BACKGROUND Castleman disease(CD) is a rare lymphoproliferative disorder that presents with various symptoms. CD accompanied with jaundice is uncommon since there are only 11 cases reported in the literature.CASE SUMMA...BACKGROUND Castleman disease(CD) is a rare lymphoproliferative disorder that presents with various symptoms. CD accompanied with jaundice is uncommon since there are only 11 cases reported in the literature.CASE SUMMARY Here we report a 62-year-old woman who was admitted to the hospital with signs and symptoms of intermittent jaundice. Biochemical tests showed higher serum levels of total and direct bilirubin, and normal serum levels of tumor markers and interleukin-6. Contrast-enhanced computed tomography detected a6 cm × 4 cm × 2.5 cm mass between the hepatoduodenal ligament and the inferior vena cava. The mass was successfully excised and the patient had a complete resolution of symptoms. A diagnosis of idiopathic unicentric CD was made based upon histological examination, which demonstrated the pathological features of CD of mixed type, including hyperplasia of follicular lymphoids with abundant plasma cells, degenerative germinal centers, interfollicular vascularity and hyaline degeneration. The diagnosis was corroborated by immunohistochemical analysis which detected multiple biomarkers.CONCLUSION This is the first study that describes the clinicopathological features of CD presenting with jaundice, which may deepen and extend our understanding of this disease.展开更多
In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology.Drug therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a smal...In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology.Drug therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents.Thus,there has been a sustained search for novel molecular targets for iCCA.The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6(PSMD6),a 19S regulatory subunit of the proteasome,in human iCCA cells and specimens.The authors employed clustered regularly interspaced short palindromic repeat(CRISPR)knockout screening technology integrated with the computational CERES algorithm,and analyzed the human protein atlas(THPA)database and tissue microarrays.The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines,and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters.The authors conclude that PSMD6 may play a promoting role in iCCA.The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening,in vivo experiments,and a discussion of plausible mechanistic cues,which,therefore,dampen the significance of the results.Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA.In addition,the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA,development of proteasome inhibitors for cancer therapy,and advantages of CRISPR screening technology,computational methods,and THPA database as experimental tools for fighting cancer.We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.展开更多
Autophagy,a cellular recycling process,plays a key role in maintaining genomic stability and regulating DNA damage repair.However,recent studies have challenged this consensus,suggesting that upregulation of autophagy...Autophagy,a cellular recycling process,plays a key role in maintaining genomic stability and regulating DNA damage repair.However,recent studies have challenged this consensus,suggesting that upregulation of autophagy may induce DNA damage and contribute to genomic instability.Notably,several investigations have demonstrated that autophagy-mediated DNA damage can occur through mechanisms involving the production of reactive oxygen species(ROS).Despite these findings,many questions remain unresolved regarding the controversial DNA-damaging effects of autophagy and its potential role in promoting genomic instability and intratumoral heterogeneity.A more comprehensive understanding of the mechanisms and implications of“autophagy-mediated DNA damage”will offer crucial insights into the development and progression of various diseases from different perspectives.A deeper insight into autophagy mechanisms will also help identify potential adverse effects of autophagy-targeted interventions and clarify the molecular basis of side effects observed in various therapies in the future.展开更多
We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be ...We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches. YB-1 predominantly binds to single-stranded nucleic acids, adding further difficulty to drug discovery. Therefore, we have developed two novel screening assays to detect compounds that interfere with the transcriptional activation properties of YB-1, both of which may be generalizable to screen for inhibitors of other nucleic acid binding molecules. The first approach is a cell-based luciferase reporter gene assay that measures the level of activation of a fragment of the E2 F1 promoter by YB-1. The second approach is a novel application of the Alpha Screen system, to detect interference of YB-1 interaction with a single-stranded DNA binding site. These complementary assays examine YB-1 binding to two discrete nucleic acid sequences using two different luminescent signal outputs and were employed sequentially to screen 7360 small molecule compounds leading to the identification of three putative YB-1 inhibitors.展开更多
Peptide-and protein-based therapeutics offer realized and potential benefits to health,due to their potent bioactivity,high specificity,and favorable safety characteristics.However,their widespread clinical applicatio...Peptide-and protein-based therapeutics offer realized and potential benefits to health,due to their potent bioactivity,high specificity,and favorable safety characteristics.However,their widespread clinical application is constrained by inherent limitations,including rapid enzymatic degradation,poor membrane permeability,and a reliance on parenteral administration,which reduces patient adherence.To overcome these challenges,extensive research has explored non-invasive delivery strategies,including topical,transdermal,and oral formulations.Despite promising advances in these delivery strategies,they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics,such as enzymatic degradation in the gastrointestinal tract,limited epithelial transport,and inherently low systemic bioavailability.This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy.It critically examines key challenges associated with various administration routes,including topical,transdermal,oral(including delivery targeting the brain),and others.Furthermore,it explores innovative strategies to enhance peptide and protein stability and bioavailability,including chemical modifications,enzyme inhibitors,penetration enhancers,physical delivery technologies,and advanced nanoparticulate formulations.Additionally,emerging trends in formulation optimization,regulatory considerations,and translational pathways for clinical implementation are discussed.By addressing these critical challenges and highlighting recent advances,this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy,and enhanced patient adherence,which is needed to fully realize the true potential of this class of therapeutics.展开更多
The serum and glucocorticoid inducible protein kinase(SGK) family members share similar structure, substrate specificity and function with AKT and signal downstream of the phosphatidylinositol 3-kinase(PI3K) signallin...The serum and glucocorticoid inducible protein kinase(SGK) family members share similar structure, substrate specificity and function with AKT and signal downstream of the phosphatidylinositol 3-kinase(PI3K) signalling pathway. They regulate a range of fundamental cellular processes such as cell proliferation and survival, thereby playing an important role in cancer development. This perspective intends to give an overview on the involvement of SGKs(particularly SGK3) in cancer progression, and compares the actions of SGK3 and AKT in cell cycle regulation, oncogenic signalling, and the potential as a therapeutic target for cancer.展开更多
Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary...Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites.In adults,hypersecretion of GH causes acromegaly,and strategies that block the release of GH or that inhibit GH receptor(GHR)activation are the primary forms of medical therapy for this disease.Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes.However,studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited,most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo.This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.展开更多
Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinos...Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)signalling pathways[1].These mutations occur in approximately 20%of melanomas and very rarely coexist with BRAF V600 mutations.NRASmutant melanoma is associated with poor survival[2]and represents an unmet clinical need,with no effective therapies available following immunotherapy failure.Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies.In this study,we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma.Typically,melanoma cell lines are cultured under ambient(∼20%)O_(2) conditions,despite O_(2 )concentrations of<8%at the epidermaldermal junction where melanocytes reside,resulting in adaptations in gene and protein expression[3].展开更多
基金Supported by the National Key Research and Development Program of China,No.2017YFC1308602the National Natural Scientific Foundation of China,No.81472321 and No.81401975
文摘BACKGROUND Castleman disease(CD) is a rare lymphoproliferative disorder that presents with various symptoms. CD accompanied with jaundice is uncommon since there are only 11 cases reported in the literature.CASE SUMMARY Here we report a 62-year-old woman who was admitted to the hospital with signs and symptoms of intermittent jaundice. Biochemical tests showed higher serum levels of total and direct bilirubin, and normal serum levels of tumor markers and interleukin-6. Contrast-enhanced computed tomography detected a6 cm × 4 cm × 2.5 cm mass between the hepatoduodenal ligament and the inferior vena cava. The mass was successfully excised and the patient had a complete resolution of symptoms. A diagnosis of idiopathic unicentric CD was made based upon histological examination, which demonstrated the pathological features of CD of mixed type, including hyperplasia of follicular lymphoids with abundant plasma cells, degenerative germinal centers, interfollicular vascularity and hyaline degeneration. The diagnosis was corroborated by immunohistochemical analysis which detected multiple biomarkers.CONCLUSION This is the first study that describes the clinicopathological features of CD presenting with jaundice, which may deepen and extend our understanding of this disease.
基金Supported by The National Key Research and Development Program of China,No.2017YFC1308602The Research Funds by the Fifth Affiliated Hospital of Harbin Medical University,No.2022-002 and No.2023-001.
文摘In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology.Drug therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents.Thus,there has been a sustained search for novel molecular targets for iCCA.The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6(PSMD6),a 19S regulatory subunit of the proteasome,in human iCCA cells and specimens.The authors employed clustered regularly interspaced short palindromic repeat(CRISPR)knockout screening technology integrated with the computational CERES algorithm,and analyzed the human protein atlas(THPA)database and tissue microarrays.The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines,and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters.The authors conclude that PSMD6 may play a promoting role in iCCA.The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening,in vivo experiments,and a discussion of plausible mechanistic cues,which,therefore,dampen the significance of the results.Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA.In addition,the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA,development of proteasome inhibitors for cancer therapy,and advantages of CRISPR screening technology,computational methods,and THPA database as experimental tools for fighting cancer.We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.
基金supported by the National Science and Technology Council(NSTC 113-2320-B-006-016),Taiwan.
文摘Autophagy,a cellular recycling process,plays a key role in maintaining genomic stability and regulating DNA damage repair.However,recent studies have challenged this consensus,suggesting that upregulation of autophagy may induce DNA damage and contribute to genomic instability.Notably,several investigations have demonstrated that autophagy-mediated DNA damage can occur through mechanisms involving the production of reactive oxygen species(ROS).Despite these findings,many questions remain unresolved regarding the controversial DNA-damaging effects of autophagy and its potential role in promoting genomic instability and intratumoral heterogeneity.A more comprehensive understanding of the mechanisms and implications of“autophagy-mediated DNA damage”will offer crucial insights into the development and progression of various diseases from different perspectives.A deeper insight into autophagy mechanisms will also help identify potential adverse effects of autophagy-targeted interventions and clarify the molecular basis of side effects observed in various therapies in the future.
基金supported by grants from Health Research Council of New Zealand(IRF213-China,13-1019 to PS,CP,AL and AB)the Ministry of Science and Technology of China(2014DFG32200 to M-WW)+1 种基金Shanghai Science and Technology Development Fund(15DZ2291600 to M-WW,China)the Thousand Talents Program in China([2011]166 to M-WW)
文摘We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches. YB-1 predominantly binds to single-stranded nucleic acids, adding further difficulty to drug discovery. Therefore, we have developed two novel screening assays to detect compounds that interfere with the transcriptional activation properties of YB-1, both of which may be generalizable to screen for inhibitors of other nucleic acid binding molecules. The first approach is a cell-based luciferase reporter gene assay that measures the level of activation of a fragment of the E2 F1 promoter by YB-1. The second approach is a novel application of the Alpha Screen system, to detect interference of YB-1 interaction with a single-stranded DNA binding site. These complementary assays examine YB-1 binding to two discrete nucleic acid sequences using two different luminescent signal outputs and were employed sequentially to screen 7360 small molecule compounds leading to the identification of three putative YB-1 inhibitors.
文摘Peptide-and protein-based therapeutics offer realized and potential benefits to health,due to their potent bioactivity,high specificity,and favorable safety characteristics.However,their widespread clinical application is constrained by inherent limitations,including rapid enzymatic degradation,poor membrane permeability,and a reliance on parenteral administration,which reduces patient adherence.To overcome these challenges,extensive research has explored non-invasive delivery strategies,including topical,transdermal,and oral formulations.Despite promising advances in these delivery strategies,they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics,such as enzymatic degradation in the gastrointestinal tract,limited epithelial transport,and inherently low systemic bioavailability.This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy.It critically examines key challenges associated with various administration routes,including topical,transdermal,oral(including delivery targeting the brain),and others.Furthermore,it explores innovative strategies to enhance peptide and protein stability and bioavailability,including chemical modifications,enzyme inhibitors,penetration enhancers,physical delivery technologies,and advanced nanoparticulate formulations.Additionally,emerging trends in formulation optimization,regulatory considerations,and translational pathways for clinical implementation are discussed.By addressing these critical challenges and highlighting recent advances,this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy,and enhanced patient adherence,which is needed to fully realize the true potential of this class of therapeutics.
基金supported by grants from the Ministry of Science and Technology of China (2014DFG32200)Shanghai Science and Technology Development Fund (15DZ2291600)the Thousand Talents Program in China ([2011]166)
文摘The serum and glucocorticoid inducible protein kinase(SGK) family members share similar structure, substrate specificity and function with AKT and signal downstream of the phosphatidylinositol 3-kinase(PI3K) signalling pathway. They regulate a range of fundamental cellular processes such as cell proliferation and survival, thereby playing an important role in cancer development. This perspective intends to give an overview on the involvement of SGKs(particularly SGK3) in cancer progression, and compares the actions of SGK3 and AKT in cell cycle regulation, oncogenic signalling, and the potential as a therapeutic target for cancer.
文摘Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites.In adults,hypersecretion of GH causes acromegaly,and strategies that block the release of GH or that inhibit GH receptor(GHR)activation are the primary forms of medical therapy for this disease.Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes.However,studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited,most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo.This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.
基金funded by the Cancer Society of New Zealand(18.14)Cancer Research Trust New Zealand(2005-PGS)University of Auckland Genomics into Medicine Strategic Research Initiatives Fund and Maurice Wilkins Centre for Molecular Biodiscovery Flexible Research Programme.
文摘Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)signalling pathways[1].These mutations occur in approximately 20%of melanomas and very rarely coexist with BRAF V600 mutations.NRASmutant melanoma is associated with poor survival[2]and represents an unmet clinical need,with no effective therapies available following immunotherapy failure.Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies.In this study,we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma.Typically,melanoma cell lines are cultured under ambient(∼20%)O_(2) conditions,despite O_(2 )concentrations of<8%at the epidermaldermal junction where melanocytes reside,resulting in adaptations in gene and protein expression[3].
