Intrahepatic cholangiocarcinomas (ICC) are neoplasms that originate from cholangiocytes and can occur at any level of the biliary tree. Surgical resection is the current therapy of choice for this highly aggressive ca...Intrahepatic cholangiocarcinomas (ICC) are neoplasms that originate from cholangiocytes and can occur at any level of the biliary tree. Surgical resection is the current therapy of choice for this highly aggressive cancer. However, the 5-year survival still is poor, with high recurrence rates. Due to the intrahepatic growth a signifi cant proportion of patients present with advanced disease and are not candidates for curative surgery or transplantation. The existing palliative options are of limited benefit and there is a great necessity for novel therapeutic options. In this article we review the role of the phosphoinositide 3-kinase(PI3K)/ AKT and extracellular regulated kinase (ERK) signaling pathways in ICC and present new data on the prognostic value of these protein kinases. Finally, we discuss future upcoming therapeutic options based on targeting these signaling pathways.展开更多
AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functi...AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML). METHODS: The role of p53 and PML in regulating cy-totoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Further-more,H-1 PV infection was combined with cytostatic drug treatment. RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis,the cytotoxicity of H-1 PV was morepronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses,H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition,H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death. CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents,and it enhances the apoptotic process which is dependent on functional PML. Thus,H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC,particularly for p53-negative tumors.展开更多
Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits t...Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.展开更多
As the current standard,surgery is applied to treat early-stage cervical cancer and selected post-irradiation pelvic relapses.Surgical therapy for local disease is based on a model of unlimited isotropic cancer cell p...As the current standard,surgery is applied to treat early-stage cervical cancer and selected post-irradiation pelvic relapses.Surgical therapy for local disease is based on a model of unlimited isotropic cancer cell propagation and dissection artifacts such as subperitoneal“ligaments”and“spaces”.For regional disease,the role of traditional surgery is diagnostic and eventually cytoreductive.However,the isotropic local tumor propagation model has to be rejected due to numerous inconsistencies with clinical facts.Likewise,the“ligament and space”approach to the subperitoneum is too crude and variable to accurately cover both local spread and intercalated lymph node metastases of cervical cancer.The ontogenetic cancer field model is fully in line with the locoregional spread patterns of carcinoma of the female genital tract.Developmentally derived(ontogenetic)anatomy enables unbiased and accurate dissection of the complex tissue structures within the subperitoneum.Cancer field surgery founded on these insights has a high potential to improve the treatment outcome of cervical carcinoma.展开更多
Background Autophagy is critical for cellular homeostasis.Autophagy related 14(ATG14)is a key regulator of autophagy initiation;however,its role in hepatocyte survival remains poorly understood.This study aimed to inv...Background Autophagy is critical for cellular homeostasis.Autophagy related 14(ATG14)is a key regulator of autophagy initiation;however,its role in hepatocyte survival remains poorly understood.This study aimed to investigate the hepatocyte-specific function of ATG14 in vivo.Methods We generated Atg14 hepatocyte-specific knockout(HepKO)mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into Atg14 floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet.Blood and tissue samples were collected for biochemical and histological analyses.Results Atg14 HepKO mice develop severe hepatomegaly under normal dietary conditions.ATG14 deficiency leads to hepatic injury,inflammation and fibrosis.Multiple forms of cell death,including apoptosis and pyroptosis,increase significantly.When challenged with a Western diet for 4 weeks,Atg14 HepKO mice exhibit exacerbated hepatic injury,inflammation and fibrosis despite no significant lipid droplet accumulation in the liver.Transcriptomic analysis reveals upregulation of several cell death pathways,including pyroptosis,apoptosis and necroptosis.Further biochemical and microscopic analyses validate the induction of multiple cell death pathways.In addition,NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in Atg14 HepKO mouse livers and ATG14-deficient hepatocytes.Conclusion Our data suggest that ATG14 is required for maintaining hepatocyte identity,survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly,tissue injury,inflammation and fibrosis.展开更多
Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in ...Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.展开更多
Objectives:Pharyngocutaneous fistula(PCF)is the most common complication to follow total laryngectomy(TL)and is associated with increases in length of hospital stay and with a need for revision surgery or readmission,...Objectives:Pharyngocutaneous fistula(PCF)is the most common complication to follow total laryngectomy(TL)and is associated with increases in length of hospital stay and with a need for revision surgery or readmission,as well as with delays in return to oral diet.Patients who require salvageTL(STL)or primary(chemo)radiation therapy are at higher risk for developing PCF.Due to the quality‐of‐life burden of PCF on patients,limiting this occurrence is crucial.Methods:We conducted a retrospective cohort study of patients undergoing STL with placement of Montgomery salivary bypass tube(MSBT)^(TM)for at least 2 weeks duration between 2013 and 2017 at a single institution.Our patients all underwent free flap reconstruction.Our primary outcome of interest was development of PCF.Secondary outcomes included demographics,previous treatment,base of tongue(BOT)involvement,extent of defect,concurrent neck dissection(ND),and margin status.Univariateχ^(2) analysis was used to evaluate factors associated with PCF.Results:Forty‐four patients underwent STL with Montgomery tube placement and free flap reconstruction.Eight developed PCF(18.2%).The average age was 61.6 years;36 patients were male(81.8%),whereas eight patients were female(18.2%).There was no association between PCF and previous chemoradiation versus radiation(15.8%vs.33.3%,P<0.30),BOT involvement versus not(11.1 vs.22.2%,P<0.38),circumferential versus partial defect(18.8%vs.17.9%,P<0.94),ND versus none(10%vs.25%,P<0.20),or margin status.Conclusion:PCF complicated 18.2%of STL cases at our institution and was not associated with differences in primary treatment modality,presence of concomitant ND,extent of pharyngeal defect,BOT involvement,or positive frozen or permanent surgical margin.展开更多
Objectives:Describe the h index as a bibliometric that can be utilized to objectively evaluate scholarly impact.Identify which otolaryngology subspecialties are the most scholarly.Describe if NIH funding to one’s cho...Objectives:Describe the h index as a bibliometric that can be utilized to objectively evaluate scholarly impact.Identify which otolaryngology subspecialties are the most scholarly.Describe if NIH funding to one’s choice of medical school,residency,or fellowship has any impact on one’s scholarly output.Determine other factors predictive of an academic otolaryngologist’s productivity.Study design:Analysis of bibliometric data of academic otolaryngologists.Methods:Active grants from the National Institutes of Health(NIH)to otolaryngology departments were ascertained via the NIH Research Portfolio Online Reporting Tools Expenditures and Reports database.Faculty listings from these departments were gleaned from departmental websites.H index was calculated using the Scopus database.Results:Forty-seven otolaryngology programs were actively receiving NIH funding.There were 838 faculty members from those departments who had a mean h index of 9.61.Otology(h index 12.50)and head and neck(h index 11.96)were significantly(P<0.0001)more scholarly than the rest of subspecialists.H index was significantly correlative(P<0.0001)with degree of NIH funding at a given institution.H index was not significantly higher for those that attended medical school(P<0.18),residency(P<0.16),and fellowship(P<0.16)at institutions with NIH funding to otolaryngology departments.Conclusions:H index is a bibliometric that can be used to assess scholarly impact.Otology and head and neck are the most scholarly subspecialists within otolaryngology.NIH funding to an individual’s medical school,residency,or fellowship of origin is not correlative with one’s scholarly impact,but current institutional affiliation and choice of subspecialty are.展开更多
K-RAS is the most frequently mutated oncogene in solid tumors,such as pancreatic,colon or lung cancer.The GTPase K-RAS can either be in an active(GTP-loaded)or inactive(GDP-loaded)form.In its active form K-RAS forward...K-RAS is the most frequently mutated oncogene in solid tumors,such as pancreatic,colon or lung cancer.The GTPase K-RAS can either be in an active(GTP-loaded)or inactive(GDP-loaded)form.In its active form K-RAS forwards signals from growth factors,cytokines or hormones to the nucleus,regulating essential pathways,such as cell proliferation and differentiation.In turn,activating somatic mutations of this proto-oncogene deregulate the complex interplay between GAP(GTPase-activating)-and GEF(Guanine nucleotide exchange factor)-proteins,driving neoplastic transformation.Due to a rather shallow surface,K-RAS lacks proper binding pockets for small molecules,hindering drug development over the past thirty years.This review summarizes recent progress in the development of low molecular antagonists and further shows insights of a newly described interaction between mutant K-RAS signaling and PD-L1 induced immunosuppression,giving new hope for future treatments of K-RAS mutated cancer.展开更多
文摘Intrahepatic cholangiocarcinomas (ICC) are neoplasms that originate from cholangiocytes and can occur at any level of the biliary tree. Surgical resection is the current therapy of choice for this highly aggressive cancer. However, the 5-year survival still is poor, with high recurrence rates. Due to the intrahepatic growth a signifi cant proportion of patients present with advanced disease and are not candidates for curative surgery or transplantation. The existing palliative options are of limited benefit and there is a great necessity for novel therapeutic options. In this article we review the role of the phosphoinositide 3-kinase(PI3K)/ AKT and extracellular regulated kinase (ERK) signaling pathways in ICC and present new data on the prognostic value of these protein kinases. Finally, we discuss future upcoming therapeutic options based on targeting these signaling pathways.
基金Grants from the German Cancer Aid (Deutsche Krebshilfe) No.10-2183/102322local university research grants,MAIFOR program,No.9728053 and 9728275
文摘AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML). METHODS: The role of p53 and PML in regulating cy-totoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Further-more,H-1 PV infection was combined with cytostatic drug treatment. RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis,the cytotoxicity of H-1 PV was morepronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses,H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition,H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death. CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents,and it enhances the apoptotic process which is dependent on functional PML. Thus,H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC,particularly for p53-negative tumors.
基金This work was supported by grants from the Deutsche Krebshilfe(70114007)Wilhelm Sander Stiftung(Nr.2021.023.1),German Cancer Consortium(DKTK),Heidelberg.
文摘Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.
文摘As the current standard,surgery is applied to treat early-stage cervical cancer and selected post-irradiation pelvic relapses.Surgical therapy for local disease is based on a model of unlimited isotropic cancer cell propagation and dissection artifacts such as subperitoneal“ligaments”and“spaces”.For regional disease,the role of traditional surgery is diagnostic and eventually cytoreductive.However,the isotropic local tumor propagation model has to be rejected due to numerous inconsistencies with clinical facts.Likewise,the“ligament and space”approach to the subperitoneum is too crude and variable to accurately cover both local spread and intercalated lymph node metastases of cervical cancer.The ontogenetic cancer field model is fully in line with the locoregional spread patterns of carcinoma of the female genital tract.Developmentally derived(ontogenetic)anatomy enables unbiased and accurate dissection of the complex tissue structures within the subperitoneum.Cancer field surgery founded on these insights has a high potential to improve the treatment outcome of cervical carcinoma.
基金the National Institute of Diabetes and Digestive and Kidney Diseases(R01DK120689,R01DK121925,P30DK097512)the National Institute on Alcohol Abuse and Alcoholism(R01AA028506),the National Institute on Aging(R21AG072288)the National Cancer Institute(P30CA082709 and P30CA023168),the Walther Cancer Foundation and the Ricks Family Foundation.
文摘Background Autophagy is critical for cellular homeostasis.Autophagy related 14(ATG14)is a key regulator of autophagy initiation;however,its role in hepatocyte survival remains poorly understood.This study aimed to investigate the hepatocyte-specific function of ATG14 in vivo.Methods We generated Atg14 hepatocyte-specific knockout(HepKO)mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into Atg14 floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet.Blood and tissue samples were collected for biochemical and histological analyses.Results Atg14 HepKO mice develop severe hepatomegaly under normal dietary conditions.ATG14 deficiency leads to hepatic injury,inflammation and fibrosis.Multiple forms of cell death,including apoptosis and pyroptosis,increase significantly.When challenged with a Western diet for 4 weeks,Atg14 HepKO mice exhibit exacerbated hepatic injury,inflammation and fibrosis despite no significant lipid droplet accumulation in the liver.Transcriptomic analysis reveals upregulation of several cell death pathways,including pyroptosis,apoptosis and necroptosis.Further biochemical and microscopic analyses validate the induction of multiple cell death pathways.In addition,NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in Atg14 HepKO mouse livers and ATG14-deficient hepatocytes.Conclusion Our data suggest that ATG14 is required for maintaining hepatocyte identity,survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly,tissue injury,inflammation and fibrosis.
基金supported in part by the Outsmarting Osteosarcoma Hero Award(Because of Sydney)the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Rose Hill Foundation Innovator Award+23 种基金supported by NCI R01CA201035,R01CA240711,R01CA229893DoD W81XWH-18-1-0223UCLA SPORE in Prostate Cancer(P50 CA092131)JCCC Cancer support grant from NIH P30 CA016042(PI:Teitell)Knut and Alice Wallenberg FoundationBertha Kamprad FoundationDavid H.Koch Prostate Cancer Foundation Young Investigator AwardSwedish Research CouncilSwedish Cancer SocietySIPEA FoundationSwedish Childhood Cancer FoundationJohn and Augusta Perssons FoundationRoyal Physiographic Society of LundFranke and Margareta Bergqvist FoundationCrafoord FoundationLund University Medical Faculty research time allocation award,IngaBrittArne Lundberg Research Foundation,the German Research Foundation(552440240)the German Cancer Consortium(DKTK)the German Federal Ministry of Education and Research(BMBFgrant no.01KD2206A/SATURN3)funding support from the Children’s Discovery Institute of the St.Louis Children’s Hospital.Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory(RRID:SCR_022789)the Leica Microsystems Center of Excellence at the California NanoSystems Institute at UCLA with funding support from NIH Shared Instrumentation Grant S10OD025017Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center(JCCC)Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697。
文摘Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.
文摘Objectives:Pharyngocutaneous fistula(PCF)is the most common complication to follow total laryngectomy(TL)and is associated with increases in length of hospital stay and with a need for revision surgery or readmission,as well as with delays in return to oral diet.Patients who require salvageTL(STL)or primary(chemo)radiation therapy are at higher risk for developing PCF.Due to the quality‐of‐life burden of PCF on patients,limiting this occurrence is crucial.Methods:We conducted a retrospective cohort study of patients undergoing STL with placement of Montgomery salivary bypass tube(MSBT)^(TM)for at least 2 weeks duration between 2013 and 2017 at a single institution.Our patients all underwent free flap reconstruction.Our primary outcome of interest was development of PCF.Secondary outcomes included demographics,previous treatment,base of tongue(BOT)involvement,extent of defect,concurrent neck dissection(ND),and margin status.Univariateχ^(2) analysis was used to evaluate factors associated with PCF.Results:Forty‐four patients underwent STL with Montgomery tube placement and free flap reconstruction.Eight developed PCF(18.2%).The average age was 61.6 years;36 patients were male(81.8%),whereas eight patients were female(18.2%).There was no association between PCF and previous chemoradiation versus radiation(15.8%vs.33.3%,P<0.30),BOT involvement versus not(11.1 vs.22.2%,P<0.38),circumferential versus partial defect(18.8%vs.17.9%,P<0.94),ND versus none(10%vs.25%,P<0.20),or margin status.Conclusion:PCF complicated 18.2%of STL cases at our institution and was not associated with differences in primary treatment modality,presence of concomitant ND,extent of pharyngeal defect,BOT involvement,or positive frozen or permanent surgical margin.
文摘Objectives:Describe the h index as a bibliometric that can be utilized to objectively evaluate scholarly impact.Identify which otolaryngology subspecialties are the most scholarly.Describe if NIH funding to one’s choice of medical school,residency,or fellowship has any impact on one’s scholarly output.Determine other factors predictive of an academic otolaryngologist’s productivity.Study design:Analysis of bibliometric data of academic otolaryngologists.Methods:Active grants from the National Institutes of Health(NIH)to otolaryngology departments were ascertained via the NIH Research Portfolio Online Reporting Tools Expenditures and Reports database.Faculty listings from these departments were gleaned from departmental websites.H index was calculated using the Scopus database.Results:Forty-seven otolaryngology programs were actively receiving NIH funding.There were 838 faculty members from those departments who had a mean h index of 9.61.Otology(h index 12.50)and head and neck(h index 11.96)were significantly(P<0.0001)more scholarly than the rest of subspecialists.H index was significantly correlative(P<0.0001)with degree of NIH funding at a given institution.H index was not significantly higher for those that attended medical school(P<0.18),residency(P<0.16),and fellowship(P<0.16)at institutions with NIH funding to otolaryngology departments.Conclusions:H index is a bibliometric that can be used to assess scholarly impact.Otology and head and neck are the most scholarly subspecialists within otolaryngology.NIH funding to an individual’s medical school,residency,or fellowship of origin is not correlative with one’s scholarly impact,but current institutional affiliation and choice of subspecialty are.
基金This work was partially supported by the European Fond for Regional Development(EFRD)(EFRE-0800951)to Mörchen B and Helfrich I(EFRE-0800947)to Shkura O and Stoll R.
文摘K-RAS is the most frequently mutated oncogene in solid tumors,such as pancreatic,colon or lung cancer.The GTPase K-RAS can either be in an active(GTP-loaded)or inactive(GDP-loaded)form.In its active form K-RAS forwards signals from growth factors,cytokines or hormones to the nucleus,regulating essential pathways,such as cell proliferation and differentiation.In turn,activating somatic mutations of this proto-oncogene deregulate the complex interplay between GAP(GTPase-activating)-and GEF(Guanine nucleotide exchange factor)-proteins,driving neoplastic transformation.Due to a rather shallow surface,K-RAS lacks proper binding pockets for small molecules,hindering drug development over the past thirty years.This review summarizes recent progress in the development of low molecular antagonists and further shows insights of a newly described interaction between mutant K-RAS signaling and PD-L1 induced immunosuppression,giving new hope for future treatments of K-RAS mutated cancer.
