摘Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of research that have elucidated the transcriptional regulation,post-translational modifications and functions of Bmi-1 in regulating the DNA damage response,cellular bioenergetics,and pathologies,the entire potential of a protein with such varied functions remains to be realized.This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer.Additionally,since cancer stem cells are emerging as a new paradigm for therapy resistance,the role of Bmi-1 in this perspective is also highlighted.The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy.Nonetheless,new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.
基金supported in part by the National Natural Science Foundation of China (81790624, 81630010, and 81800261)。
文摘Coronavirus disease 2019(COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients(≥18 years old) between January 29,2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups—non-critically ill,critically ill, and death groups—in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol(LDL-C), and high-density lipoproteins cholesterol(HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old(interquartile range(IQR), 52–71). Among the patients enrolled in the study, 2,008(76.6%) were diagnosed as non-critically ill and 615(23.4%) were critically ill patients, including 383(14.6%) critically ill survivors and 232(8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein(LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time(APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients.
基金This work was partially or in full funded by the Oklahoma Center for the Advancement of Science and Technology(No.OCAST-HR19-045)National Institutes of Health(No.NIH-P20GM103639)NIH-NCI Cancer Center Support Grant(No.P30CA225520).
文摘Neuroblastoma(NB),the most common cancer at infancy,is derived from a selective sympathoadrenal lineage of the neural crest cells[1-3].The majority of NB is found in children younger than 5 years(median age:2 years)and is rare in children older than 10 years.Although NB accounts for only 5-6%of the childhood cancers,it heavily contributes(about 15%)to pediatric cancer deaths[4,5].
基金The authors are supported by research funding from the National Institutes of Health(NIH 1P20GM103639-01)from the COBRE Program of NIHand OUHSC Department of Radiation Oncology Research Development Funds.
文摘Neuroblastoma(NB)deriving from neural crest cells is the most common extra-cranial solid cancer at infancy.NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body.Clinically,NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance.MicroRNAs(miRNAs,miRs)are small(19-22 nt in length)non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling,growth,differentiation,death,stemness,and maintenance.Consequently,the function of miRs in tumorigenesis,progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution,therapy resistance,and poor clinical outcomes.Over the last two decades,much attention has been devoted to understanding the functional roles of miRs in NB biology.This review focuses on highlighting the important implications of miRs within the context of NB disease progression,particularly miRs’influences on NB disease evolution and therapy resistance.In this review,we discuss the functions of both the“oncomiRs”and“tumor suppressor miRs”in NB progression/therapy resistance.These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance.
文摘Neuroblastoma is the most common extracranial solid tumor in children and comprises one-tenth of all childhood cancer deaths.The current clinical therapy for this deadly disease is multimodal,involving an induction phase with alternating regimens of high-dose chemotherapeutic drugs and load reduction surgery;a consolidation phase with more intensive chemotherapy,radiotherapy,and stem cell transplant;and a maintenance phase with immunotherapy and immune-activating cytokine treatment.Despite such intensive treatment,children with neuroblastoma have unacceptable life quality and survival,warranting preventive measures to regulate the cellular functions that orchestrate tumor progression,therapy resistance,metastasis,and tumor relapse/recurrence.Globally,active efforts are underway to identify novel chemopreventive agents,define their mechanism(s)of action,and assess their clinical benefit.Some chemoprevention strategies(e.g.,retinoids,difluoromethylornithine)have already been adopted clinically as part of maintenance phase therapy.Several agents are in the pipeline,while many others are in preclinical characterization.Here we review the classes of chemopreventive agents investigated for neuroblastoma,including cellular events targeted,mode(s)of action,and the level of development.Our review:(i)highlights the pressing need for new and improved chemopreventive strategies for progressive neuroblastoma;(ii)lists the emerging classes of chemopreventive agents for neuroblastoma;and(iii)recognizes the relevance of targeting dynamically evolving hallmark functions of tumor evolution(e.g.,survival,differentiation,lineage transformation).With recent gains in the understanding of tumor evolution processes and preclinical and clinical efforts,it is our strong opinion that effective chemopreventive strategies for aggressive neuroblastoma are a near reality.
