Background:Sexual and gender minority youth frequently experience bullying,which often contributes to higher depressive symptoms and lower self-esteem.Given that physical activity(PA)can mitigate depressive symptoms a...Background:Sexual and gender minority youth frequently experience bullying,which often contributes to higher depressive symptoms and lower self-esteem.Given that physical activity(PA)can mitigate depressive symptoms and improve self-esteem,we examined the moderating effect of PA on the relationship between bullying and mental health among sexual and gender minority youth.Methods:Data from the Lesbian,Gay,Bisexual,Transgender,and Queer National Teen Survey(n=9890)were analyzed.Hierarchical regression analyses examined the influence of history and frequency of being bullied,PA,and the interaction of these variables on depressive symptoms and self-esteem.Simple slopes analyses were used to probe significant interactions.Results:Results indicated the importance of accounting for bullying history when examining effects of PA on mental health.PA was negatively related to depression(t=-4.18,p<0.001)and positively related to self-esteem(t=12.11,p<0.001).Bullying frequency was positively related to depression(t=19.35,p<0.001)and negatively related to self-esteem(t=-12.46,p<0.001).There was a significant interaction between bullying frequency and PA for depression(t=4.45,p<0.001)and self-esteem(t=-4.69,p<0.001).Post hoc analyses suggested that the positive effects of PA on mental health may be limited to those not bullied because it had a negligible effect on those who were bullied.Conclusion:Results suggest that sexual and gender minority youth exercise interventions aiming to improve mental health should first address bullying history;otherwise,their effectiveness may be limited to those who have been bullied.展开更多
BACKGROUND Laparoscopic Heller myotomy(LHM)has been the traditional surgical treatment for achalasia.Recently,peroral endoscopic myotomy(POEM)has demonstrated similar clinical outcomes with shorter procedure times.Stu...BACKGROUND Laparoscopic Heller myotomy(LHM)has been the traditional surgical treatment for achalasia.Recently,peroral endoscopic myotomy(POEM)has demonstrated similar clinical outcomes with shorter procedure times.Studies comparing the direct cost-effectiveness of POEM vs LHM are limited.AIM To compare costs of POEM vs LHM.METHODS Haider SA et al.Comparing costs:POEM vs Heller myotomy WJGE https://www.wjgnet.com 594 October 16,2023 Volume 15 Issue 10 This retrospective chart review aimed to compare the outcomes and cost of clinical care between patients who underwent POEM and LHM procedures for achalasia.The study was conducted at a tertiary academic center from January 2019 to December 2020.Clinical outcomes,including post-operative Eckardt scores and adverse events,were assessed and compared between the two groups.Direct cost variance analysis was utilized to evaluate the cost of clinical care incurred by patients undergoing POEM in the year preceding the procedure,during the index admission,and one year post-procedure,in comparison to patients undergoing LHM.RESULTS Of 30 patients were included(15 POEM and 15 LHM)in the study.Patients in the POEM group had a mean Eckardt score of 0.5±0.5 post-procedure,which was no different from patients in the LHM group(0.7±0.6,P=0.17)indicating comparative efficacy.However,the total costs of the admission for the procedure in the LHM group were on average$1827 more expensive than in the POEM group(P<0.01).Total healthcare costs one year prior to index procedure were$7777 higher in the LHM group,but not statistically different(P=0.34).The patients in the LHM group one year after the index procedure had accrued$19730.24 larger total cost,although this was not statistically different from POEM group(P=0.68).CONCLUSION Despite similar clinical outcomes,the cost of the index procedure admission for POEM was significantly lower than for LHM.The difference was primarily related to shorter time increments utilized in the operating room during the index procedure,and shorter length of hospital stay following POEM.展开更多
Neuroendocrine tumors(NET) are a heterogeneous group of cancers, with indolent behavior. The most common primary origin is the gastro-intestinal tract but can also appear in the lungs, kidneys, adrenals, ovaries and o...Neuroendocrine tumors(NET) are a heterogeneous group of cancers, with indolent behavior. The most common primary origin is the gastro-intestinal tract but can also appear in the lungs, kidneys, adrenals, ovaries and other organs. In general, NET is usually discovered in the metastatic phase(40%-80%). The liver is the most common organ involved when metastases occur(40%-93%), followed by bone(12%-20%) and lung(8%-10%).A number of different therapeutic options are available for the treatment of hepatic metastases including surgical resection, transplantation, ablation, trans-arterial chemoembolization, chemotherapy and somatostatin analogues. Recently, molecular targeted therapies have been used, usually in combination with other treatment options, to improve outcomes in patients with metastases. This article emphasizes on the role of surgery in the treatment of liver metastases from NET.展开更多
The establishment of pregnancy is a complex process that requires a well-coordinated interaction between the implanting conceptus and the maternal uterus. In pigs, the conceptus undergoes dramatic morphological and fu...The establishment of pregnancy is a complex process that requires a well-coordinated interaction between the implanting conceptus and the maternal uterus. In pigs, the conceptus undergoes dramatic morphological and functional changes at the time of implantation and introduces various factors, including estrogens and cytokines,interleukin-1β2(IL1 B2), interferon-γ(IFNG), and IFN-δ(IFND), into the uterine lumen. In response to ovarian steroid hormones and conceptus-derived factors, the uterine endometrium becomes receptive to the implanting conceptus by changing its expression of cell adhesion molecules, secretory activity, and immune response. Conceptus-derived estrogens act as a signal for maternal recognition of pregnancy by changing the direction of prostaglandin(PG) F2αfrom the uterine vasculature to the uterine lumen. Estrogens also induce the expression of many endometrial genes,including genes related to growth factors, the synthesis and transport of PGs, and immunity. IL1 B2, a pro-inflammatory cytokine, is produced by the elongating conceptus. The direct effect of IL1 B2 on endometrial function is not fully understood. IL1 B activates the expression of endometrial genes, including the genes involved in IL1 B signaling and PG synthesis and transport. In addition, estrogen or IL1 B stimulates endometrial expression of IFN signaling molecules,suggesting that estrogen and IL1 B act cooperatively in priming the endometrial function of conceptus-produced IFNG and IFND that, in turn, modulate endometrial immune response during early pregnancy. This review addresses information about maternal-conceptus interactions with respect to endometrial gene expression in response to conceptus-derived factors, focusing on the roles of estrogen and IL1 B during early pregnancy in pigs.展开更多
A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pat...A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pathology and repair (Scivoletto et al., 2003). While decreased neuroplasticity or physical strength with age may contribute to functional deficits, work from our lab and others have identified exacerbated acute inflammatory events as contributors to age-dependent secondary injury. Specifically, our recent paper identified that increased production of reactive oxygen species (ROS) from macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with age exacerbates secondary injury after SCI (Zhang et al., 2019).展开更多
BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 aff...BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.展开更多
We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HER2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test th...We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HER2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two murine tumor cell lines: MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor cells:MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.展开更多
BACKGROUND Gastric antral vascular ectasia(GAVE)is a significant complication of cirrhosis.Numerous medical,surgical,and endoscopic treatment modalities have been proposed with varied satisfactory results.In a few sma...BACKGROUND Gastric antral vascular ectasia(GAVE)is a significant complication of cirrhosis.Numerous medical,surgical,and endoscopic treatment modalities have been proposed with varied satisfactory results.In a few small studies,GAVE and associated anemia have resolved after orthotopic liver transplantation(OLT).AIM To assess the impact of OLT on the resolution of GAVE and related anemia.METHODS We retrospectively reviewed clinical records of adult patients with GAVE who underwent OLT between September 2012 and September 2019.Demographics and other relevant clinical findings were collected,including hemoglobin levels and upper endoscopy findings before and after OLT.The primary outcome was the resolution of GAVE and its related anemia after OLT.RESULTS Sixteen patients were identified.Mean pre-OLT Hgb was 7.7 g/dL and mean 12 mo post-OLT Hgb was 11.9 g/dL,(P=0.001).Anemia improved(defined as Hgb increased by 2g)in 87.5%of patients within 6 to 12 mo after OLT and resolved completely in half of the patients.Post-OLT esophagogastroduodenoscopy was performed in 10 patients,and GAVE was found to have resolved entirely in 6 of those patients(60%).Although GAVE and associated anemia completely resolved in the majority of our patients after OLT,GAVE persisted in a few patients after transplant.Further studies in a large group of patients are necessary to understand the causality of disease and to better understand the factors associated with the persistence of GAVE post-transplant.展开更多
BACKGROUND Persistent inflammation on histology after successful hepatitis C(HCV)treatment has been reported.However,data regarding the long-term impact in liver transplant recipients is limited,particularly after usi...BACKGROUND Persistent inflammation on histology after successful hepatitis C(HCV)treatment has been reported.However,data regarding the long-term impact in liver transplant recipients is limited,particularly after using direct-acting antiviral(DAA)therapies.AIM To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients.METHODS We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014.All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy.Only patients with at least one liver biopsy at or after treatment were included.We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA.RESULTS Persistent inflammation was seen in 12/13 patients on end of treatment biopsy.Inflammation was still seen in the available five follow-up biopsies(range 38-48 wk after the end of treatment).Intrahepatic HCV RNA was undetectable in all biopsies.All patients had preserved graft function for a mean follow-up of 2.5 years,except one that developed chronic rejection.CONCLUSION After successful HCV treatment with DAAs,liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA.The clinical outcome remained favorable in most patients.Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.展开更多
For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein th...For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.展开更多
CD4^(+)T cells,particularly IL-17-secreting helper CD4^(+)T cells,play a central role in the inflammatory processes underlying autoimmune disorders.Eukaryotic Elongation Factor 2 Kinase(eEF2K)is pivotal in CD8^(+)T ce...CD4^(+)T cells,particularly IL-17-secreting helper CD4^(+)T cells,play a central role in the inflammatory processes underlying autoimmune disorders.Eukaryotic Elongation Factor 2 Kinase(eEF2K)is pivotal in CD8^(+)T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension.However,its specific immunological role in CD4^(+)T cell activities and related inflammatory diseases remains elusive.Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4^(+)T cells,impairs their ability to secrete cytokines.Notably,this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17,fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4^(+)T cells.Furthermore,the absence of eEF2K in CD4^(+)T cells is linked to increased metabolic activity and mitochondrial bioenergetics.We have shown that eEF2K regulates mitochondrial function and CD4^(+)T cell activity through the upregulation of the transcription factor,signal transducer and activator of transcription 3(STAT3).Crucially,the deficiency of eEF2K exacerbates the severity of inflammation-related diseases,including rheumatoid arthritis,multiple sclerosis,and ulcerative colitis.Strikingly,the use of C188-9,a small molecule targeting STAT3,mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout(KO)CD4^(+)T cells.These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4^(+)T cells and its indispensable involvement in inflammation-related diseases.Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.展开更多
Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter ...Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.展开更多
Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition(EMT) is a vital proce...Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition(EMT) is a vital process for large-scale cell movement during morphogenesis at the time of embryonic development.Tumor cells usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis.Several transcription factors and signals are involved in these events.In this review,we summarize recent advances in breast cancer researches that have provided new insights in the molecular mechanisms underlying EMT regulation during breast cancer progression and metastasis.We especially focus on the molecular pathways that control EMT.展开更多
To examine the neural mechanisms o working memory in children, event-related potentials (ERPs) were recorded from the 12―13 year-old while they performed a delayed match-to-sample task. The ERP results revealed that ...To examine the neural mechanisms o working memory in children, event-related potentials (ERPs) were recorded from the 12―13 year-old while they performed a delayed match-to-sample task. The ERP results revealed that new and studied objects both evoked a late positive ERP componen peaking around 350 ms during the working memory process. New objects evoke a more positive ERP waveform than the studied objects. The scalp distri bution showed that the frontal-central electrode sites were associated with object working memory proc esses. When tracking new or studied targets among visual distracters, ERPs of targets and distracters revealed differential responses as early as 150 ms The visual targets evoked larger and more positive ERP responses than the distracters. The typica old-new effect was observed between ERPs of stud ied and new distracters. However, ERPs of new and studied targets differed at about 250 ms, in which new targets evoked more positive-going and slightly earlier ERP responses. In addition, a P3a componen was found for new targets only, and was absent in ERPs of studied targets at frontal and central sites The present study results reveal the spatial and temporal characteristics of neural mechanisms un derlying working memory in children, some of which are distinct from those in adults.展开更多
The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tum...The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition(EMT),and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer(CRPC).Neuroendocrine prostate cancer(NEPC)is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics.The androgen receptor(AR)is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC.The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions,and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive,acquire the neuroendocrine phenotype,and rapidly metastasize.Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients,but therapeutic resistance invariability develops,leading to mortality.Compelling evidence from our group recently demonstrated that chemotherapy(cabazitaxel,second line taxane chemotherapy),or TGF-β receptor signaling targeted therapy,caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation,in in vitro and in vivo prostate cancer models.In this review,we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotypedthe newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.展开更多
Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide i...Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase(PDI)family.As a critical member of the PDI family,thioredoxin domain containing protein 5(TXNDC5)assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions.Interestingly,TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer.In this review,we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development.Findings of TXNDC5 in the activation of intracellular signaling pathways,stimulation of cell growth&proliferation,facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed.These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.展开更多
基金This work was supported through funding by the National Institute on Drug Abuse(Grant No.K01DA047918)awarded to Ryan J.Watson.
文摘Background:Sexual and gender minority youth frequently experience bullying,which often contributes to higher depressive symptoms and lower self-esteem.Given that physical activity(PA)can mitigate depressive symptoms and improve self-esteem,we examined the moderating effect of PA on the relationship between bullying and mental health among sexual and gender minority youth.Methods:Data from the Lesbian,Gay,Bisexual,Transgender,and Queer National Teen Survey(n=9890)were analyzed.Hierarchical regression analyses examined the influence of history and frequency of being bullied,PA,and the interaction of these variables on depressive symptoms and self-esteem.Simple slopes analyses were used to probe significant interactions.Results:Results indicated the importance of accounting for bullying history when examining effects of PA on mental health.PA was negatively related to depression(t=-4.18,p<0.001)and positively related to self-esteem(t=12.11,p<0.001).Bullying frequency was positively related to depression(t=19.35,p<0.001)and negatively related to self-esteem(t=-12.46,p<0.001).There was a significant interaction between bullying frequency and PA for depression(t=4.45,p<0.001)and self-esteem(t=-4.69,p<0.001).Post hoc analyses suggested that the positive effects of PA on mental health may be limited to those not bullied because it had a negligible effect on those who were bullied.Conclusion:Results suggest that sexual and gender minority youth exercise interventions aiming to improve mental health should first address bullying history;otherwise,their effectiveness may be limited to those who have been bullied.
文摘BACKGROUND Laparoscopic Heller myotomy(LHM)has been the traditional surgical treatment for achalasia.Recently,peroral endoscopic myotomy(POEM)has demonstrated similar clinical outcomes with shorter procedure times.Studies comparing the direct cost-effectiveness of POEM vs LHM are limited.AIM To compare costs of POEM vs LHM.METHODS Haider SA et al.Comparing costs:POEM vs Heller myotomy WJGE https://www.wjgnet.com 594 October 16,2023 Volume 15 Issue 10 This retrospective chart review aimed to compare the outcomes and cost of clinical care between patients who underwent POEM and LHM procedures for achalasia.The study was conducted at a tertiary academic center from January 2019 to December 2020.Clinical outcomes,including post-operative Eckardt scores and adverse events,were assessed and compared between the two groups.Direct cost variance analysis was utilized to evaluate the cost of clinical care incurred by patients undergoing POEM in the year preceding the procedure,during the index admission,and one year post-procedure,in comparison to patients undergoing LHM.RESULTS Of 30 patients were included(15 POEM and 15 LHM)in the study.Patients in the POEM group had a mean Eckardt score of 0.5±0.5 post-procedure,which was no different from patients in the LHM group(0.7±0.6,P=0.17)indicating comparative efficacy.However,the total costs of the admission for the procedure in the LHM group were on average$1827 more expensive than in the POEM group(P<0.01).Total healthcare costs one year prior to index procedure were$7777 higher in the LHM group,but not statistically different(P=0.34).The patients in the LHM group one year after the index procedure had accrued$19730.24 larger total cost,although this was not statistically different from POEM group(P=0.68).CONCLUSION Despite similar clinical outcomes,the cost of the index procedure admission for POEM was significantly lower than for LHM.The difference was primarily related to shorter time increments utilized in the operating room during the index procedure,and shorter length of hospital stay following POEM.
文摘Neuroendocrine tumors(NET) are a heterogeneous group of cancers, with indolent behavior. The most common primary origin is the gastro-intestinal tract but can also appear in the lungs, kidneys, adrenals, ovaries and other organs. In general, NET is usually discovered in the metastatic phase(40%-80%). The liver is the most common organ involved when metastases occur(40%-93%), followed by bone(12%-20%) and lung(8%-10%).A number of different therapeutic options are available for the treatment of hepatic metastases including surgical resection, transplantation, ablation, trans-arterial chemoembolization, chemotherapy and somatostatin analogues. Recently, molecular targeted therapies have been used, usually in combination with other treatment options, to improve outcomes in patients with metastases. This article emphasizes on the role of surgery in the treatment of liver metastases from NET.
基金Support for the work from the authors’laboratory described in this review paper has been provided by the Bio Green 21 Program(20050603050120070301034040+8 种基金 20080401034003 PJ007997 PJ009610 PJ01110301PJ01119103)the Rural Development Administrationa National Research Foundation grant funded by the Korean Government(KRF-2005-003-F00017,KRF-2007-521-F00030,NRF-2010-0012304,NRF-2010-10012304 NRF-2012R1A2A2A01047079 NRF-2015R1D1A1A01058356,Republic of Korea
文摘The establishment of pregnancy is a complex process that requires a well-coordinated interaction between the implanting conceptus and the maternal uterus. In pigs, the conceptus undergoes dramatic morphological and functional changes at the time of implantation and introduces various factors, including estrogens and cytokines,interleukin-1β2(IL1 B2), interferon-γ(IFNG), and IFN-δ(IFND), into the uterine lumen. In response to ovarian steroid hormones and conceptus-derived factors, the uterine endometrium becomes receptive to the implanting conceptus by changing its expression of cell adhesion molecules, secretory activity, and immune response. Conceptus-derived estrogens act as a signal for maternal recognition of pregnancy by changing the direction of prostaglandin(PG) F2αfrom the uterine vasculature to the uterine lumen. Estrogens also induce the expression of many endometrial genes,including genes related to growth factors, the synthesis and transport of PGs, and immunity. IL1 B2, a pro-inflammatory cytokine, is produced by the elongating conceptus. The direct effect of IL1 B2 on endometrial function is not fully understood. IL1 B activates the expression of endometrial genes, including the genes involved in IL1 B signaling and PG synthesis and transport. In addition, estrogen or IL1 B stimulates endometrial expression of IFN signaling molecules,suggesting that estrogen and IL1 B act cooperatively in priming the endometrial function of conceptus-produced IFNG and IFND that, in turn, modulate endometrial immune response during early pregnancy. This review addresses information about maternal-conceptus interactions with respect to endometrial gene expression in response to conceptus-derived factors, focusing on the roles of estrogen and IL1 B during early pregnancy in pigs.
文摘A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pathology and repair (Scivoletto et al., 2003). While decreased neuroplasticity or physical strength with age may contribute to functional deficits, work from our lab and others have identified exacerbated acute inflammatory events as contributors to age-dependent secondary injury. Specifically, our recent paper identified that increased production of reactive oxygen species (ROS) from macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with age exacerbates secondary injury after SCI (Zhang et al., 2019).
基金the Changsha Municipal Natural Science Foundation,No.kq2014258.
文摘BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.
文摘We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HER2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two murine tumor cell lines: MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor cells:MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.
文摘BACKGROUND Gastric antral vascular ectasia(GAVE)is a significant complication of cirrhosis.Numerous medical,surgical,and endoscopic treatment modalities have been proposed with varied satisfactory results.In a few small studies,GAVE and associated anemia have resolved after orthotopic liver transplantation(OLT).AIM To assess the impact of OLT on the resolution of GAVE and related anemia.METHODS We retrospectively reviewed clinical records of adult patients with GAVE who underwent OLT between September 2012 and September 2019.Demographics and other relevant clinical findings were collected,including hemoglobin levels and upper endoscopy findings before and after OLT.The primary outcome was the resolution of GAVE and its related anemia after OLT.RESULTS Sixteen patients were identified.Mean pre-OLT Hgb was 7.7 g/dL and mean 12 mo post-OLT Hgb was 11.9 g/dL,(P=0.001).Anemia improved(defined as Hgb increased by 2g)in 87.5%of patients within 6 to 12 mo after OLT and resolved completely in half of the patients.Post-OLT esophagogastroduodenoscopy was performed in 10 patients,and GAVE was found to have resolved entirely in 6 of those patients(60%).Although GAVE and associated anemia completely resolved in the majority of our patients after OLT,GAVE persisted in a few patients after transplant.Further studies in a large group of patients are necessary to understand the causality of disease and to better understand the factors associated with the persistence of GAVE post-transplant.
文摘BACKGROUND Persistent inflammation on histology after successful hepatitis C(HCV)treatment has been reported.However,data regarding the long-term impact in liver transplant recipients is limited,particularly after using direct-acting antiviral(DAA)therapies.AIM To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients.METHODS We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014.All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy.Only patients with at least one liver biopsy at or after treatment were included.We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA.RESULTS Persistent inflammation was seen in 12/13 patients on end of treatment biopsy.Inflammation was still seen in the available five follow-up biopsies(range 38-48 wk after the end of treatment).Intrahepatic HCV RNA was undetectable in all biopsies.All patients had preserved graft function for a mean follow-up of 2.5 years,except one that developed chronic rejection.CONCLUSION After successful HCV treatment with DAAs,liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA.The clinical outcome remained favorable in most patients.Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.
基金supported by Hong Kong Spinal Cord Injury Fund (HKSCIF),China (to HZ)。
文摘For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.
文摘CD4^(+)T cells,particularly IL-17-secreting helper CD4^(+)T cells,play a central role in the inflammatory processes underlying autoimmune disorders.Eukaryotic Elongation Factor 2 Kinase(eEF2K)is pivotal in CD8^(+)T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension.However,its specific immunological role in CD4^(+)T cell activities and related inflammatory diseases remains elusive.Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4^(+)T cells,impairs their ability to secrete cytokines.Notably,this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17,fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4^(+)T cells.Furthermore,the absence of eEF2K in CD4^(+)T cells is linked to increased metabolic activity and mitochondrial bioenergetics.We have shown that eEF2K regulates mitochondrial function and CD4^(+)T cell activity through the upregulation of the transcription factor,signal transducer and activator of transcription 3(STAT3).Crucially,the deficiency of eEF2K exacerbates the severity of inflammation-related diseases,including rheumatoid arthritis,multiple sclerosis,and ulcerative colitis.Strikingly,the use of C188-9,a small molecule targeting STAT3,mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout(KO)CD4^(+)T cells.These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4^(+)T cells and its indispensable involvement in inflammation-related diseases.Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.
基金supported by NIH,Nos.NIH R01 NS116068(to JCG)and NIH T32 NS077889(to OHW)。
文摘Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.
基金supported by grants from The National Natural Science Foundation of China(30770725,31070916,31300856)National Science&Technology Pillar Program of China(2009BAI77B03)+1 种基金the Knowledge Innovation Program of the Chinese Academy of Sciences(KSCX2-EW-J-8)Specialized Research Fund for the Doctoral Program of Higher Education(20130182120013)~~
基金supported by the grants from NIH (RO1CA125454)the Susan G. Komen Foundation (KG081310)the Mary Kay Ash Foundation (to B.P. Zhou)
文摘Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition(EMT) is a vital process for large-scale cell movement during morphogenesis at the time of embryonic development.Tumor cells usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis.Several transcription factors and signals are involved in these events.In this review,we summarize recent advances in breast cancer researches that have provided new insights in the molecular mechanisms underlying EMT regulation during breast cancer progression and metastasis.We especially focus on the molecular pathways that control EMT.
基金This research was conducted in the Beijing Key Laboratory and in conjunction with the Beijing Key Course.This work was supported by the Chinese Ministry of Education(Grant No.20040028001)the National Natural Science Foundation of China(Grant Nos.30170322&30570603)+1 种基金Ministry of Science and Technology grant 95-special-09Jing Yang is supported by National Institutes of Health(Grant No.AG00986).
文摘To examine the neural mechanisms o working memory in children, event-related potentials (ERPs) were recorded from the 12―13 year-old while they performed a delayed match-to-sample task. The ERP results revealed that new and studied objects both evoked a late positive ERP componen peaking around 350 ms during the working memory process. New objects evoke a more positive ERP waveform than the studied objects. The scalp distri bution showed that the frontal-central electrode sites were associated with object working memory proc esses. When tracking new or studied targets among visual distracters, ERPs of targets and distracters revealed differential responses as early as 150 ms The visual targets evoked larger and more positive ERP responses than the distracters. The typica old-new effect was observed between ERPs of stud ied and new distracters. However, ERPs of new and studied targets differed at about 250 ms, in which new targets evoked more positive-going and slightly earlier ERP responses. In addition, a P3a componen was found for new targets only, and was absent in ERPs of studied targets at frontal and central sites The present study results reveal the spatial and temporal characteristics of neural mechanisms un derlying working memory in children, some of which are distinct from those in adults.
基金This work is supported by a Schwab Foundation Grant and the James F.Hardymon Endowment in Urologic Research at the University of Kentucky(NK,PJH)the University of Kentucky Summer Undergraduate Research Experience in Environmental Health Sciences(SURES)program(HD).
文摘The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition(EMT),and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer(CRPC).Neuroendocrine prostate cancer(NEPC)is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics.The androgen receptor(AR)is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC.The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions,and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive,acquire the neuroendocrine phenotype,and rapidly metastasize.Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients,but therapeutic resistance invariability develops,leading to mortality.Compelling evidence from our group recently demonstrated that chemotherapy(cabazitaxel,second line taxane chemotherapy),or TGF-β receptor signaling targeted therapy,caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation,in in vitro and in vivo prostate cancer models.In this review,we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotypedthe newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.
基金This work was partially supported by the National Institutes of Health(NCI grant number R01CA222596)Department of Defense(grant number W81XWH-16-1-0203)+1 种基金American Cancer Society(grant number RSG-16-213-01-TBE)Kentucky Lung Cancer Research Program(KLCRP2016).
文摘Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase(PDI)family.As a critical member of the PDI family,thioredoxin domain containing protein 5(TXNDC5)assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions.Interestingly,TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer.In this review,we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development.Findings of TXNDC5 in the activation of intracellular signaling pathways,stimulation of cell growth&proliferation,facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed.These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.