AIM： To evaluate the feasibility and utility of confocal laser endomicroscopy （CLE） in the description of normal gastrointestinal （GI） mucosa and in the diagnosis of GI disorders in children, in comparison to his...AIM： To evaluate the feasibility and utility of confocal laser endomicroscopy （CLE） in the description of normal gastrointestinal （GI） mucosa and in the diagnosis of GI disorders in children, in comparison to histology.METHODS： Forty-four patients （19 female） median age 10.9 years （range 0.7-16.6 years） with suspected or known GI pathology underwent esophago-gastro- duodenoscopy （OGD） （n = 36） and/or ileocolonoscopy （IC） （n = 31） with CLE using sodium fluorescein and acriflavine as contrast agents. Histological sections were compared with same site confocal images by two experienced pediatric and GI histopathologists and endoscopists, respectively.RESULTS： Duodenum and ileum were intubated in all but one patient undergoing OGD and IC. The median procedure time was 16.4 min （range 7-25 rain） for OGD and 27.9 min （range 15-45 min） for IC. A total of 4798 confocal images were compared with 153 biopsies from the upper GI tract from 36 procedures, and 4661 confocal images were compared with 188 biopsies from the ileocolon from 31 procedures.Confocal images were comparable to conventional histology both in normal and in pathological conditions such as esophagitis, Helicobacter pylori gastritis, celiac disease, inflammatory bowel disease, colonic heterotopia, and graft versus host disease.CONCLUSION： CLE offers the prospect of targeting biopsies to abnormal mucosa, thereby increasing diagnostic yield, reducing the number of biopsies, decreasing the burden on the histopathological services, and reducing costs.展开更多
Marginal zone lymphoma (MZL) is an indolent neoplasm of mature B cells, classified by the World Health Organization into three categories: nodal, splenic, and extranodal MZL of mucosa-associated lymphoid tissue (MALT ...Marginal zone lymphoma (MZL) is an indolent neoplasm of mature B cells, classified by the World Health Organization into three categories: nodal, splenic, and extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma). We present an unusual case of MZL with cutaneous, leukemic, and bone marrow involvement at presentation and expression of an aberrant myeloid-monocytic phenotype. This case is best classified as MZL of leukemic subtype. To the extent permissible under applicable laws, no responsibility is assumed by the Publisher nor by the Co-publisher for any injury and/or damage to persons or property as a result of any actual or alleged libelous statement, infringement of intellectual property or privacy rights, or products liability, whether resulting from negligence or otherwise, or from any use or operation of any ideas, instructions, procedures, products or methods contained in the material therein. The publication of an advertisement in the Translation does not constitute on the part of the Publisher or the Co-publisher a guarantee or endorsement of the quality or value of the advertised products or services described therein or of any of the representations or the claims made by the advertisers with respect to such products or services.展开更多
To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A sub...To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.展开更多
In a landmark study recently published in Nature,Petropoulous et al.demonstrated that synthetic lethality of poly(ADP-ribose)polymerase(PARP)inhibitors in cells with defective homologous recombination repair(HR)result...In a landmark study recently published in Nature,Petropoulous et al.demonstrated that synthetic lethality of poly(ADP-ribose)polymerase(PARP)inhibitors in cells with defective homologous recombination repair(HR)results predominantly from transcription replication conflicts(TRC)and not,as previously proposed,from PARP trapping on DNA(Fig.1).The article unveils a new mechanism behind synthetic lethality of PARP inhibitors with relevance for cancer therapy.展开更多
The interaction of nanoparticles with proteins is extremely complex, important for understanding the biological properties of nanomaterials, but is very poorly understood. We have employed a combinatorial library of s...The interaction of nanoparticles with proteins is extremely complex, important for understanding the biological properties of nanomaterials, but is very poorly understood. We have employed a combinatorial library of surface modified gold nanoparticles to interrogate the relationships between the nanoparticle surface chemistry and the specific and nonspecific binding to a common, important, and representative enzyme, acetylcholinesterase （ACHE）. We also used Bayesian neural networks to generate robust quantitative structure-property relationship （QSPR） models relating the nanoparticle surface to the AChE binding that also provided significant understanding into the molecular basis for these interactions. The results illustrate the insights that result from a synergistic blending of experimental combinatorial synthesis and biological testing of nanoparticles with quantitative computational methods and molecular modeling.展开更多
A finite-difference time-domain approach was used to investigate the excitation of surface plasmons of the circular sub-wavelength apertures on an optical fiber endface. This phenomenon provided the basis of a sensiti...A finite-difference time-domain approach was used to investigate the excitation of surface plasmons of the circular sub-wavelength apertures on an optical fiber endface. This phenomenon provided the basis of a sensitive liquid refractive index sensor. The proposed sensor is compact and has the potential to be used in biomedical applications, having a sensitivity of （373 ± 16）nm per refractive index unit （RIU） as found through the variation of a reflection minimum with the wavelength.展开更多
Objective:To review and evaluate outcomes of patients with aspirin-exacerbated respiratory disease(AERD)following endoscopic sinus surgery and subsequent aspirin desensitization.Methods:Electronic searches of OVID MED...Objective:To review and evaluate outcomes of patients with aspirin-exacerbated respiratory disease(AERD)following endoscopic sinus surgery and subsequent aspirin desensitization.Methods:Electronic searches of OVID MEDLINE(1948 to September 10,2019),EMBASE(1980 to September 10,2019),and PubMed were performed on September 10,2019.A systematic review of the literature was performed using the 2009 PRISMA guidelines.Studies with both preoperative and postoperative data for patients with AERD who underwent sinus surgery and aspirin desensitization were considered appropriate for inclusion.Publications were written in English and included patients aged 18 years or older.Results:Six studies met inclusion criteria for this systematic review.The primary outcome measure was change in symptom profile measured by patient-reported quality of life scores.The results demonstrate statistically significant improvement in symptoms following endoscopic sinus surgery,with sustained improvement following aspirin desensitization.Revision surgery rates were significantly lower in patients maintained on aspirin therapy.Conclusion:This review suggests that surgery followed by aspirin desensitization results in improvement in both subjective and objective outcome measures.The adjunctive use of aspirin desensitization allows for long-term stability in symptom scores.Recurrence of polyps and worsening symptoms requiring revision surgery occurs when aspirin maintenance therapy is inter-rupted.展开更多
Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromi...Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromic sensorineural hearing loss(SNHL).No wave was detected in the pure-tone audiometry,and the auditory brainstem response was absent in all patients.Computed tomography of the patients,as well as of two sporadic SNHL cases,showed bilateral inner ear anomaly,cochlear maldevelopment,absence of the osseous spiral lamina,and an enlarged vestibular aqueduct.Such findings were absent in nonaffected persons.We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4 KB gene(p.Gln121 Arg)encoding phosphatidylinositol 4-kinaseβ(PI4 KB)from the patients in this family.In addition,3 missense PI4 KB(p.Val434 Gly,p.Glu667 Lys,and p.Met739 Arg)mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases.No such mutations were present within 600 Chinese controls,the 1000 genome project,gnom AD,or similar databases.Depleting pi4 kb m RNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment,mimicking the patient phenotypes.Moreover,overexpression of 4 human missense PI4 KB mutant m RNAs in zebrafish embryos resulted in impaired hearing function,suggesting dominant-negative effects.Taken together,our results reveal that PI4 KB mutations can cause SNHL and inner ear malformation.PI4 KB should be included in neonatal deafness screening.展开更多
Neonatal respiratory distress syndrome(RDS),also known as hyaline membrane disease,is a leading cause of neonatal mortality in the US,which affects 1%of all newborns and 10%of preterm babies[1,2].It is also one of the...Neonatal respiratory distress syndrome(RDS),also known as hyaline membrane disease,is a leading cause of neonatal mortality in the US,which affects 1%of all newborns and 10%of preterm babies[1,2].It is also one of the most common causes of admission to neonatal intensive care unit[3].Preeclampsia(PE)is a common pregnancy complication that affects an estimated 5%of pregnancies across the world[4].It is a significant cause of low birth weight and preterm delivery,which are risk factors for RDS[5].However,in the literature,the relationship between PE and RDS remains controversial[6-9].展开更多
Scaffolding proteins play pivotal roles in the assembly of macromolecular machines such as the spliceosome.The adaptor protein CD2BP2,originally identified as a binding partner of the adhesion molecule CD2,is a pre-sp...Scaffolding proteins play pivotal roles in the assembly of macromolecular machines such as the spliceosome.The adaptor protein CD2BP2,originally identified as a binding partner of the adhesion molecule CD2,is a pre-spliceosomal assembly factor that utilizes its glycine-tyrosine-phenylalanine(GYF)domain to co-localize with spliceosomal proteins.So far,its function in vertebrates is unknown.Using conditional gene targeting in mice,we show that CD2BP2 is crucial for embryogenesis,leading to growth retardation,defects in vascularization,and premature death at embryonic day 10.5 when absent.Ablation of the protein in bone marrow-derived macrophages indicates that CD2BP2 is involved in the alternative splicing of mRNA transcripts from diverse origins.At the molecular level,we identified the phosphatase PP1 to be recruited to the spliceosome via the N-terminus of CD2BP2.Given the strong expression of CD2BP2 in podocytes of the kidney,we use selective depletion of CD2BP2,in combination with next-generation sequencing,to monitor changes in exon usage of genes critical for podocyte functions,including VEGF and actin regulators.CD2BP2-depleted podocytes display foot process effacement,and cause proteinuria and ultimately lethal kidney failure in mice.Collectively,our study defines CD2BP2 as a non-redundant splicing factor essential for embryonic development and podocyte integrity.展开更多
Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al.published in Stem Cell Reports suggests a coun...Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al.published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.展开更多
基金Supported by Peel Research Foundation and Yorkshire Cancer ResearchThe Egyptian Cultural Bureau
文摘AIM： To evaluate the feasibility and utility of confocal laser endomicroscopy （CLE） in the description of normal gastrointestinal （GI） mucosa and in the diagnosis of GI disorders in children, in comparison to histology.METHODS： Forty-four patients （19 female） median age 10.9 years （range 0.7-16.6 years） with suspected or known GI pathology underwent esophago-gastro- duodenoscopy （OGD） （n = 36） and/or ileocolonoscopy （IC） （n = 31） with CLE using sodium fluorescein and acriflavine as contrast agents. Histological sections were compared with same site confocal images by two experienced pediatric and GI histopathologists and endoscopists, respectively.RESULTS： Duodenum and ileum were intubated in all but one patient undergoing OGD and IC. The median procedure time was 16.4 min （range 7-25 rain） for OGD and 27.9 min （range 15-45 min） for IC. A total of 4798 confocal images were compared with 153 biopsies from the upper GI tract from 36 procedures, and 4661 confocal images were compared with 188 biopsies from the ileocolon from 31 procedures.Confocal images were comparable to conventional histology both in normal and in pathological conditions such as esophagitis, Helicobacter pylori gastritis, celiac disease, inflammatory bowel disease, colonic heterotopia, and graft versus host disease.CONCLUSION： CLE offers the prospect of targeting biopsies to abnormal mucosa, thereby increasing diagnostic yield, reducing the number of biopsies, decreasing the burden on the histopathological services, and reducing costs.
文摘Marginal zone lymphoma (MZL) is an indolent neoplasm of mature B cells, classified by the World Health Organization into three categories: nodal, splenic, and extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma). We present an unusual case of MZL with cutaneous, leukemic, and bone marrow involvement at presentation and expression of an aberrant myeloid-monocytic phenotype. This case is best classified as MZL of leukemic subtype. To the extent permissible under applicable laws, no responsibility is assumed by the Publisher nor by the Co-publisher for any injury and/or damage to persons or property as a result of any actual or alleged libelous statement, infringement of intellectual property or privacy rights, or products liability, whether resulting from negligence or otherwise, or from any use or operation of any ideas, instructions, procedures, products or methods contained in the material therein. The publication of an advertisement in the Translation does not constitute on the part of the Publisher or the Co-publisher a guarantee or endorsement of the quality or value of the advertised products or services described therein or of any of the representations or the claims made by the advertisers with respect to such products or services.
文摘To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.
基金This work was supported in part by DFG grant KO6390/1-1,C3R,and Fritz Thyssen Foundation 80003214-01 to M.K.by general support of Max Delbruck Center for Molecular Medicine in the Helmholtz Association(MDC)to C.S.
文摘In a landmark study recently published in Nature,Petropoulous et al.demonstrated that synthetic lethality of poly(ADP-ribose)polymerase(PARP)inhibitors in cells with defective homologous recombination repair(HR)results predominantly from transcription replication conflicts(TRC)and not,as previously proposed,from PARP trapping on DNA(Fig.1).The article unveils a new mechanism behind synthetic lethality of PARP inhibitors with relevance for cancer therapy.
文摘The interaction of nanoparticles with proteins is extremely complex, important for understanding the biological properties of nanomaterials, but is very poorly understood. We have employed a combinatorial library of surface modified gold nanoparticles to interrogate the relationships between the nanoparticle surface chemistry and the specific and nonspecific binding to a common, important, and representative enzyme, acetylcholinesterase （ACHE）. We also used Bayesian neural networks to generate robust quantitative structure-property relationship （QSPR） models relating the nanoparticle surface to the AChE binding that also provided significant understanding into the molecular basis for these interactions. The results illustrate the insights that result from a synergistic blending of experimental combinatorial synthesis and biological testing of nanoparticles with quantitative computational methods and molecular modeling.
文摘A finite-difference time-domain approach was used to investigate the excitation of surface plasmons of the circular sub-wavelength apertures on an optical fiber endface. This phenomenon provided the basis of a sensitive liquid refractive index sensor. The proposed sensor is compact and has the potential to be used in biomedical applications, having a sensitivity of （373 ± 16）nm per refractive index unit （RIU） as found through the variation of a reflection minimum with the wavelength.
文摘Objective:To review and evaluate outcomes of patients with aspirin-exacerbated respiratory disease(AERD)following endoscopic sinus surgery and subsequent aspirin desensitization.Methods:Electronic searches of OVID MEDLINE(1948 to September 10,2019),EMBASE(1980 to September 10,2019),and PubMed were performed on September 10,2019.A systematic review of the literature was performed using the 2009 PRISMA guidelines.Studies with both preoperative and postoperative data for patients with AERD who underwent sinus surgery and aspirin desensitization were considered appropriate for inclusion.Publications were written in English and included patients aged 18 years or older.Results:Six studies met inclusion criteria for this systematic review.The primary outcome measure was change in symptom profile measured by patient-reported quality of life scores.The results demonstrate statistically significant improvement in symptoms following endoscopic sinus surgery,with sustained improvement following aspirin desensitization.Revision surgery rates were significantly lower in patients maintained on aspirin therapy.Conclusion:This review suggests that surgery followed by aspirin desensitization results in improvement in both subjective and objective outcome measures.The adjunctive use of aspirin desensitization allows for long-term stability in symptom scores.Recurrence of polyps and worsening symptoms requiring revision surgery occurs when aspirin maintenance therapy is inter-rupted.
基金supported by the grants from the National Key R&D Program of China(2018YFA0801200)the National Natural Science Foundation of China(31970777,31771628,and 31601165)+1 种基金Guangdong Natural Science Fund for Distinguished Young Scholars(2017A030306024)to J.Z.the Deutsche Forschungsgemeinschaft(DFG:GO 1990/1-1)to M.G
文摘Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromic sensorineural hearing loss(SNHL).No wave was detected in the pure-tone audiometry,and the auditory brainstem response was absent in all patients.Computed tomography of the patients,as well as of two sporadic SNHL cases,showed bilateral inner ear anomaly,cochlear maldevelopment,absence of the osseous spiral lamina,and an enlarged vestibular aqueduct.Such findings were absent in nonaffected persons.We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4 KB gene(p.Gln121 Arg)encoding phosphatidylinositol 4-kinaseβ(PI4 KB)from the patients in this family.In addition,3 missense PI4 KB(p.Val434 Gly,p.Glu667 Lys,and p.Met739 Arg)mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases.No such mutations were present within 600 Chinese controls,the 1000 genome project,gnom AD,or similar databases.Depleting pi4 kb m RNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment,mimicking the patient phenotypes.Moreover,overexpression of 4 human missense PI4 KB mutant m RNAs in zebrafish embryos resulted in impaired hearing function,suggesting dominant-negative effects.Taken together,our results reveal that PI4 KB mutations can cause SNHL and inner ear malformation.PI4 KB should be included in neonatal deafness screening.
基金supported by the National Heart Lung and Blood Institute(No.K01HL146944)theNational Institute on Minority Health and Health Disparities ofthe National Institutes of Health(No.U54MD012393),FIU-RCMI and theFL-DOH.
文摘Neonatal respiratory distress syndrome(RDS),also known as hyaline membrane disease,is a leading cause of neonatal mortality in the US,which affects 1%of all newborns and 10%of preterm babies[1,2].It is also one of the most common causes of admission to neonatal intensive care unit[3].Preeclampsia(PE)is a common pregnancy complication that affects an estimated 5%of pregnancies across the world[4].It is a significant cause of low birth weight and preterm delivery,which are risk factors for RDS[5].However,in the literature,the relationship between PE and RDS remains controversial[6-9].
基金This work was supported by grants from the Deutsche Forschungsgemeinschaft(FG806,SFB854)to C.F.and from the Focus Area DynAge to H.S.and C.F.
文摘Scaffolding proteins play pivotal roles in the assembly of macromolecular machines such as the spliceosome.The adaptor protein CD2BP2,originally identified as a binding partner of the adhesion molecule CD2,is a pre-spliceosomal assembly factor that utilizes its glycine-tyrosine-phenylalanine(GYF)domain to co-localize with spliceosomal proteins.So far,its function in vertebrates is unknown.Using conditional gene targeting in mice,we show that CD2BP2 is crucial for embryogenesis,leading to growth retardation,defects in vascularization,and premature death at embryonic day 10.5 when absent.Ablation of the protein in bone marrow-derived macrophages indicates that CD2BP2 is involved in the alternative splicing of mRNA transcripts from diverse origins.At the molecular level,we identified the phosphatase PP1 to be recruited to the spliceosome via the N-terminus of CD2BP2.Given the strong expression of CD2BP2 in podocytes of the kidney,we use selective depletion of CD2BP2,in combination with next-generation sequencing,to monitor changes in exon usage of genes critical for podocyte functions,including VEGF and actin regulators.CD2BP2-depleted podocytes display foot process effacement,and cause proteinuria and ultimately lethal kidney failure in mice.Collectively,our study defines CD2BP2 as a non-redundant splicing factor essential for embryonic development and podocyte integrity.
基金The authors declare no competing financial or commercial interests and acknowledge support from the Fritz Thyssen Foundation(grant AZ.10.11.2.160 to A.P.)the European Union(funding/FP7(FP7/2007-2013)/Grant Agreement n°305299/AgedBrainSYSBIO to J.A.).
文摘Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al.published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.
