Publications by authors named "Soyoung Kim"

206 Publications

Tumor Glucose Metabolism and Its Heterogeneity on F-18 FDG PET/CT Provide Better Prognostication in Nonmetastatic Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma.

Cancers (Basel) 2021 Nov 4;13(21). Epub 2021 Nov 4.

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.

Background: We aimed to evaluate the prognostic role of metabolic parameters on baseline F-18 fluorodeoxyglucose (FDG) PET/CT in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC).

Methods: We retrospectively reviewed patients who were diagnosed with nonmetastatic HPV-related OPSCC using the 8th TNM staging system from 2010 to 2015 and underwent baseline F-18 FDG PET/CT. Tumor SUV to liver SUV ratio (SUV-TLR), metabolic tumor volume (MTV), tumor total lesion glycolysis to liver SUV ratio (TLG-TLR), and coefficient of variation (CV) of the primary tumor were measured. Patients were primarily treated with surgery or radiotherapy. Endpoints were progression-free survival (PFS) and overall survival (OS).

Results: Ninety consecutive patients (male, 72; female, 18) were enrolled. They were followed up for a median of 77.4 months (interquartile range, 48.4-106.4). Sixteen patients progressed, and 13 died. Multivariate analysis revealed that patients with advanced age, overall stage, and higher SUV-TLR or CV had poorer PFS and OS.

Conclusion: Higher SUV-TLR and CV of the primary tumor on baseline F-18 FDG PET/CT were associated with poorer PFS and OS in patients with nonmetastatic HPV-related OPSCC. Further study is warranted to address the possible implications of F-18 FDG PET/CT on treatment de-intensification in these patients.
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http://dx.doi.org/10.3390/cancers13215538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583647PMC
November 2021

Different prognostic impact of glucose uptake in visceral adipose tissue according to sex in patients with colorectal cancer.

Sci Rep 2021 Nov 3;11(1):21556. Epub 2021 Nov 3.

Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea.

The purpose of this study was to investigate whether sex differences in visceral fat volume and glucose uptake measured by positron emission tomography/computed tomography (PET/CT) in abdominal visceral fat can stratify overall survival (OS) in patients with colorectal cancer (CRC). We retrospectively enrolled 293 patients diagnosed with CRC who underwent PET/CT before surgical resection. Fluorodeoxyglucose uptake of visceral adipose tissue (VAT-SUV) and subcutaneous adiposity tissue (SAT-SUV) were measured using PET/CT. The relative VAT (rVAT) was defined as the visceral fat volume normalized to the total volume of fat (VAT plus SAT). We defined sex-specific cutoff values for VAT-SUV, SAT-SUV, and rVAT. Univariate and multivariate analyses using Cox proportional hazard regression analysis were performed to identify the independent prognostic factors. The study population comprised 181 men and 112 women. The rVAT (0.40 vs. 0.29, p < 0.001) and VAT-SUV (0.55 vs. 0.48, p = 0.007) were significantly greater in men than in women. High rVAT (than low rVAT) and high VAT-SUV (than low VAT-SUV) showed a worse prognosis in male and female patients, respectively. Multivariate analysis indicated that the combination of rVAT and VAT-SUV was an independent prognostic factor for predicting OS in both male and female patients. The combination of rVAT and VAT-SUV could differentiate the patients with the best survival outcome from the other three individual groups in female patients, but not in males. Glucose uptake and relative volume of visceral fat may provide a new risk stratification for patients with CRC, especially female patients.
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http://dx.doi.org/10.1038/s41598-021-01086-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566460PMC
November 2021

Allogeneic Transplant and CAR-T Therapy After Autologous Transplant Failure in DLBCL: A Noncomparative Cohort Analysis.

Blood Adv 2021 Oct 21. Epub 2021 Oct 21.

Moffitt Cancer Center, Tampa, Florida, United States.

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR) T-cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto) HCT. While the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis we report outcomes of DLBCL patients (≥18 years), undergoing a reduced intensity alloHCT or CAR-T therapy during 2012-2019, after a prior auto-HCT failure, and apply CIBMTR prognostic model to CAR-T recipients. 584 patients were included. The 1-year relapse, non-relapse mortality, overall survival (OS) and progression-free survival (PFS) for CAR-T treatment after autoHCT failure were were 39.5%, 4.8%, 73.4% and 55.7%, respectively. The corresponding rates in alloHCT cohort were 26.2%, 20.0%, 65.6% and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3, respectively (p=0.002). The corresponding rates for low-, intermediate- and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (p<0.001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in subset of DLBCL patients relapsing after a prior autoHCT. The simple, CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high risk patients.
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http://dx.doi.org/10.1182/bloodadvances.2021005788DOI Listing
October 2021

Outcomes in Hematopoietic Stem Cell Transplantation for Congenital Amegakaryocytic Thrombocytopenia.

Transplant Cell Ther 2021 Oct 17. Epub 2021 Oct 17.

Center for International Blood and Marrow Transplant Research, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, inherited bone marrow failure syndrome. Hematopoietic stem cell transplantation (HSCT) is considered a curative treatment option, but existing descriptions of patient and transplant characteristics and outcomes after related and unrelated donor HSCT are sparse. We describe outcomes after HSCT for congenital amegakaryocytic thrombocytopenia (CAMT; n = 86) from 2000 to 2018. We conducted an analysis of data collected by the Center for International Blood and Marrow Transplant Research on patients with CAMT receiving therapeutic allogeneic HSCT. The predominant donor type was HLA-matched or mismatched unrelated donors (n = 58, 67%). The remaining included HLA-matched sibling (n = 23, 27%) and HLA-mismatched relative (n = 5, 6%). The predominant graft types were bone marrow (n = 53, 62%) and cord blood (n = 25, 29%). The median age at transplantation was 3 years, with 82 of 86 patients being transplanted aged ≤10 years. The 5-year graft failure-free and overall survival were 83% (95% confidence interval [CI], 74-90) and 86% (95% CI, 78-93), respectively. An examination for risk factors confirmed mortality was higher after HLA-mismatched relative and mismatched unrelated donor HSCT compared to HLA-matched sibling and matched unrelated donor HSCT (hazard ratio 3.52, P = .04; 75% versus 93%). The 1-year incidence of graft failure was 19% after HLA-mismatched HSCT (n = 32) compared to 7% after HLA-matched HSCT (n = 54, P = .15). Day-100 grade II-IV acute graft-versus-host disease was 13%, 26%, and 30% after HLA-matched sibling, HLA-matched and mismatched unrelated donor HSCT. The 5-year incidence of chronic graft-versus-host disease was 33% with 24 of 28 patients having received grafts from HLA-matched (n = 13) and mismatched unrelated (n = 11) donors. Although HLA-matched donors are preferred, HLA-mismatched donors also extend survival for CAMT.
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http://dx.doi.org/10.1016/j.jtct.2021.10.009DOI Listing
October 2021

Rapid, multiplexed detection of the let-7 miRNA family using γPNA amphiphiles in micelle-tagging electrophoresis.

Biopolymers 2021 Oct 13:e23479. Epub 2021 Oct 13.

Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

miRNA is a promising class of biomarkers whose levels can be assayed to detect various forms of cancer and other serious diseases. These short, noncoding nucleic acids are difficult to detect due to their low abundance and the marginal stability of their duplexes with DNA probes. In addition, miRNAs within the same family have high sequence homology, and often, related miRNA differ in sequence by only a single base. In this report, we demonstrate an independent detection seven members of the let-7 family of miRNA in a single run. Key to success is the use of mini-PEG-substituted PNA amphiphiles (γPNAA) and highly fluorescent DNA nanotags in micelle tagging electrophoresis (MTE). Multiplexed detection is accomplished in capillary electrophoresis (CE) using oligomeric nanotags of pre-programmed lengths where the presence of a specific miRNA links its nanotag to a micelle drag-tag, which shifts the nanotag elution time to a defined region for detection. We further demonstrate that the peak shape and elution time are unaffected by the presence of up to 10 mg/ml of serum protein in the sample, with a total runtime of less than 4 min and a LOD of 10-100 pM. We discuss efforts to substantially decrease the detection limit using nanotags that are >1000 bp in length.
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http://dx.doi.org/10.1002/bip.23479DOI Listing
October 2021

Post-Transplantation Cyclophosphamide Is Associated with an Increase in Non-Cytomegalovirus Herpesvirus Infections in Patients with Acute Leukemia and Myelodysplastic Syndrome.

Transplant Cell Ther 2021 Sep 26. Epub 2021 Sep 26.

Division of Hematology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.
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http://dx.doi.org/10.1016/j.jtct.2021.09.015DOI Listing
September 2021

Mirabegron has longer treatment persistence than antimuscarinics: Real-world data from a Korean national cohort database.

Neurourol Urodyn 2021 11 6;40(8):1972-1980. Epub 2021 Sep 6.

Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea.

Aims: To descriptively evaluate treatment persistence among adults who received mirabegron or antimuscarinics in South Korea.

Methods: This study involved a retrospective analysis of the Health Insurance Review and Assessment (HIRA) database. Patients (≥18 years) who had a new prescription for an overactive bladder (OAB) target medication (mirabegron/antimuscarinic) within an 8-month index period (July 1, 2015-February 29, 2016) were included. The date when the target (index) medication was dispensed was the index date. The 6-month period before the index date was used to assess patient eligibility. A 12-month post-index period was used to assess medication persistence, which was defined as the time to discontinuation. Overall data were analyzed and the results were also stratified by age group (≤65, >65 years), sex, or prior OAB medication experience. Persistence rates were calculated after the 1st, 3rd, 6th, 9th, and 12th months.

Results: A data set of 52 722 cases was obtained (mirabegron: 11 424, antimuscarinics: 41 298). The mean age was 60.9 ± 16.1 years and the majority of the patients were female (30 862 [58.5%] patients). Median persistence was longer with mirabegron (51 days) versus antimuscarinics (25 days). The persistence rate with mirabegron was higher throughout the study compared with all the antimuscarinics (12-month data: 13.5% and 4.9%, respectively). Longer treatment persistence was noted in older, male, and treatment-experienced patients.

Conclusion: The results from the HIRA database showed that persistence was longer with mirabegron than with antimuscarinics in South Korea. This finding may help inform clinical decision-making within the South Korean healthcare system.
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http://dx.doi.org/10.1002/nau.24776DOI Listing
November 2021

The regulatory impact of RNA-binding proteins on microRNA targeting.

Nat Commun 2021 08 20;12(1):5057. Epub 2021 Aug 20.

School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.

Argonaute is the primary mediator of metazoan miRNA targeting (MT). Among the currently identified >1,500 human RNA-binding proteins (RBPs), there are only a handful of RBPs known to enhance MT and several others reported to suppress MT, leaving the global impact of RBPs on MT elusive. In this study, we have systematically analyzed transcriptome-wide binding sites for 150 human RBPs and evaluated the quantitative effect of individual RBPs on MT efficacy. In contrast to previous studies, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers rather than suppressors, by making the local secondary structure of the target site accessible to Argonaute. Our findings illuminate the unappreciated regulatory impact of human RBPs on MT, and as these RBPs may play key roles in the gene regulatory network governed by metazoan miRNAs, MT should be understood in the context of co-regulating RBPs.
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http://dx.doi.org/10.1038/s41467-021-25078-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379221PMC
August 2021

Case-cohort design in hematopoietic cell transplant studies.

Bone Marrow Transplant 2021 Aug 16. Epub 2021 Aug 16.

Division of Biostatistics, Medical College of Wisconsin, Wauwatosa, WI, USA.

Series Editors- Note: Imagine you and your colleagues have done 1000 transplants in persons with acute myeloid leukaemia in 1st remission. 5% of the 20% of recipients relapsing posttransplant have an isolated central nervous system relapse. You are curious and want to know whether there is anything special about this 5%, specifically whether this risk corelates with any pretransplant clinical and laboratory co-variates. You have extensive clinical data and some typical laboratory data on all 1000 but you suspect the culprit is mutation topography. What to do? Fortunately you have bio-banked DNA from the 1000. If resources and monies are not limiting you can do targeted or next generation sequencing on all 1000 DNA samples and off you go. However, most of us lack unlimited resources and monies. How can you sensibly and efficiently tackle this research problem? The answer is a case-cohort design study. In the typescript which follows Profs. Cai and Kim explain how to accomplish this. If you follow their advice you may need only to analyze samples from <300 recipients rather than 1000 to test your hypothesis. They explain how to design such a study and provide references to estimate sample size. Sadly, their typescript will not tell you how to get funding for the study, whish poor devil who will have to write the protocol, worse, who will shepherd it though endless committees for approval and the like. Help on these issues is outside the scope of our statistics series. In this context we suggest advice from Woody Allen's article in the New Yorker: The Kugelmass Episode (April 24, 1977). When Prof. Kugelmass (English, City College) tells his analyst Dr. Mandel he has fallen in love with Emma Bovary who died of arsenic poisoning near Rouen, France 120 years earlier the analyst says: After all, I'm an analyst, not a magician. Kugelmass' reply: Then perhaps what I need is a magician and is off to Coney Island to find one. Good luck, the magician may still be there! (Note: This typescript is R-rated. It contains an equation.).
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http://dx.doi.org/10.1038/s41409-021-01433-4DOI Listing
August 2021

Comparison of hematopoietic cell transplant conditioning regimens for hemophagocytic lymphohistiocytosis disorders.

J Allergy Clin Immunol 2021 Aug 8. Epub 2021 Aug 8.

Center for International Blood and Marrow Transplant Research, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisc.

Background: Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.

Objective: The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.

Methods: We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.

Results: Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).

Conclusions: Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
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http://dx.doi.org/10.1016/j.jaci.2021.07.031DOI Listing
August 2021

Acyl-CoA synthetase-4 mediates radioresistance of breast cancer cells by regulating FOXM1.

Biochem Pharmacol 2021 10 3;192:114718. Epub 2021 Aug 3.

Department of Pharmacology, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 38066, Republic of Korea. Electronic address:

The development of radioresistance during radiotherapy is a major cause of tumor recurrence and metastasis. To provide new insights of the mechanisms underlying radioresistance, we established radioresistant cell lines derived from two different subtypes of breast cancer cells, HER2-positive SK-BR-3 and ER-positive MCF-7 breast cancer cells, by exposing cells to 48 ~ 70 Gy of radiation delivered at 4-5 Gy twice weekly over 9 ~ 10 months. The established radioresistant SK-BR-3 (SR) and MCF-7 (MR) cells were resistant not only to a single dose of radiation (2 Gy or 4 Gy) but also to fractionated radiation delivered at 2 Gy/day for 5 days. Furthermore, these cells exhibited tumor-initiating potential in vivo and high CD24-/CD44 + ratio. To identify novel therapeutic molecular targets, we analyzed differentially expressed genes in both radioresistant cell lines and found that the expression of ACSL4 was significantly elevated in both cell lines. Targeting ACSL4 improved response to irradiation and inhibited migration activities. Furthermore, inhibition of ACLS4 using ASCL4 siRNA or triacsin C suppressed FOXM1 expression, whereas inhibition of FOXM1 using thiostrepton did not affect ACSL4 expression. Targeting the ACSL4-FOXM1 signaling axis by inhibiting ASCL4 or FOXM1 overcame the radioresistance by suppressing DNA damage responses and inducing apoptosis. This is the first study to report that ACSL4 plays a crucial role in mediating the radioresistance of breast cancer by regulating FOXM1. We propose the ACSL4-FOXM1 signaling axis be considered a novel therapeutic target in radioresistant breast cancer and suggest treatment strategies targeting this signaling axis might overcome breast cancer radioresistance.
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http://dx.doi.org/10.1016/j.bcp.2021.114718DOI Listing
October 2021

Characteristics of surgically transposed ovaries on F-FDG PET/CT among patients with cancer.

Ann Nucl Med 2021 Oct 26;35(10):1100-1108. Epub 2021 Jul 26.

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemungu, Seoul, 03722, Korea.

Objective: Fertility preservation in women with cancer is important for improving their quality of life. Successful ovarian transposition protects the ovary from radiation and preserves ovarian endocrine function and fertility. With the increasing use of F-FDG PET/CT in gynecologic malignancies, the findings of transposed ovaries sometimes vary. This study aimed to characterize the F-FDG PET/CT findings of surgically transposed ovaries among a large number of patients with various medical conditions.

Methods: We retrospectively reviewed the medical records, including surgical history, and analyzed the findings of the transposed ovaries of patients who underwent ovarian transposition. Quantitative analysis was performed, and the maximum standardized uptake values (SUVs) were recorded. The Hounsfield unit (HU) and size (measured using the long diameter on the axial image) of the transposed ovary were evaluated.

Results: No significant change was found in the SUV of the transposed ovaries in relation to age and time after surgery. In two cases in which metastasis occurred in the transposed ovary, the lesions showed higher SUVs and HUs than did the other non-metastatic transposed ovaries. In several serial follow-up cases, varying F-FDG uptake was observed.

Conclusion: The F-FDG uptake pattern of the transposed ovary did not differ from that of the normal ovary. Misinterpretation should be avoided by considering surgical records, presence of surgical clips, and patients' disease state. If there is a high uptake in the transposed ovary, it is necessary to check for soft tissue lesions and differentiate metastasis from the physiologic uptake.
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http://dx.doi.org/10.1007/s12149-021-01645-0DOI Listing
October 2021

Course of tic disorders over the lifespan.

Curr Dev Disord Rep 2021 Jun 10;8(2):121-132. Epub 2021 Apr 10.

Department of Cognitive Science, University of California, San Diego, La Jolla, California, 92093.

Purpose Of Review: To summarize and update information on the course of tic disorders from childhood through later life.

Recent Findings: Tics tend to improve substantially over the first year after they appear. However, contrary to widespread opinion, tics usually last longer than one year, though usually at minimal severity. Tics often wane to clinical insignificance over the teen years, possibly resurging occasionally over the lifespan. However, in an important minority of patients, tics remain clinically relevant throughout life. Tics rarely first come to clinical attention later in adulthood, but new reports describe additional such cases.

Summary: Recent publications have shown tics to persist past a few months more often than previously thought, though often at minimal severity, and recurrence after an asymptomatic period is common. The safety and efficacy of behavior therapy for tics, together with prospective indicators of early prognosis, make feasible the possibility of bettering the lifetime course of tic disorders with early intervention.
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http://dx.doi.org/10.1007/s40474-021-00231-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223879PMC
June 2021

Correlates and clinical implications of tic suppressibility.

Curr Dev Disord Rep 2021 Jun 4;8(2):112-120. Epub 2021 Apr 4.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.

Purpose Of Review: Tic disorders are common in the pediatric population and are differentiated from other movement disorders by tic suppressibility. Understanding the mechanism of tic suppression may provide new insights to the pathophysiology of tic disorders. This article highlights clinical phenomenology and neuronal correlates of tic suppressibility.

Recent Findings: Recent studies suggest that tic suppressibility exists in children shortly after onset of their tics. Moreover, those who are better able to suppress their tics have better tic outcomes. Interoceptive awareness and automatic action inhibition may be involved in tic suppression.

Summary: We illustrate a possible underlying mechanism of tic suppressibility and its clinical correlations and implications. New concepts such as interoceptive awareness and action inhibition may help explain tic disorders. Further study will be useful to fill remaining knowledge gaps.
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http://dx.doi.org/10.1007/s40474-021-00230-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224814PMC
June 2021

Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation.

Br J Haematol 2021 07 14;194(1):145-157. Epub 2021 Jun 14.

Department of Medicine, City of Hope, Duarte, CA, USA.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.
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http://dx.doi.org/10.1111/bjh.17563DOI Listing
July 2021

Prognostic significance of bone marrow and spleen F-FDG uptake in patients with colorectal cancer.

Sci Rep 2021 06 9;11(1):12137. Epub 2021 Jun 9.

Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea.

Serum inflammatory markers are used in the prognostication of colorectal cancer (CRC); however, the corresponding role of positron emission tomography (PET)-derived inflammatory markers remains unclear. This study aimed to investigate the prognostic value of F-fluorodeoxyglucose (FDG) uptake in the bone marrow and spleen of patients with CRC and evaluate the relationship between FDG uptake estimates in these organs and serum inflammatory markers. In total, 411 patients who underwent preoperative FDG PET/computed tomography (CT) within 1 month of surgery were enrolled. The mean standardized uptake values of the bone marrow and spleen were normalized to the value of the liver, thereby generating bone marrow-to-liver uptake ratio (BLR) and spleen-to-liver uptake ratio (SLR) estimates. The value of BLR and SLR in predicting overall survival (OS) was assessed using the Cox proportional hazards model. The correlation between BLR or SLR and neutrophil-to-lymphocyte ratio (NLR) was evaluated. The predictive accuracy of BLR alone and in combination with SLR was compared using the integrated area under the receiver operating characteristic curves (iAUC). In the univariate analysis, BLR (> 1.06) and SLR (> 0.93) were significant predictors of OS. In the multivariate analysis, BLR was an independent predictor of OS (hazard ratio = 5.279; p < 0.001). Both BLR and SLR were correlated with NLR (p < 0.001). A combination of BLR and SLR was better than BLR alone at CRC prognostication (iAUC, 0.561 vs. 0.542). FDG uptake estimates in the bone marrow and spleen may be useful imaging-derived biomarkers of systemic inflammation, supporting CRC prognostication.
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http://dx.doi.org/10.1038/s41598-021-91608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190120PMC
June 2021

Tamoxifen overcomes the trastuzumab-resistance of SK-BR-3 tumorspheres by targeting crosstalk between cytoplasmic estrogen receptor α and the EGFR/HER2 signaling pathway.

Biochem Pharmacol 2021 08 28;190:114635. Epub 2021 May 28.

Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Dongdae-ro 123, Gyeongju, Gyeongsangbuk-do 38066, Republic of Korea. Electronic address:

Since trastuzumab-resistance remains a major obstacle to the successful treatment of HER2-positive breast cancer, a detailed understanding of the mechanisms responsible is required to direct future pharmacotherapeutic strategies. Recently, several studies have indicated that the quiescent natures of cancer stem cells contribute to treatment resistance and tumor recurrence. Thus, in this study, we investigated the mechanism underlying trastuzumab resistance in a quiescent cell population using tumorsphere cultures and explored better therapeutic strategies to overcome trastuzumab resistance in HER2-positive breast cancer patients. We observed that most cells in SK-BR-3 tumorspheres were quiescent, showing the accumulation of cells at the G0/G1 phase as compared to cells in monolayer culture. Furthermore, SK-BR-3 tumorspheres exhibited enhanced EGFR/HER2 signaling, which was incompletely inhibited by trastuzumab, and subsequently led to trastuzumab-resistance. Interestingly, cytoplasmic estrogen receptor α (ERα) expression was markedly elevated in tumorspheres and was associated with enhanced EGFR/HER2 signaling. Accordingly, inhibition of ERα with tamoxifen selectively targeted tumorspheres rather than cells in monolayer culture and overcame trastuzumab resistance in tumorspheres. Taken together, our findings indicate that crosstalk between cytoplasmic ERα and the HER2/EGFR signaling pathway can be considered a novel therapeutic target for quiescent cell populations within HER2-positive breast cancer and that simultaneous inhibition of ER and the EGFR/HER2 pathway may prevent trastuzumab resistance. We hope that these results provide a basis for the use of combinations of tamoxifen and trastuzumab in HER2-positive breast cancer patients.
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http://dx.doi.org/10.1016/j.bcp.2021.114635DOI Listing
August 2021

Optimal treatment regimes for competing risk data using doubly robust outcome weighted learning with bi-level variable selection.

Comput Stat Data Anal 2021 Jun 14;158. Epub 2021 Jan 14.

Division of Biostatistics, Medical College of Wisconsin, Milwaukee WI 53226, USA.

The goal of the optimal treatment regime is maximizing treatment benefits via personalized treatment assignments based on the observed patient and treatment characteristics. Parametric regression-based outcome learning approaches require exploring complex interplay between the outcome and treatment assignments adjusting for the patient and treatment covariates, yet correctly specifying such relationships is challenging. Thus, a robust method against misspecified models is desirable in practice. Parsimonious models are also desired to pursue a concise interpretation and to avoid including spurious predictors of the outcome or treatment benefits. These issues have not been comprehensively addressed in the presence of competing risks. Recognizing that competing risks and group variables are frequently present, we propose a doubly robust estimation with adaptive penalties to select important variables at both group and within-group levels for competing risks data. The proposed method is applied to hematopoietic cell transplantation data to personalize the graft source choice for treatment-related mortality (TRM). While the existing medical literature attempts to find a uniform solution ignoring the heterogeneity of the graft source effects on TRM, the analysis results show the effect of the graft source on TRM could be different depending on the patient-specific characteristics.
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http://dx.doi.org/10.1016/j.csda.2021.107167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117077PMC
June 2021

Synergistic Effect of Methyl Jasmonate and Abscisic Acid Co-Treatment on Avenanthramide Production in Germinating Oats.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Korea.

The oat ( L.) is a grain of the Poaceae grass family and contains many powerful anti-oxidants, including avenanthramides as phenolic alkaloids with anti-inflammatory, anti-oxidant, anti-itch, anti-irritant, and anti-atherogenic activities. Here, the treatment of germinating oats with methyl jasmonate (MeJA) or abscisic acid (ABA) resulted in 2.5-fold (582.9 mg/kg FW) and 2.8-fold (642.9 mg/kg FW) increase in avenanthramide content, respectively, relative to untreated controls (232.6 mg/kg FW). Moreover, MeJA and ABA co-treatment synergistically increased avenanthramide production in germinating oats to 1505 mg/kg FW. Individual or combined MeJA and ABA treatment increased the expression of genes encoding key catalytic enzymes in the avenanthramide-biosynthesis pathway, including hydroxycinnamoyl-CoA:hydrocyanthranilate N-hydroxycinnamoyl transferase (HHT). Further analyses showed that six AsHHT genes were effectively upregulated by MeJA or ABA treatment, especially AsHHT4 for MeJA and AsHHT5 for ABA, thereby enhancing the production of all three avenanthramides in germinating oats. Specifically, AsHHT5 exhibited the highest expression following MeJA and ABA co-treatment, indicating that AsHHT5 played a more crucial role in avenanthramide biosynthesis in response to MeJA and ABA co-treatment of germinating oats. These findings suggest that elicitor-mediated metabolite farming using MeJA and ABA could be a valuable method for avenanthramide production in germinating oats.
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http://dx.doi.org/10.3390/ijms22094779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125723PMC
April 2021

Transcriptomic Analysis of Rice Plants Overexpressing in Response to Salinity Stress.

Genes (Basel) 2021 04 25;12(5). Epub 2021 Apr 25.

National Institute of Agricultural Science, Rural Development Administration, Jeonju 54874, Korea.

In plants, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a main enzyme in the glycolytic pathway. It plays an essential role in glycerolipid metabolism and response to various stresses. To examine the function of PsGAPDH ( GAPDH) in response to abiotic stress, we generated transgenic rice plants with single-copy/intergenic/homozygous overexpression (-OX) and investigated their responses to salinity stress. Seedling growth and germination rates of -OX were significantly increased under salt stress conditions compared to those of the wild type. To elucidate the role of -OX in salt stress tolerance of rice, an Illumina HiSeq 2000 platform was used to analyze transcriptome profiles of leaves under salt stress. Analysis results of sequencing data showed that 1124 transcripts were differentially expressed. Using the list of differentially expressed genes (DEGs), functional enrichment analyses of DEGs such as Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed. KEGG pathway enrichment analysis revealed that unigenes exhibiting differential expression were involved in starch and sucrose metabolism. Interestingly, () genes, of which expression was enhanced by abiotic stress, showed a significant difference in -OX. Findings of this study suggest that PsGAPDH plays a role in the adaptation of rice plants to salt stress.
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http://dx.doi.org/10.3390/genes12050641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146104PMC
April 2021

Chaga mushroom extract induces autophagy via the AMPK-mTOR signaling pathway in breast cancer cells.

J Ethnopharmacol 2021 Jun 30;274:114081. Epub 2021 Mar 30.

Department of Radiation Oncology, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju, Gyeongsangbuk-do, 38066, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Chaga mushrooms (Inonotus obliquus) are commonly used in traditional treatments in Eastern Europe and Asia due to their diverse pharmacological effects, including anti-tumor and immunologic effects. Thus, many cancer patients take Chaga mushrooms as a complementary medicine, even during chemotherapy or radiotherapy. However, few studies have investigated the effects or molecular targets of Chaga mushrooms in breast cancer.

Aim Of The Study: Herein, we examined the anticancer effects of Chaga mushrooms in different types of breast cancer cell lines, and explored the underlying molecular mechanism to better understand their effects and benefits.

Materials And Methods: Chaga mushroom extract (CME) was prepared by extracting Chaga mushrooms with 70% ethanol. The cytotoxic effects of CME were assessed by MTT assay and protein expressions were evaluated by western blotting. To evaluate in vivo anti-tumor effects of CME, CME (2 g/kg) was orally administered to 4T1 tumor-bearing BALB/c mice every other day over 30 days (15 administrations), and tumor sizes were measured. Silica gel column chromatography was used to fractionate CME, and major constituents responsible for cytotoxic effects of CME were identified by H/C-NMR and LC-MS.

Results: CME inhibited the proliferation of 4T1 mouse breast cancer cells in a dose and time-dependent manner. The expression of LC3 and phosphorylation of AMPK were increased by CME, while the phosphorylation of mTOR, S6, and S6K1 were suppressed, suggesting that CME induced autophagy by activating AMPK and inhibiting mTOR signaling pathways. Consistent with its observed cytotoxic effect in vitro, CME effectively suppressed tumor growth in 4T1 tumor-bearing BALB/c mice. In addition, inotodiol and trametenolic acid were identified as the major constituents responsible for the cytotoxic effects of CME on breast cancer cells. Moreover, inotodiol and trametenolic acid-enriched fractions both exhibited cytotoxic effects regardless of breast cancer cell subtypes and did not interfere with the cytotoxic effects of conventional drugs.

Conclusions: Taken together, Chaga mushroom extract induced autophagy by activating AMPK and inhibiting the mTOR signaling pathway. Our data suggest Chaga mushrooms may be a beneficial complementary medicine for breast cancer patients.
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http://dx.doi.org/10.1016/j.jep.2021.114081DOI Listing
June 2021

Overexpression of VlPRX21 and VlPRX35 genes in Arabidopsis plants leads to bioconversion of trans-resveratrol to δ-viniferin.

Plant Physiol Biochem 2021 May 12;162:556-563. Epub 2021 Mar 12.

Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup, 56212, Republic of Korea. Electronic address:

Stilbenes, including resveratrol and viniferins, a small family of polyphenols, are considered the most important phytoalexin group in Vitis species. In a previous study, we found that co-treatment of methyl jasmonate (MJ) and stevioside (STE) resulted in enhanced extracellular production of viniferins in grapevine cell suspension cultures. Thus, to further understand the mechanisms of viniferin production in grapevine cell cultures, we performed transcriptome analysis and isolated seven candidates of grapevine peroxidase genes (VlAPX6, VlGPX5, VlPRX13, VlPRX21, VlPRX35, VlPRX40, and VlPRX50). Bioconversion of trans-resveratrol to δ-viniferin was examined using crude protein extracts isolated from agroinfiltration-based transient expression of VlPRXs in Nicotiana benthamiana. In addition, we found that crude protein extracts from VlPRX21-, VlPRX35-, and VlPRX40-overexpressing (OX) transgenic Arabidopsis plants led to the conversion of trans-resveratrol to δ-viniferin. We found that in vitro experiments with crude protein extracts from VlPRX21-OX and VlPRX35-OX Arabidopsis plants catalyzed the dimerization of trans-resveratrol to δ-viniferin. Our results suggest that VlPRX21 and VlPRX35 encode functional grapevine class III peroxidases and catalyze the oxidative dimerization of trans-resveratrol to form δ-viniferin in grapevine.
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http://dx.doi.org/10.1016/j.plaphy.2021.03.015DOI Listing
May 2021

PARsylated transcription factor EB (TFEB) regulates the expression of a subset of Wnt target genes by forming a complex with β-catenin-TCF/LEF1.

Cell Death Differ 2021 Sep 22;28(9):2555-2570. Epub 2021 Mar 22.

Department of Life Science, University of Seoul, Seoul, Republic of Korea.

Wnt signaling is mainly transduced by β-catenin via regulation of the β-catenin destruction complex containing Axin, APC, and GSK3β. Transcription factor EB (TFEB) is a well-known master regulator of autophagy and lysosomal biogenesis processes. TFEB's nuclear localization and transcriptional activity are also regulated by various upstream signals. In this study, we found that Wnt signaling induces the nuclear localization of TFEB and the expression of Wnt target genes is regulated by TFEB-β-catenin-TCF/LEF1 as well as β-catenin-TCF/LEF1 complexes. Our biochemical data revealed that TFEB is a part of the β-catenin destruction complex, and destabilization of the destruction complex by knockdown of either Axin or APC causes nuclear localization of TFEB. Interestingly, RNA-sequencing analysis revealed that about 27% of Wnt3a-induced genes were TFEB dependent. However, these "TFEB mediated Wnt target genes" were different from TFEB target genes involved in autophagy and lysosomal biogenesis processes. Mechanistically, we found that Tankyrase (TNKS) PARsylates TFEB with Wnt ON signaling, and the nuclear localized PARsylated TFEB forms a complex with β-catenin-TCF/LEF1 to induce the "TFEB mediated Wnt target genes". Finally, we found that in various types of cancer, the levels of TFEB mediated Wnt target genes exhibit strong correlations with the level of Axin2, which represents the activity of Wnt signaling. Overall, our data suggest that Wnt signaling induces the expression of a subset of genes that are distinct from previously known genes regulated by the β-catenin-TCF/LEF1 complex or TFEB, by forming a transcription factor complex consisting of PARsylated TFEB and β-catenin-TCF/LEF1.
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http://dx.doi.org/10.1038/s41418-021-00770-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408140PMC
September 2021

The Impact of Ignoring a Crossed Factor in Cross-Classified Multilevel Modeling.

Front Psychol 2021 3;12:637645. Epub 2021 Mar 3.

Department of Education, Korea University, Seoul, South Korea.

The present study investigated estimate biases in cross-classified random effect modeling (CCREM) and hierarchical linear modeling (HLM) when ignoring a crossed factor in CCREM considering the impact of the feeder and the magnitude of coefficients. There were six simulation factors: the magnitude of coefficient, the correlation between the level 2 residuals, the number of groups, the average number of individuals sampled from each group, the intra-unit correlation coefficient, and the number of feeders. The targeted interests of the coefficients were four fixed effects and two random effects. The results showed that ignoring a crossed factor in cross-classified data causes a parameter bias for the random effects of level 2 predictors and a standard error bias for the fixed effects of intercepts, level 1 predictors, and level 2 predictors. Bayesian information criteria generally outperformed Akaike information criteria in detecting the correct model.
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http://dx.doi.org/10.3389/fpsyg.2021.637645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965978PMC
March 2021

A new function for MAP4K4 inhibitors during platelet aggregation and platelet-mediated clot retraction.

Biochem Pharmacol 2021 06 15;188:114519. Epub 2021 Mar 15.

Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do, 38066, Republic of Korea. Electronic address:

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is implicated in type 2 diabetes mellitus, insulin tolerance, inflammation, cancer, and atherosclerosis. We found that GNE 495 and PF 06260933 (both potent and selective MAP4K4 inhibitors) regulated human platelet activation. Immunoblotting revealed human platelets express MAP4K4, and that GNE 495 and PF 06260933 inhibited collagen-, ADP-, and thrombin-induced platelet aggregation and eventually suppressed granule release, TXA generation, integrin αβ activation, and clot retraction. In addition, both inhibitors elevated intracellular levels of cAMP, and coincubation with GNE 495 and aspirin or dipyridamole (a phosphodiesterase inhibitor) synergistically inhibited collagen-induced platelet aggregation and TXA generation. Moreover, both inhibitors phosphorylated VASP (ser), IP3 receptor, and PKA and attenuated MAPK and PI3K/Akt/GSK3β signaling pathways. This study is the first to demonstrate that MAP4K4 inhibitors reduce thrombus formation by inhibiting platelet activation. These findings also suggest MAP4K4 be considered an emerging target protein for the treatment of thrombosis.
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http://dx.doi.org/10.1016/j.bcp.2021.114519DOI Listing
June 2021

Comparative Efficacy and Safety of Peficitinib Versus Tofacitinib and Baricitinib for Treatment of Rheumatoid Arthritis: A Systematic Review and Network Meta-Analysis.

Rheumatol Ther 2021 Jun 16;8(2):729-750. Epub 2021 Mar 16.

Astellas Pharma Global Development, Inc., Northbrook, USA.

Introduction: Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment.

Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity.

Results: The network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes.

Conclusions: Peficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors.
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http://dx.doi.org/10.1007/s40744-021-00284-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217393PMC
June 2021

Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis.

Blood 2021 06;137(23):3291-3305

Center for International Blood and Marrow Transplantation Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R- patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.
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http://dx.doi.org/10.1182/blood.2020009362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351903PMC
June 2021

Mistletoe Extract Targets the STAT3-FOXM1 Pathway to Induce Apoptosis and Inhibits Metastasis in Breast Cancer Cells.

Am J Chin Med 2021 20;49(2):487-504. Epub 2021 Feb 20.

Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Dongdae-ro 123, Gyeongju, Gyeongsangbuk-do 38066, Republic of Korea.

Mistletoe extracts ( L.) have been widely used as complementary and alternative medicines for the treatment of cancer, and their cytotoxic effects have been reported on various types of cancer. However, the molecular targets of mistletoe extracts have not been well studied. Herein, we investigated molecules associated with the and anticancer effects of mistletoe extract using 4T1 murine breast cancer cells. Mistletoe extract induced apoptosis and inhibited the signal transducer and activator of transcription3 (STAT3) phosphorylation. This inhibition was accompanied by the downregulations of forkhead box M1 (FOXM1) and the DNA repair proteins, RAD51 and survivin. Mistletoe extract simultaneously increased the expression of the DNA damage marker proteins, phosphorylated H2A histone family member X (H2A.X), and phosphorylated p38. Furthermore, mistletoe extract effectively suppressed tumor growth in 4T1 tumor-bearing BALB/c mice. In addition to tumor growth inhibition, mistletoe extract inhibited lung metastasis in the tumor-bearing mice and cell invasiveness by downregulating the expressions of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA), uPA receptor, and markers of epithelial-mesenchymal transition (snail and fibronectin). Taken together, our results suggest that mistletoe extract targets the STAT3-FOXM1 pathway for its cytotoxic effects, and that mistletoe extracts might be useful for the treatment of patients with cancers highly expressing the STAT3-FOXM1 pathway.
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http://dx.doi.org/10.1142/S0192415X21500221DOI Listing
August 2021

A microneedle platform for buccal macromolecule delivery.

Sci Adv 2021 Jan 22;7(4). Epub 2021 Jan 22.

Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.
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http://dx.doi.org/10.1126/sciadv.abe2620DOI Listing
January 2021

Prognostic value of metabolic tumor volume and total lesion glycolysis on preoperative F-FDG PET/CT in patients with localized primary gastrointestinal stromal tumors.

Cancer Metab 2021 Jan 28;9(1). Epub 2021 Jan 28.

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: This study aimed to evaluate the prognostic value of pretreatment F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) in patients with localized primary gastrointestinal stromal tumors (GISTs) and to compare the predictive values of F-FDG PET/CT parameters with those of clinicopathological prognostic factors.

Methods: Sixty-two localized GIST patients who underwent staging with F-FDG PET/CT from January 2007 to December 2013 before surgery were retrospectively enrolled. A volume of interest with a standardized uptake value (SUV) threshold of 2.5 was used to determine the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These metabolic indices, along with the maximum SUV (SUVmax), were analyzed to evaluate recurrence-free survival (RFS). Other significant clinical and pathologic indices were also retrospectively reviewed for RFS analysis.

Results: Patients were followed up for a median of 42.0 months (range, 5.6-111.5). During the follow-up period, 13 patients (21.0%) experienced disease recurrence. In univariate analysis, tumor size (> 5 cm), mitotic count (> 5/high-power field), modified National Institutes of Health (NIH) consensus criteria, adjuvant imatinib treatment, SUVmax (≥ 7.04), MTV (≥ 50.76 cm), and TLG (≥ 228.79 g) were significant prognostic factors affecting RFS (p < 0.05). In multivariate analysis, only MTV (hazard ratio, 17.69; 95% confidence interval [CI], 2.03-154.17, p = 0.009) and TLG (hazard ratio, 20.48; 95% CI, 2.19-191.16, p = 0.008) were independent prognostic factors for RFS. The 5-year RFS rates were 96.4% and 96.6% in patients with a low MTV and TLG and 27.3% and 23.6% in patients with a high MTV and TLG, respectively (p < 0.001).

Conclusion: MTV and TLG are independent prognostic factors for predicting recurrence in patients with localized primary GIST. Patients with a high MTV or TLG are at risk for poor prognosis and should be closely observed for disease recurrence.
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http://dx.doi.org/10.1186/s40170-021-00244-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844977PMC
January 2021
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