This brief study explores the diverse and long-term mental impacts of the COVID-19 pandemic on societies worldwide. Based on the recent existing literature, six primary categories of mental effects are identified to v...This brief study explores the diverse and long-term mental impacts of the COVID-19 pandemic on societies worldwide. Based on the recent existing literature, six primary categories of mental effects are identified to verify how people are affected by reoccurring lockdowns and social isolations. The study urges holistic research in this field, suggesting that researchers must not neglect the diversity of mental health impacts and context-specific factors. While long-term mental and psychological impacts are mostly hidden for now, we anticipate them to fuel other health issues already experienced by the vulnerable groups, healthcare units, and those fighting the pandemic at the front line. The paper aims to highlight primary mental health impacts of the COVID-19 pandemic due to reoccurring lockdowns and social isolations. This is an opinion paper reflecting on ongoing research related to mental health issues of the ongoing pandemic, some of that could be looked at through case study research or extended research and comparative studies. This brief study suggests further case study-based analysis to evaluate the impacts of lockdowns and social isolations on societal wellbeing and mental health. Globally, the ongoing pandemic has made public health unstable and is expected to continue with its long-term consequences on societies. Research studies should help make governments and policymakers more aware of such long-term consequences to ensure they can respond more effectively to foreseeing public health issues.展开更多
Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR...Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis;these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.展开更多
Cellular function and behavior are controlled by various signals during development and disease progression in mammals.It is important to understand how signals ultimately alter the function and structure of DNA regul...Cellular function and behavior are controlled by various signals during development and disease progression in mammals.It is important to understand how signals ultimately alter the function and structure of DNA regulatory elements,especially enhancers,causing the changes of gene expression patterns.On average,each mature human cell harbors at least^100000 enhancers,but only a small percent of them have the function to activate gene expression.For instance,only^12%–18%of ERα-bound enhancers are active enhancers.How enhancers become functionally active is critical for our overall understanding of enhancer biology and gene regulation.Enhancers are recognized by signaling-dependent DNA binding transcription factors(TFs),resulting in the recruitment of different enhancer activation components that allow distal enhancers to interact with their target promoters through chromatin looping(Plank and Dean,2014).Increasing evidence indicates that the recruitment and switching of enhancer components underlie enhancer activation and the deregulation in enhancer component or architecture profoundly alters signal-regulated transcriptional machineries,leading to developmental defects or diseases.展开更多
At 11:37 on March 27,2022,Dr.Jianfeng Zhou,a renowned hematologist in China and a leader in the field of CAR-T treat-ment in hematological tumors,died unexpectedly at the age of 56 because of sudden coronary dissectio...At 11:37 on March 27,2022,Dr.Jianfeng Zhou,a renowned hematologist in China and a leader in the field of CAR-T treat-ment in hematological tumors,died unexpectedly at the age of 56 because of sudden coronary dissection rupture(acute myo-cardial infarction secondary to spontaneous coronary artery dissection).I have known Jianfeng for>20 years(Figs.1 and 2),he was one of the most outstanding,compassionate,and hard-work-ing clinician-scientist I have come across with.He dedicated his career to improving healthcare outcomes for every patient in his care,as well as to medical innovations that brought novel treatments to hundreds of thousands more patients.展开更多
Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms(MPNs);however,a considerable number of patients respond suboptimally.Here,we evaluated the efficacy of micheliolide(MCL),a na...Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms(MPNs);however,a considerable number of patients respond suboptimally.Here,we evaluated the efficacy of micheliolide(MCL),a natural guaianolide sesquiterpene lactone,alone or in combination with ruxolitinib in samples from patients with MPNs,JAK2V617F-mutated MPN cell lines,and a Jak2V617F knock-in mouse model.MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro.Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone.Moreover,dimethylaminomicheliolide(DMAMCL),an orally available derivative of MCL,significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis.Importantly,MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo.Mechanistically,MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation,thus inhibiting JAK/STAT signaling.Overall,these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.展开更多
文摘This brief study explores the diverse and long-term mental impacts of the COVID-19 pandemic on societies worldwide. Based on the recent existing literature, six primary categories of mental effects are identified to verify how people are affected by reoccurring lockdowns and social isolations. The study urges holistic research in this field, suggesting that researchers must not neglect the diversity of mental health impacts and context-specific factors. While long-term mental and psychological impacts are mostly hidden for now, we anticipate them to fuel other health issues already experienced by the vulnerable groups, healthcare units, and those fighting the pandemic at the front line. The paper aims to highlight primary mental health impacts of the COVID-19 pandemic due to reoccurring lockdowns and social isolations. This is an opinion paper reflecting on ongoing research related to mental health issues of the ongoing pandemic, some of that could be looked at through case study research or extended research and comparative studies. This brief study suggests further case study-based analysis to evaluate the impacts of lockdowns and social isolations on societal wellbeing and mental health. Globally, the ongoing pandemic has made public health unstable and is expected to continue with its long-term consequences on societies. Research studies should help make governments and policymakers more aware of such long-term consequences to ensure they can respond more effectively to foreseeing public health issues.
基金This work was supported by the DOD BCRP (No. W81XWH-18-1-0016 (R.K.V)W81XWH-18-1-0015 (H.B.N)+2 种基金NCI R44CA235991 (H.B.N))NCI Cancer Center Support (No. P30CA054174-17)Elsa U. Pardee foundation (No. 166675-44096 (S.V), NIH (No. 1R01CA179120-01 (R.K.V)).Acknow。
文摘Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis;these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.
文摘Cellular function and behavior are controlled by various signals during development and disease progression in mammals.It is important to understand how signals ultimately alter the function and structure of DNA regulatory elements,especially enhancers,causing the changes of gene expression patterns.On average,each mature human cell harbors at least^100000 enhancers,but only a small percent of them have the function to activate gene expression.For instance,only^12%–18%of ERα-bound enhancers are active enhancers.How enhancers become functionally active is critical for our overall understanding of enhancer biology and gene regulation.Enhancers are recognized by signaling-dependent DNA binding transcription factors(TFs),resulting in the recruitment of different enhancer activation components that allow distal enhancers to interact with their target promoters through chromatin looping(Plank and Dean,2014).Increasing evidence indicates that the recruitment and switching of enhancer components underlie enhancer activation and the deregulation in enhancer component or architecture profoundly alters signal-regulated transcriptional machineries,leading to developmental defects or diseases.
文摘At 11:37 on March 27,2022,Dr.Jianfeng Zhou,a renowned hematologist in China and a leader in the field of CAR-T treat-ment in hematological tumors,died unexpectedly at the age of 56 because of sudden coronary dissection rupture(acute myo-cardial infarction secondary to spontaneous coronary artery dissection).I have known Jianfeng for>20 years(Figs.1 and 2),he was one of the most outstanding,compassionate,and hard-work-ing clinician-scientist I have come across with.He dedicated his career to improving healthcare outcomes for every patient in his care,as well as to medical innovations that brought novel treatments to hundreds of thousands more patients.
基金Supported in part by Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00033)CAMS Initiative Fund for Medical Sciences(Nos.2022-I2M-1-022)+1 种基金Clinical Research Fund of National Clinical Research Centre for Blood Diseases(Nos.2023NCRCA0117 and 2023NCRCA0103)National Natural Science Funds(Nos.82170139,82104785,82070134 and 81530008).
文摘Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms(MPNs);however,a considerable number of patients respond suboptimally.Here,we evaluated the efficacy of micheliolide(MCL),a natural guaianolide sesquiterpene lactone,alone or in combination with ruxolitinib in samples from patients with MPNs,JAK2V617F-mutated MPN cell lines,and a Jak2V617F knock-in mouse model.MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro.Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone.Moreover,dimethylaminomicheliolide(DMAMCL),an orally available derivative of MCL,significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis.Importantly,MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo.Mechanistically,MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation,thus inhibiting JAK/STAT signaling.Overall,these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.
