Publications by authors named "Kenji Shimizu"

174 Publications

How to treat remnant cholecystitis after subtotal cholecystectomy: two case reports.

Surg Case Rep 2021 May 3;7(1):109. Epub 2021 May 3.

Department of Surgery, Saiseikai Kumamoto Hospital, 5-3-1, Chikami, Minami-ku, Kumamoto, Japan.

Background: Subtotal cholecystectomy in patients with severe acute cholecystitis is considered a "bailout" option when the safety of the bile duct cannot be guaranteed. However, subtotal cholecystectomy has a long-term risk of remnant cholecystitis. The appropriate management of remnant cholecystitis has not been fully elucidated.

Case Presentation: Case 1 was a 66-year-old man who had undergone subtotal cholecystectomy 14 years prior to the development of remnant cholecystitis. We first performed endoscopic gallbladder drainage to minimize inflammation, and then proceeded with elective surgery. We performed a reconstituting procedure for the residual gallbladder due to significant adhesions between the cystic and common bile ducts. Case 2 was a 56-year-old man who had undergone subtotal cholecystectomy for abscess-forming perforated cholecystitis 2 years prior to the development of remnant cholecystitis. He underwent endoscopic drainage followed by complete remnant cholecystectomy 4 months later.

Conclusion: Endoscopic gallbladder drainage is a useful strategy to improve inflammation and reduce the risk of bile duct injury during remnant cholecystectomy.
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http://dx.doi.org/10.1186/s40792-021-01183-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093147PMC
May 2021

Rupture of a huge infectious abdominal chronic expanding hematoma.

Clin J Gastroenterol 2021 Apr 8. Epub 2021 Apr 8.

Department of Surgery, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto, 861-4193, Japan.

A 72-year-old woman was referred to our hospital with the diagnosis of peritonitis due to the rupture of a huge abdominal cystic tumor, 27 cm in diameter. Abdominal computed tomography 14 years before revealed the tumor, which was 18 cm in diameter. She had undergone no examinations or treatment in the interim. She was in shock upon presentation to our hospital. She was intubated immediately and underwent an emergent laparotomy. The huge ruptured tumor with adherent small intestine was resected. The tumor weighed 6 kg and consisted of solid and cystic components filled with 4 kg of brown feces-like fluid. Bacteroides fragilis was detected in a fluid specimen. The cystic component of the tumor was filled with old blood clots, and a portion of the tumor wall was highly calcified. Old blood and fibrin with blood vessels of various sizes inside the tumor were observed during the pathologic evaluation; there were no malignant features. The final pathologic diagnosis was a chronic expanding hematoma (CEH). The patient had an uneventful recovery and was discharged 16 days post-operatively. She was involved in a traffic accident approximately 30 years before the current hospital admission; however, she did not recall if she had abdominal pain at that time. A CEH is a benign lesion, but rupture of a CEH can be life-threatening.
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http://dx.doi.org/10.1007/s12328-021-01366-xDOI Listing
April 2021

TARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens.

Nat Commun 2021 01 4;12(1):94. Epub 2021 Jan 4.

Center for Animal Disease Models, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba, 278-0022, Japan.

TARM1 is a member of the leukocyte immunoglobulin-like receptor family and stimulates macrophages and neutrophils in vitro by associating with FcRγ. However, the function of this molecule in the regulation of the immune system is unclear. Here, we show that Tarm1 expression is elevated in the joints of rheumatoid arthritis mouse models, and the development of collagen-induced arthritis (CIA) is suppressed in Tarm1 mice. T cell priming against type 2 collagen is suppressed in Tarm1 mice and antigen-presenting ability of GM-CSF-induced dendritic cells (GM-DCs) from Tarm1 mouse bone marrow cells is impaired. We show that type 2 collagen is a functional ligand for TARM1 on GM-DCs and promotes DC maturation. Furthermore, soluble TARM1-Fc and TARM1-Flag inhibit DC maturation and administration of TARM1-Fc blocks the progression of CIA in mice. These results indicate that TARM1 is an important stimulating factor of dendritic cell maturation and could be a good target for the treatment of autoimmune diseases.
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http://dx.doi.org/10.1038/s41467-020-20307-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782728PMC
January 2021

Laser stabilization to neutral Yb in a discharge with polarization-enhanced frequency modulation spectroscopy.

Rev Sci Instrum 2020 Dec;91(12):123002

Centre for Quantum Dynamics, Griffith University, Brisbane, Queensland 4111, Australia.

Isotope selective optical excitation of atoms is important for experiments with neutral atoms, metrology, and work with trapped ions, including quantum information processing. Polarization-enhanced absorption spectroscopy is used to frequency stabilize a tunable external cavity laser diode system at 398.9 nm for isotope selective photoionization of neutral Yb atoms. This spectroscopy technique is used to measure isotope resolved dispersive features from transitions within a see-through configuration ytterbium hollow-cathode discharge lamp. This Doppler-free dichroic polarization spectroscopy is realized by retro-reflecting a laser beam through the discharge and analyzing the polarization dependent absorption with balanced detection. The spectroscopy signal is recovered using lock-in detection of frequency modulation induced by current modulation of the external cavity laser diode. Here, we show an order of magnitude improvement in the long-term stability using polarization-enhanced absorption spectroscopy of Yb compared to polarization spectroscopy.
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http://dx.doi.org/10.1063/5.0019252DOI Listing
December 2020

Human NINEIN polymorphism at codon 1111 is associated with the risk of colorectal cancer.

Biomed Rep 2020 Nov 27;13(5):45. Epub 2020 Aug 27.

Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

NINEIN serves an essential role in centrosome function as a microtubule organizing center, and in the reformation of the interphase centrosome architecture following mitosis. In the present study, the association between Pro1111Ala (rs2236316), a missense single nucleotide polymorphism, and the risk of colorectal cancer (CRC), related to smoking and alcohol consumption habits in 200 patients with CRC and 1,141 cancer-free control participants were assessed in a case-control study performed in Japan. The results showed that the Ala/Ala genotype compared with the Pro/Pro genotype was significantly more associated with an increased risk of CRC, and the males with the Ala/Ala genotype exhibited a significantly increased risk of CRC compared with those with Pro/Pro and Pro/Ala genotypes. Stratified analyses of the Ala/Ala genotype with CRC risk further showed an increased association in never/light drinkers (<23 g of ethanol/day), in male never/light drinkers and in male patients with rectal cancer. These findings suggest that the genetic variant of the Pro1111Ala polymorphism has a significant effect on CRC susceptibility in the Japanese population.
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http://dx.doi.org/10.3892/br.2020.1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469573PMC
November 2020

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan.

J Hum Genet 2020 Dec 13;65(12):1045-1053. Epub 2020 Jul 13.

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.
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http://dx.doi.org/10.1038/s10038-020-0802-2DOI Listing
December 2020

Multichannel optomechanical switch and locking system for wavemeters.

Appl Opt 2020 Jun;59(17):5136-5141

Here we present a cost-effective multichannel optomechanical switch and software proportional-integral-derivative (PID) controller system for locking multiple lasers to a single-channel commercial wavemeter. The switch is based on a rotating cylinder that selectively transmits one laser beam at a time to the wavemeter. The wavelength is read by the computer, and an error signal is output to the lasers to correct wavelength drifts every millisecond. We use this system to stabilize 740 nm (subsequently frequency doubled to 370 nm), 399 nm, and 935 nm lasers for trapping and cooling different isotopes of a ion. We characterize the frequency stability of the three lasers by using a second, more precise, commercial wavemeter. We also characterize the absolute frequency stability of the 740 nm laser using the fluorescence drift rate of a trapped ion. For the 740 nm laser we demonstrate an Allan deviation of 3×10 (at 20 s integration time), equivalent to sub-200 kHz stability.
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http://dx.doi.org/10.1364/AO.390881DOI Listing
June 2020

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial.

Dermatol Ther (Heidelb) 2020 Aug 8;10(4):635-650. Epub 2020 May 8.

Department of Dermatology, Nagasaki University, Nagasaki, Japan.

Introduction: Our previous clinical studies have demonstrated the short-term efficacy and safety of the sirolimus gel for patients with tuberous sclerosis complex (TSC). However, long-term clinical evidence is lacking. Our objective was to assess the safety and efficacy of long-term treatment with the sirolimus gel for the skin lesions of TSC patients.

Methods: We conducted a multicenter, open-label, uncontrolled clinical trial in 94 Japanese patients with TSC. Patients applied the 0.2% sirolimus gel on their face or head twice daily for > 52 weeks (maximum 136 weeks for safety). The safety endpoints were the rate of adverse event (AE)-caused discontinuation (primary endpoint) and the incidence of AEs. The efficacy endpoint was the response rate of angiofibromas, cephalic plaques, and hypomelanotic macules.

Results: Among 94 enrolled patients (mean age, 21 years; range 3-53 years), the rate of AE-caused discontinuation was 2.1% (2/94 patients). Although application site irritation and dry skin occurred relatively frequently, none of the drug-related AEs were serious; most of the drug-related AEs resolved rapidly. The major drug-related AEs (≥ 5% in incidence) were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), dermatitis acneiform (6.4%), and dermatitis contact (5.3%). The response rates of angiofibromas, cephalic plaques, and hypomelanotic macules were 78.2% [95% confidence interval (CI) 68.0-86.3%], 66.7% (95% CI 51.1-80.0%), and 72.2% (95% CI 46.5-90.3%), respectively.

Conclusions: The gel was well tolerated for a long time by patients with TSC involving facial skin lesions and continued to be effective.

Trial Registration: ClinicalTrials.gov identifier: NCT02634931.
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http://dx.doi.org/10.1007/s13555-020-00387-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367957PMC
August 2020

[Primary Small Intestinal Cancer-A Clinicopathological Study of Seven Cases].

Gan To Kagaku Ryoho 2020 Jan;47(1):171-173

Dept. of Surgery, Saiseikai Kumamoto Hospital.

The clinicopathological features of primarysmall intestinal cancer were assessed retrospectively. Seven patients underwent resection of small bowel cancer in our hospital between June 2011 and January 2019. The mean age of the patients was 62.9 years, and the male to female ratio was 4:3. Five patients were symptomatic, and the correct preoperative diagnosis rate was 28.6%. The average tumor diameter was 5.3 cm, and the median resected intestine length was 25 cm. Histopathological examination revealed that there were 2 patients with poorlydifferentiated tumors and 3 patients with pStage ⅡA, 3 with pStage ⅡB, and 1 with pStage ⅢA disease. Recurrence after surgeryoccurred in 4 patients, including local recurrence in 2 patients and lymph node recurrence in 1 patient. Median survival was 24.5 months. The resected intestinal length was longer and the mesenteric arterydissection was more extensive in survivors than in dead patients. In contrast, the dead patients were older than the survivors and had undifferentiated tumor, ly2/ly3, lymph node metastasis, and recurrence. Moreover, recur- rence occurred in 4 patients who had lymph node metastasis, and/or undifferentiated tumor type, and/or ly2/ly3. An adequate intestinal excision margin along with mesenteric lymph node dissection might be required to improve the survival of patients with primaryintestinal cancer.
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January 2020

[Perforated Marginal Ulcer after Subtotal Stomach Preserving Pancreaticoduodenectomy-Report of Five Cases].

Gan To Kagaku Ryoho 2020 Jan;47(1):156-158

Division of Surgery, Saiseikai Kumamoto Hospital.

Purpose: Perforated marginal ulcer after pancreaticoduodenectomy(PD)is a delayed complication. We evaluated the characteristics of the patients presenting perforated marginal ulcer after PD.

Methods: Five cases of perforated marginal ulcer after PD were reported at our hospital between 2008 and 2018, and the characteristics of these patients were evaluated.

Results: All 5 patients(4 females)with median age 73 years underwent subtotal stomach-preserving PD(SSPPD). In spite of the administration of gastric antisecretory medication, perforated marginal ulcer occurred in 3 patients(60%). All patients were treated with direct suture and omentum patch, and no mortality was reported.

Conclusions: The perforating marginal ulcer after SSPPD occurred despite the administration of the gastric antisecretory medication. Treatment with direct suture and omentum patch was effective in perforated marginal ulcer after SSPPD.
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January 2020

Establishment of Novel High-Standard Chemiluminescent Assay for NTPase in Two Protozoans and Its High-Throughput Screening.

Mar Drugs 2020 Mar 13;18(3). Epub 2020 Mar 13.

Center for Therapeutic Innovation, Gene Research Center for Frontiers Life Sciences, Nagasaki University, Graduate School of Biomedical Sciences, 1-12-14 Sakamoto, Nagasaki 852-8523, Japan.

is a major protozoan parasite and infects human and many other warm-blooded animals. The infection leads to Toxoplasmosis, a serious issue in AIDS patients, organ transplant recipients and pregnant women. , another type of protozoa, is closely related to Infections of the protozoa in animals also causes serious diseases such as Encephalomyelitis and Myositis-Polyradiculitis in dogs or abortion in cows. Both and have similar nucleoside triphosphate hydrolases (NTPase), NcNTPase and TgNTPase-I in and , respectively. These possibly play important roles in propagation and survival. Thus, we targeted the enzymes for drug discovery and tried to establish a novel high-standard assay by a combination of original biochemical enzyme assay and fluorescent assay to determine ADP content. We then validated whether or not it can be applied to high-throughput screening (HTS). Then, it fulfilled criterion to carry out HTS in both of the enzymes. In order to identify small molecules having inhibitory effects on the protozoan enzyme, we also performed HTS using two synthetic compound libraries and an extract library derived from marine bacteria and then, identified 19 compounds and 6 extracts. Nagasaki University collected many extracts from over 18,000 marine bacteria found in local Omura bay, and continues to compile an extensive collection of synthetic compounds from numerous drug libraries established by Japanese chemists.
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http://dx.doi.org/10.3390/md18030161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142789PMC
March 2020

A Diagnostic Approach to Myelopathy Based on Prognostic Factors in Patients With Lower Extremity Symptoms.

Spine (Phila Pa 1976) 2020 Jul;45(13):E792-E798

Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Study Design: Case-control study.

Objective: We aimed to identify predictors for latent myelopathy and to develop a diagnostic protocol based on these factors.

Summary Of Background Data: There is no diagnostic protocol for latent myelopathy to avoid misdiagnosis in patients complaining only of lower extremity symptoms.

Methods: This case-control study identified 791 patients discussed at conferences from April 2006 to August 2012. Overall, 460 patients complaining only of lower extremity symptoms and who underwent spine surgery were included as participants; 54 underwent surgery involving the cervical and thoracic vertebrae and were assigned to the cervical-thoracic group (C-T group); 406 underwent lumbar surgery and were assigned to the lumbar group (L group).

Results: By univariate analysis, age ≥67 years, patellar tendon (PT) hyperreflexia, Achilles tendon (AT) hyperreflexia, spastic gait, and gait inability were more common in the C-T group than in the L group. By multivariate analysis, age ≥67 years (OR, 8; P = 0.001), AT hyperreflexia (OR, 20.5; P < 0.001), spastic gait (OR, 225; P < 0.001), and gait inability (OR, 64; P < 0.001) were significant predictive factors. In patients with age ≥67 years, PT hyperreflexia, and/or AT hyperreflexia, the sensitivity for myelopathy diagnosis was 98%. In patients with spastic gait or gait inability, the specificity of myelopathy diagnosis was 96%.

Conclusions: We analyzed factors that predict latent myelopathy in patients complaining only of lower extremity symptoms. We believe a diagnostic protocol based on the predictors shown in this study would contribute to the accurate diagnosis of latent myelopathy.

Level Of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000003411DOI Listing
July 2020

Novel Reporter System Monitoring IL-18 Specific Signaling Can Be Applied to High-Throughput Screening.

Mar Drugs 2020 Jan 17;18(1). Epub 2020 Jan 17.

Center for Therapeutic Innovation, Gene Research Center for Frontiers Life Sciences, Nagasaki University, Graduate School of Biomedical Sciences, 1-12-14 Sakamoto, Nagasaki 852-8523-0022, Japan.

Very recently, the immunotherapies against cancer, autoimmune diseases, and infection have been feasible and promising. Thus, we have examined the possibility whether or not human gamma delta T cells can be applied for the novel immunotherapies. We previously established the cells stably maintaining NFkB-driven human secreted embryonic alkaline phosphatase (SEAP) expression. The cells can be used to determine the transcription activity of NFkB with high-standard dynamic range and accuracy. Because IL-18 is a kind of cytokines that enhances cytotoxicity and activity of human gamma delta T cells through NFkB activation, we have focused on the activity and signaling of IL-18. In this study, we modified the previous reporter cell that can determine the transcription activity of NFkB to express two subunits consisted of human IL-18 receptor. The modified cells secreted SEAP in response to treatment with human recombinant IL-18 in a concentration-dependent manner. We also observed the concentration-dependently enhancement of NFkB activity in the cells treated with mouse recombinant IL-18 although the affinity was lower compared to human recombinant IL-18. We also previously established the cells stably expressing and secreting human recombinant IL-18 and then validated whether or not the conditioned medium from the cells activate NFkB transcription activity using this assay. Our university has kept collecting many extracts from over 18,000 marine bacteria in our local sea around Omura bay-fungi, plants for Chinese herbal medicine, and so on-and also have kept gathering synthetic compounds from many Japanese chemists as drug libraries. Finally, in order to identify drugs mimicking IL-18 biological activity or possessing inhibitory effects on IL-18-induced NFkB, we demonstrated drug screening using number of extracts derived from marine bacteria and synthetic compounds.
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http://dx.doi.org/10.3390/md18010060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024245PMC
January 2020

Possible mitochondrial dysfunction in a patient with deafness, dystonia, and cerebral hypomyelination (DDCH) due to BCAP31 Mutation.

Mol Genet Genomic Med 2020 03 17;8(3):e1129. Epub 2020 Jan 17.

Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.

Background: Deafness, dystonia, and cerebral hypomyelination (DDCH) is an X-linked disorder due to hemizygous mutations of BCAP31.

Methods: We report an 8-year-old boy with DDCH who possibly accompanied mitochondrial dysfunction. Clinical evaluation, respiratory chain enzyme assay, and whole exome sequencing analysis were performed.

Results: Mitochondrial dysfunction was suspected by respiratory chain enzyme assay on his cultured skin fibroblasts which showed significantly decreased complex I enzyme activity. Whole exome sequencing analysis revealed a recurrent BCAP31 mutation (c.97C>T:p.Gln33*) which confirmed the diagnosis of DDCH for the patient.

Conclusion: We speculate that mitochondrial dysfunction may be a feature in patients with DDCH.
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http://dx.doi.org/10.1002/mgg3.1129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057082PMC
March 2020

PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation.

Mol Cell 2020 03 8;77(5):937-950.e6. Epub 2020 Jan 8.

Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. Electronic address:

Targeted blockade of programmed cell death 1 (PD-1), an immune-checkpoint receptor that inhibits T cell activation, provides clinical benefits in various cancers. However, how PD-1 modulates gene expression in T cells remains enigmatic. Here we investigated how PD-1 affects transcriptome changes induced by T cell receptor (TCR) activation. Intriguingly, we identified a huge variance in PD-1 sensitivity among TCR-inducible genes. When we quantified the half maximal effective concentration (EC) as the relationship between change in gene expression and TCR signal strength, we found that genes associated with survival and proliferation were efficiently expressed upon TCR activation and resistant to PD-1-mediated inhibition. Conversely, genes encoding cytokines and effector molecules were expressed less efficiently and sensitive to PD-1-mediated inhibition. We further demonstrated that transcription factor binding motifs and CpG frequency in the promoter region affect EC and thus the PD-1 sensitivity of genes. Our findings explain how PD-1, dependent on the TCR signal strength, calibrates cellular transcriptomes to shape functional properties of T cell populations.
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http://dx.doi.org/10.1016/j.molcel.2019.12.012DOI Listing
March 2020

Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells.

J Biol Chem 2019 12 13;294(52):19896-19906. Epub 2019 Nov 13.

Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan

The inhibitory co-receptor programmed cell death 1 (PD-1, ) plays critical roles in the regulation of autoimmunity, anticancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function to suppress harmful immune responses. Here we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell surface molecules. GC-induced up-regulation of PD-1 depended on transactivation of PD-1 transcription mediated through the glucocorticoid receptor. We further found that a GC response element 2525 bp upstream of the transcription start site of is responsible for GC-mediated transactivation. We also observed that administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level.
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http://dx.doi.org/10.1074/jbc.RA119.010379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937557PMC
December 2019

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

PD-1 aborts the activation trajectory of autoreactive CD8 T cells to prohibit their acquisition of effector functions.

J Autoimmun 2019 12 2;105:102296. Epub 2019 Jul 2.

Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 770-8503, Japan. Electronic address:

Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8 T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8 T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8 T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8 T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8 T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.
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http://dx.doi.org/10.1016/j.jaut.2019.06.007DOI Listing
December 2019

Buoyant hydrous mantle plume from the mantle transition zone.

Sci Rep 2019 Apr 25;9(1):6549. Epub 2019 Apr 25.

Graduate School of Science, Hokkaido University, Sapporo, Japan.

Magmatism at some intraplate volcanoes and large igneous provinces (LIPs) in continental areas may originate from hydrous mantle upwelling (i.e. a plume) from the mantle transition zone (MTZ) at 410-660 km depths in the Earth's deep interior. However, the ultimate origin of the magmatism, i.e. why mantle plumes could have been generated at the MTZ, remains unclear. Here, we study the buoyancy of a plume by investigating basalts from the Changbaishan volcano, beneath which a mantle plume from the hydrous MTZ is observed via seismology. Based on carefully determined water contents of the basalts, the potential temperature of the source mantle is estimated to be 1310-1400 °C, which is within the range of the normal upper mantle temperature. This observation suggests that the mantle plume did not have a significant excess heat, and that the plume upwelled because of buoyancy resulting from water supplied from the Pacific slab in the MTZ. Such a hydrous mantle plume can account for the formation of extremely hydrous LIP magmatism. The water was originally sourced from a stagnant slab and stored in the MTZ, and then upwelled irrespective of the presence or absence of a deep thermal plume.
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http://dx.doi.org/10.1038/s41598-019-43103-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484022PMC
April 2019

PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation.

Front Immunol 2019 29;10:630. Epub 2019 Mar 29.

Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.

Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (T) cells that required ICOS co-stimulation was persistently restrained by PD-1 . These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor.
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http://dx.doi.org/10.3389/fimmu.2019.00630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455061PMC
August 2020

Restriction of PD-1 function by -PD-L1/CD80 interactions is required for optimal T cell responses.

Science 2019 05 18;364(6440):558-566. Epub 2019 Apr 18.

Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which -PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.
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http://dx.doi.org/10.1126/science.aav7062DOI Listing
May 2019

Polymyxin B enhances acrosomal exocytosis triggered by calcium and the calcium ionophore A23187 in ejaculated boar spermatozoa.

Anim Sci J 2019 Jun 11;90(6):705-711. Epub 2019 Apr 11.

The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.

Polymyxin B (PMB) is beneficial for boar semen storage since it neutralizes the endotoxin of bacteria. However, the direct effect of PMB on boar spermatozoa has been unknown. This study aimed to examine the effect of PMB on acrosomal exocytosis, an essential process for successful fertilization in boar spermatozoa. Ejaculated spermatozoa stored with BTS extender at 17°C were washed and incubated with 0-100 μM PMB for 20 min and then examined for % total motililty, vigor grade and viability. None of the parameters was significantly different between 0 and 50 μM PMB with a gradual decline at higher concentrations. Thus the effect on acrosomal exocytosis was investigated at 0-50 μM of PMB. Spermatozoa were preincubated with PMB for 10 min, incubated for stimulation of acrosomal exocytosis with Ca and the calcium ionophore A23187 and then fixed with glutaraldehyde at 5, 10 and 15 min. Preincubation with PMB at 0.01-50 μM and 0.05-50 μM resulted in significant enhancement of acrosomal exocytosis at 10 min and 15 min of incubation, respectively. Preincubation with PMB followed by incubation without A23187 did not affect acrosomal exocytosis. These results suggest that PMB exerts effects on the acrosomal exocytosis triggered by Ca and A23187 in boar spermatozoa.
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http://dx.doi.org/10.1111/asj.13155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826241PMC
June 2019

Magmatic Response to Subduction Initiation: Part 1. Fore-arc Basalts of the Izu-Bonin Arc From IODP Expedition 352.

Geochem Geophys Geosyst 2019 Jan 16;20(1):314-338. Epub 2019 Jan 16.

Department of Geology Centenary College Shreveport LA USA.

The Izu-Bonin-Mariana (IBM) fore arc preserves igneous rock assemblages that formed during subduction initiation circa 52 Ma. International Ocean Discovery Program (IODP) Expedition 352 cored four sites in the fore arc near the Ogasawara Plateau in order to document the magmatic response to subduction initiation and the physical, petrologic, and chemical stratigraphy of a nascent subduction zone. Two of these sites (U1440 and U1441) are underlain by fore-arc basalt (FAB). FABs have mid-ocean ridge basalt (MORB)-like compositions, however, FAB are consistently lower in the high-field strength elements (TiO, PO, Zr) and Ni compared to MORB, with NaO at the low end of the MORB field and FeO* at the high end. Almost all FABs are light rare earth element depleted, with low total REE, and have low ratios of highly incompatible to less incompatible elements (Ti/V, Zr/Y, Ce/Yb, and Zr/Sm) relative to MORB. Chemostratigraphic trends in Hole U1440B are consistent with the uppermost lavas forming off axis, whereas the lower lavas formed beneath a spreading center axis. Axial magma of U1440B becomes more fractionated upsection; overlying off-axis magmas return to more primitive compositions. Melt models require a two-stage process, with early garnet field melts extracted prior to later spinel field melts, with up to 23% melting to form the most depleted compositions. Mantle equilibration temperatures are higher than normal MORB (1,400 °C-1,480 °C) at relatively low pressures (1-2 GPa), which may reflect an influence of the Manus plume during subduction initiation. Our data support previous models of FAB origin by decompression melting but imply a source more depleted than normal MORB source mantle.
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http://dx.doi.org/10.1029/2018GC007731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392113PMC
January 2019

Exploring the unique function of imprinting control centers in the PWS/AS-responsible region: finding from array-based methylation analysis in cases with variously sized microdeletions.

Clin Epigenetics 2019 02 28;11(1):36. Epub 2019 Feb 28.

Department of Molecular Endocrinology, National Center for Child Health and Development, 2-10-1 Ohkura, Setagaya-ku, Tokyo, 157-8535, Japan.

Background: Human 15q11-13 is responsible for Prader-Willi syndrome (PWS) and Angelman syndrome (AS) and includes several imprinted genes together with bipartite elements named AS-IC (imprinting center) and PWS-IC. These concertedly confer allele specificity on 15q11-13. Here, we report DNA methylation status of 15q11-13 and other autosomal imprinted differentially methylated regions (iDMRs) in cases with various deletions within the PWS/AS-responsible region.

Methods: We performed array-based methylation analysis and examined the methylation status of CpG sites in 15q11-13 and in 71 iDMRs in six cases with various microdeletions, eight cases with conventional deletions within 15q11-13, and healthy controls.

Results: We detected 89 CpGs in 15q11-13 showing significant methylation changes in our cases. Of them, 14 CpGs in the SNORD116s cluster presented slight hypomethylation in the PWS cases and hypermethylation in the AS cases. No iDMRs at regions other than 15q11-13 showed abnormal methylation.

Conclusions: We identified CpG sites and regions in which methylation status is regulated by AS-IC and PWS-IC. This result indicated that each IC had unique functions and coordinately regulated the DNA methylation of respective alleles. In addition, only aberrant methylation at iDMRs in 15q11-13 leads to the development of the phenotypes in our cases.
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http://dx.doi.org/10.1186/s13148-019-0633-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396496PMC
February 2019

PD-1 efficiently inhibits T cell activation even in the presence of co-stimulation through CD27 and GITR.

Biochem Biophys Res Commun 2019 04 14;511(3):491-497. Epub 2019 Feb 14.

Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. Electronic address:

Cancer immunotherapies targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 revolutionized cancer treatment and instigated various trials to develop new cancer immunotherapies with higher therapeutic efficacy. Agonistic Abs against tumor necrosis factor receptor super family (TNFRSF) molecules are highly expected due to their high potential to enhance survival, proliferation, and effector function of T cells. To date, agonistic antibodies (Abs) against CD27, GITR, OX40, and 4-1BB have been reported to increase the efficacy of anti-PD-1 therapy in animal models and clinical trials of these combinatorial therapies are underway. However, the mechanisms how agonistic Abs against TNFRSF molecules potentiate anti-PD-1 therapy are not well understood. Here we examined the potency of PD-1 to inhibit the antigen-dependent activation of T cells in the presence of co-stimulation through CD27 and GITR by using in vitro and ex vivo co-culture systems of T cells and antigen presenting cells. The cytokine secretion from T cells upon antigen stimulation was strongly augmented by the engagement of CD27 or GITR with their corresponding ligands. Remarkably, PD-1 efficiently inhibited the activation of T cells even in the presence of co-stimulation through CD27 or GITR. Accordingly, cytokine secretion was synergistically augmented when PD-1 blockade was combined with triggering of CD27 or GITR. These results indicate that the triggering of TNFRSF molecules and PD-1 blockade can act on the same individual cells simultaneously to augment the magnitude of T cell activation, providing the rationale for the combinatorial usage of agonistic Abs against TNFRSF molecules and blocking Abs against PD-1 or PD-L1.
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http://dx.doi.org/10.1016/j.bbrc.2019.02.004DOI Listing
April 2019

Establishment of Novel Cells Stably Secreting Various Human IL-18 Recombinant Proteins.

Curr Pharm Biotechnol 2019 ;20(1):47-55

Center for Therapeutic Innovation, Gene Research Center for Frontiers Life Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-14 Sakamoto, Nagasaki 852-8523, Japan.

Background: The immunotherapies against cancer, autoinmmune diseases or infection are remarkable development. These days programmed cell death (PD)-1 antibody-induced immune checkpoint blockade or chimeric antigen receptor-T cells (CAR-T) have been shown to have eminent therapeutic effects on tumor development. We have focused on adoptive transfer with human gamma delta T cells for novel immunotherapies. Additionally, IL-18 is one of the cytokines that enhances cytokine secretion and cytotoxicity of human gamma delta T cells.

Method: Thus, we established novel cell lines stably expressing and secreting various types of human recombinant IL-18 proteins to their culture supernatants using episomal vector. We also differentiated primary cultured human gamma delta T cells from peripheral blood mononuclear leukocytes to validate biological activity of the IL-18 proteins using measuring IFN-γ by ELISA.

Results And Conclusion: Finally, we demonstrated that the supernatant could activate human gamma delta T cells using monitoring interferon gamma in culture medium.
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http://dx.doi.org/10.2174/1389201020666190206203640DOI Listing
June 2019

Tiny droplets of ocean island basalts unveil Earth's deep chlorine cycle.

Nat Commun 2019 01 4;10(1):60. Epub 2019 Jan 4.

Kochi Institute for Core Sample Research, Japan Agency for Marine-Earth Science and Technology, Nankoku, 783-8502, Japan.

Fully characterising the exchange of volatile elements between the Earth's interior and surface layers has been a longstanding challenge. Volatiles scavenged from seawater by hydrothermally altered oceanic crust have been transferred to the upper mantle during subduction of the oceanic crust, but whether these volatiles are carried deeper into the lower mantle is poorly understood. Here we present evidence of the deep-mantle Cl cycle recorded in melt inclusions in olivine crystals in ocean island basalts sourced from the lower mantle. We show that Cl-rich melt inclusions are associated with radiogenic Pb isotopes, indicating ancient subducted oceanic crust in basalt sources, together with lithophile elements characteristic of melts from a carbonated source. These signatures collectively indicate that seawater-altered and carbonated oceanic crust conveyed surface Cl downward to the lower mantle, forming a Cl-rich reservoir that accounts for 13-26% or an even greater proportion of the total Cl in the mantle.
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http://dx.doi.org/10.1038/s41467-018-07955-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320363PMC
January 2019

LAG-3 inhibits the activation of CD4 T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII.

Nat Immunol 2018 12 22;19(12):1415-1426. Epub 2018 Oct 22.

Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.

The success of tumor immunotherapy targeting the inhibitory co-receptors PD-1 and CTLA-4 has indicated that many other co-receptors might be potential druggable targets, despite limited information about their functional differences. Here we identified a unique target selectivity for the inhibitory co-receptor LAG-3 that was intrinsic to its immunoregulatory roles. Although LAG-3 has been reported to recognize major histocompatibility complex (MHC) class II, it did not recognize MHC class II universally; instead, we found that it selectively recognized stable complexes of peptide and MHC class II (pMHCII). LAG-3 did not directly interfere with interactions between the co-receptor CD4 and MHC class II or between the T cell antigen receptor and MHC class II. Instead, LAG-3 preferentially suppressed T cells responsive to stable pMHCII by transducing inhibitory signals via its intracellular region. Thus, LAG-3 might function more selectively than previously thought and thereby maintain tolerance to dominant autoantigens.
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http://dx.doi.org/10.1038/s41590-018-0217-9DOI Listing
December 2018

Suppression of IL-17F, but not of IL-17A, provides protection against colitis by inducing T cells through modification of the intestinal microbiota.

Nat Immunol 2018 07 18;19(7):755-765. Epub 2018 Jun 18.

Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan.

The cytokines IL-17A and IL-17F have 50% amino-acid identity and bind the same receptor; however, their functional differences have remained obscure. Here we found that Il17f mice resisted chemically induced colitis, but Il17a mice did not, and that Il17f CD45RBCD4 T cells induced milder colitis in lymphocyte-deficient Rag2 mice, accompanied by an increase in intestinal regulatory T cells (T cells). Clostridium cluster XIVa in colonic microbiota capable of inducing T cells was increased in both Il17f mice and mice given transfer Il17f T cells, due to decreased expression of a group of antimicrobial proteins. There was substantial production of IL-17F, but not of IL-17A, not only by naive T cells but also by various colon-resident cells under physiological conditions. Furthermore, antibody to IL-17F suppressed the development of colitis, but antibody to IL-17A did not. These observations suggest that IL-17F is an effective target for the treatment of colitis.
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http://dx.doi.org/10.1038/s41590-018-0134-yDOI Listing
July 2018

Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial.

JAMA Dermatol 2018 07;154(7):781-788

Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Importance: Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment.

Objective: To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions.

Design, Setting, And Patients: Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC.

Interventions: Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks.

Main Outcomes And Measures: The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated."

Results: Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment.

Conclusions And Relevance: Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality.

Trial Registration: ClinicalTrials.gov Identifier: NCT02635789.
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http://dx.doi.org/10.1001/jamadermatol.2018.1408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128500PMC
July 2018