Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

GLP-1 reduces the migration of hepatocellular carcinoma cells via suppression of the stress-activated protein kinase/c-Jun N-terminal kinase pathway.

Incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are hormones secreted from small intestine accompanied with oral intake. We previously showed that transforming growth factor (TGF)-α stimulates the migration of hepatocellular carcinoma (HCC) cells via mitogen-activated protein (MAP) kinases, AKT and Rho-kinase. However, it remains to be elucidated whether incretins affect HCC cell functions. In the present study, therefore, we investigated whether incretins affect the migration of HCC cells using human HCC-derived HuH7 cells. GLP-1, but not GIP, reduced both TGF-α- and hepatocyte growth factor (HGF)-induced cell migration. IBMX, an inhibitor of cyclic nucleotide phosphodiesterase, enhanced the suppressive effect of GLP-1. GLP-1 attenuated the phosphorylation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) by TGF-α and HGF. Our results strongly suggest that GLP-1 suppresses TGF-α- and HGF-induced migration of HCC cells through inhibiting the SAPK/JNK signaling pathway, and that the inhibition by GLP-1 is due to cAMP production.

Quercetin suppresses the migration of hepatocellular carcinoma cells stimulated by hepatocyte growth factor or transforming growth factor-α: Attenuation of AKT signaling pathway.

Flavonol, which is found abundantly in plants such as fruits and vegetables, belongs to the family of flavonoid, natural polyphenols. Quercetin, one of the flavonol, reportedly has anti-cancer effects and prevents the proliferation of various cancer cells, including hepatocellular carcinoma (HCC). However, the effects of quercetin on HCC cells migration have not yet been clarified. We have previously shown that the migration of human HCC-derived HuH7 cells induced by hepatocyte growth factor (HGF) or transforming growth factor-α (TGF-α) is mediated through p38 MAPK and AKT. In this study, we investigated whether quercetin affects the HGF- or TGF-α-induced migration of HuH7 cells. Quercetin significantly suppressed both HGF- and TGF-α-induced migration of HuH7 cells in a dose-dependent manner. In addition, myricetin, another flavonol, also showed significant inhibition of the cell migration. Each HGF- and TGF-α-induced autophosphorylation of receptors were not affected by quercetin or myricetin. Quercetin did not suppress HGF- or TGF-α-induced p38 MAPK phosphorylation. On the contrary, quercetin and myricetin inhibited the growth factors-induced phosphorylation of AKT. Our results strongly suggest that quercetin suppresses the growth factor-induced migration of HCC cells by inhibiting the signaling pathway of AKT but not p38 MAPK.

[Selection of Operative Procedure for Breast Cancer in Carriers of BRCA VUS in Japan].

Risk classification and clinical management of the DNA variant of unknown significance(VUS)in BRCA 1/2 remains unestablished. The Japanese hereditary breast and ovarian cancer(HBOC)consortium and myriad genetics reported that the VUS rate of BRCA is 6.5% in Japanese patients, but is <2% in the USA. The types of mutation supposedly differ between Asian and European ethnicities. Breast-conserving therapy(BCT)is not recommended in HBOC breast cancer, according to the 2017 Japanese guidelines by the Ministry of Health, because of the risk of ipsilateral breast recurrence(IBR)and carcinogenesis by radiation. In our hospital, we recommend an initial mastectomy and breast reconstruction with an implant for patients with HBOC breast cancer, considering future surgery on the contralateral side and symmetry of the reconstructed breast. However, the risk of IBR after BCT is not significantly high in patients with HBOC breast cancer, and BCT is a reasonable option even for definite HBOC breast cancer under low risk conditions. Hence, BCT is feasible for treating breast cancer in carriers of VUS following decision-making and informed consent from the patients.

Effects of aromatherapy massage on face-down posture-related pain after vitrectomy: a randomized controlled trial.

Postoperative face-down posturing (FDP) is recommended to optimize the effects of intraocular gas tamponade after vitrectomy. However, patients undergoing FDP usually experience physical and psychological burdens. This 3-armed, randomized, single-center trial investigated the effects of aromatherapy on FDP-related physical pain. Sixty-three patients under FDP were randomly allocated to one of three treatment groups: aromatherapy massage with essential oil (AT), oil massage without essential oil (OT), and a control group. The AT and OT groups received 10 minutes of massage by ward nurses trained by an aromatherapist, while the control group received usual care. Outcomes were assessed as short-term (pre- to post-intervention) and long-term (first to third postoperative day) changes in physical pain in five body regions using face-scale. The AT and OT groups both revealed similar short-term pain reductions after intervention, compared with the control group. Regarding long-term effects, neither group experienced significant effects until the second day. Significantly more pain reduction compared with usual care occurred on the third day, mainly in the AT group, though there were few significant differences between the AT and OT groups. In conclusion, this study suggests that simple oil massage is an effective strategy for immediate pain reduction in patients undergoing FDP, while aromatherapy may have a long-term effect on pain reduction.

Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Test-retest paradigm of the forced swimming test in female mice is not valid for predicting antidepressant-like activity: participation of acetylcholine and sigma-1 receptors.

The forced swimming test (FST) in mice is widely used to predict the antidepressant activity of a drug, but information describing the immobility of female mice is limited. We investigated whether a prior swimming experience affects the immobility duration in a second FST in female mice and whether the test-retest paradigm is a valid screening tool for antidepressants. Female ICR mice were exposed to the FST using two experimental paradigms: a single FST and a double FST in which mice had experienced FST once 24 h prior to the second trail. The initial FST experience reliably prolonged immobility duration in the second FST. The antidepressants imipramine and paroxetine significantly reduced immobility duration in the single FST, but not in the double FST. Scopolamine and the sigma-1 (σ1) antagonist NE-100 administered before the second trial significantly prevented the prolongation of immobility. Neither a 5-HT1A nor a 5-HT2A receptor agonist affected immobility duration. We suggest that the test-retest paradigm in female mice is not adequate for predicting antidepressant-like activity of a drug; the prolongation of immobility in the double FST is modulated through acetylcholine and σ1 receptors.

SERMs (selective estrogen receptor modulator), acting as estrogen receptor ß agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway.

Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-α promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-α-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) ß agonists, inhibited the TGF-α-induced cell migration whereas PPT, an ERα agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and c-Jun N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-α. Furthermore, PHTPP, an ERß antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-α-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-α-induced migration of HCC cells through ERß-mediated inhibition of the AKT signaling pathway.

Aberrant resting-state functional connectivity of major depressive disorder with higher risk of suicide.

Aim: Suicide prevention for depressive patients is an important clinical issue in psychiatry. However, not all depressive patients plan or attempt suicide. In this study, we investigated the differences of functional brain networks between a high-risk group and a low-risk group for suicide by comparing resting-state functional connectivity (rsFC). Methods: The subjects were 29 patients with major depressive disorder, nine of whom had attempted suicide. The suicidal ideation of all subjects was assessed with the Columbia-Suicide Severity Rating Scale, then the subjects were divided into two groups based on the most severe suicidal ideation (MSI) in their lifetime. We compared rsFC between the two groups. Results: Of the 29 subjects, 16 were in the severe MSI group. We found that the severe MSI group members had significantly smaller rsFC in two networks: one comprised the right dorsolateral prefrontal cortex and the default-mode network, and the other comprised the left rostrolateral prefrontal cortex and the striatum, amygdala, and hippocampus. These regions are reported to be associated with rumination, retrieval suppression, and delay discounting (DD). Conclusion: Our results suggest that functional networks related to rumination, retrieval suppression, and DD might be impaired in depressive patients with severe suicidal ideation. It might be beneficial for psychiatrists to assess these characteristics in terms of suicide prevention for depressive patients.

Cellular Functions of Small Heat Shock Proteins (HSPB) in Hepatocellular Carcinoma.

Heat shock proteins (HSPs) play an essential role as molecular chaperones in proteostasis. Small HSPs are a group of low-molecular-weight HSPs in the range of 12- 43 kDa and are classified as HSPB. Within the ten members of the family, HSPB1(HSP27), HSPB5 (αB-crystallin), HSPB6 (HSP20), and HSPB8 (HSP22) ubiquitously exist in various tissues, including liver tissue. These small HSPs undergo phosphorylation as a post-translational modification, and their functions are modulated. Hepatocellular carcinoma (HCC) is one of the most frequent cancers and the fourth leading cause of cancer-related death worldwide. HSPs play a cytoprotective role as molecular chaperones. Thus, HSPB has been generally considered to protect HCC cells and help the progression of HCC. On the other hand, recent studies from our laboratories have demonstrated suppressive roles of phospho-HSPB1, HSPB6, and HSPB8 in the progression of HCC. These findings may provide a basis for a novel defense system by HSPB against HCC progression. This review focuses on the cellular functions of HSPB in HCC and summarizes the current research.

[Clinical analysis of 12 cases of pneumothorax during intensive chemotherapy for malignant neoplasms].

Twelve cases of pneumothorax during intensive chemotherapy for malignant neoplasms were found in a retrospective study of patients being treated at our hospital in the period 2001-2009. All of the patients were men, and their diseases were lung cancer (9 cases), gastric cancer (2 cases) and esophageal cancer (one case). Operation for pneumothorax was performed 9 times in 7 patients(twice in two patients). Thoracoscopic surgery was done in 6 patients, and one patient with severe pulmonary emphysema was performed by open thoracotomy. Pleurodesis was performed 5 times using OK-432 only or OK-432 and minocyclin. Five patients died during the treatment for pneumothorax. The causes of death were interstitial pneumonia after pleurodesis (one case), and progression of cancer during interruption of chemotherapy (4 cases). Development of pneumothorax during intensive chemotherapy should be recognized and treated as soon as possible because it may hinder the treatment for malignant tumors and lead to severe pulmonary dysfunction.

Heat shock protein 70 positively regulates transforming growth factor-α-induced hepatocellular carcinoma cell migration via the AKT signaling pathway.

Heat shock proteins (HSPs) are induced in response to extracellular stress and manage the quality of proteins as molecular chaperones. HSP70, a highly conserved HSP, has been reported to correlate with the proliferation and migration of human cancer cells, such as oral, prostate, lung and liver cancer. Regarding hepatocellular carcinoma (HCC), the HSP70 levels in the tumor tissues from patients are significantly higher than those in the normal liver tissues. HSP70 reportedly upregulates the migration and invasion of HCC. The AKT, p38 mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK) and Rho-kinase signaling pathways regulate the transforming growth factor (TGF)-α-induced migration of human HCC-derived HuH7 cells. However, the exact mechanism underlying the role of HSP70 in growth factor-induced HCC migration remains unclear. Therefore, in the present study, the mechanism underlying the involvement of HSP70 in TGF-α-induced HCC cell migration was investigated. Treatment with the HSP70 inhibitors VER155008 and YM-08 and the downregulation of HSP70 protein were confirmed to significantly suppress the TGF-α-induced cell migration of HuH7 cells. Both VER155008 and YM-08 reduced the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK, JNK or Rho-kinase. These results strongly suggest that HSP70 positively regulates the TGF-α-induced migration of HCC cells via the AKT signaling pathway.

[Determinants of chilliness among young women and their application to psychopharmacological trials].

Chilliness is a common complaint among menopausal women. Increasing evidence indicates that young women also suffer from chilliness, resulting in decreased learning, motivation, and concentration. Neither diagnostic criteria nor drug therapies exist for chilliness, and thus, young women suffer from insomnia, fatigue, and mood disturbance. Because chilliness is correlated with hormonal changes observed during premenstrual, postpartum, and menopausal periods, reproductive hormones are likely involved. Recently, we elucidated methodological issues related to identifying young women with chilliness. We used a new questionnaire to determine complaint severity with regard to chills and assessed physical parameters (BMI, body fat ratio, basal metabolism, blood pressure), peripheral circulation, and recovery of skin surface temperature after mild cold-water finger immersion. Using a discriminant analysis (hit ratio, 84.5%), we demonstrated that four parameters (blood flow, difference between underarm and surface temperature, recovery rate after mild cold exposure, and score for chilliness-related complaints) were important determinants of chilliness. Among traditional candidate substances for alleviating chilliness, Piper longum and royal jelly showed significant effects. Additionally, we investigated seasonal change in the experience of chilliness and found that young women suffer from chilliness during the summer. These findings have important implications for understanding chilliness in women.

[Effects of Piper longum L. on chills in Japanese young women: time-dependent changes in skin surface temperature and its recovery rate following the exposure to mild cold stress].

Chills can lead to problems such as insomnia, mental fatigue, and unstable emotions. Increasing evidence shows that young women, as well as menopausal women, suffer from chills. The present study investigated the effect of Piper longum L. on chills in young women. Participants with (n = 16) and without (n = 16) chills were sampled randomly from female university students using reported discriminative criteria (Yamada et al, 2007). Each participant was randomly assigned to low- (15 mg) and high-dose (30 mg) P. longum groups. We determined the severity of complaints related to chills, physical parameters (body mass index, body fat ratio, and blood pressure), the peripheral circulation dynamics using a laser tissue blood flow-meter, and the skin surface temperature in the fingers using a thermograph. Mild cold stress was applied 10 min after taking a capsule containing P. longum or a dextrin placebo. Then, a thermograph was recorded every minute for 11 min. Piper longum significantly facilitated the recovery of skin surface temperature at either low or high dosages in participants with chills. In subjects without chills, neither high- nor low-dosage of P. longum had an effect. Our findings have important implications for the utility of P. longum in women with chills.

Olive oil polyphenols suppress the TGF-α-induced migration of hepatocellular carcinoma cells.

Oleuropein and 3-hydroxytyrosol (3-HT) are natural polyphenols present in olive oil that are known to exhibit potent anti-oxidant activities and exert protective effects against a number of human diseases. In the liver, olive oil polyphenols have been demonstrated to prevent hepatocellular carcinoma (HCC) cell growth. However, little is known about their effects against HCC cell migration. Therefore, the present study investigated whether or not oleuropein and 3-HT were involved in the suppression of transforming growth factor-α (TGF-α)-induced migration of human HCC cells using human HCC-derived HuH7 cells. The TGF-α-induced migration of HuH7 cells was significantly and dose-dependently suppressed by oleuropein and 3-HT. This study group demonstrated previously that the TGF-α-induced activation of AKT and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) were involved in HuH7 cell migration. In addition to these protein kinases, the present study examined the involvement of TGF-α-induced activation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and Rho kinase in HuH7 cell migration. TGF-α-induced HuH7 cell migration was decreased by SB203580, a p38 MAPK inhibitor, and Y27632, a Rho kinase inhibitor. However, PD98059, an inhibitor of the upstream kinase activating ERK, did not suppress the TGF-α-induced migration of HuH7 cells. Although AKT, SAPK/JNK, p38 MAPK and Rho kinase pathways were suggested to be involved in the TGF-α-induced migration of HuH7 cells, 10-30 µM 3-HT did not exhibit any suppressive effect on the TGF-α-stimulated activities of these kinases. The results of the present study suggest that olive oil polyphenols suppressed the TGF-α-induced migration of HCC cells.

Degradation of vitamin B12 in dietary supplements.

Beverages and solid dietary supplements rich in various added vitamins and minerals have recently become available. It seems reasonable to consider that the intake of these foods is convenient for easy ingestion of nutrients, but problems caused by blending different nutrients in high concentrations have arisen. We focused on vitamin B12 (B12) among vitamins and determined the B12 contents of beverages and solid dietary supplements purchased from a retail shop. The B12 contents of three of five beverages were less than stated on the labels. On the other hand, certain beverages unexpectedly contained much more B12 than stated on the labels. In these beverages the amount of B12 decreased rapidly with time, whereas B12 content was lower than stated on the label in only one of four solid dietary supplements. The content of B12 was affected by storage time, light exposure, temperature and vitamin C. From experimental analysis with a competitive binding assay method employing a ACS Chemiluminescent B12 kit, examining differential binding by intrinsic factors and spectral analysis of B12, it was determined that some of the B12 might have been converted into B12 analogues or small degradation products by multinutrient interaction during storage.

[Subjective syndromes of perimenopausal women in China assessed using a multidimensional inventory: a canonical correlation analysis between the severity of subjective symptoms and the self-efficacy score].

We assessed subjective menopausal symptoms in Chinese women using a multidimensional inventory that covered five dimensions: sexual function, mental condition, interpersonal anxiety, autonomic balance, and other subjective symptoms. We elucidated its relationship with the score on a self-efficacy scale. We surveyed subjective menopausal symptoms in 281 women between 40 and 59 years old, who resided in an urban area in northwest China using both 60-item self-reported subjective menopausal symptoms and 16-item general self-efficacy scales. The dimensional structure was evaluated statistically using confirmatory factor analysis. The five-factor model appeared to fit the data, with sufficient validity (RMSEA = 0.075) and the instrument had appropriate internal consistency, with an average Cronbach's alpha of 0.964. The subjects were divided into pre-menopause, menopause-transition, and post-menopause groups based on the number of menstruations per year. Factorial analysis of variance revealed a significant difference in the severity of subjective symptoms among the three groups. The correlation between the severity of subjective symptoms and the self-efficacy score was determined using canonical correlation analysis. All factors except sexual function had a negative influence on the self-efficacy score.

Sphingosine 1-phosphate (S1P) reduces hepatocyte growth factor-induced migration of hepatocellular carcinoma cells via S1P receptor 2.

A bioactive lipid, sphingosine 1-phosphate (S1P), acts extracellularly as a potent mediator, and is implicated in the progression of various cancers including hepatocellular carcinoma (HCC). S1P exerts its functions by binding to five types of specific receptors, S1P receptor 1 (S1PR1), S1PR2, S1PR3, S1PR4 and S1PR5 on the plasma membrane. However, the exact roles of S1P and each S1PR in HCC cells remain to be clarified. In the present study, we investigated the effect of S1P on the hepatocyte growth factor (HGF)-induced migration of human HCC-derived HuH7 cells, and the involvement of each S1PR. S1P dose-dependently reduced the HGF-induced migration of HuH7 cells. We found that all S1PRs exist in the HuH7 cells. Among each selective agonist for five S1PRs, CYM5520, a selective S1PR2 agonist, significantly suppressed the HGF-induced HuH7 cell migration whereas selective agonists for S1PR1, S1PR3, S1PR4 or S1PR5 failed to affect the migration. The reduction of the HGF-induced migration by S1P was markedly reversed by treatment of JTE013, a selective antagonist for S1PR2, and S1PR2- siRNA. These results strongly suggest that S1P reduces the HGF-induced HCC cell migration via S1PR2. Our findings may provide a novel potential of S1PR2 to therapeutic strategy for metastasis of HCC.

Effects of FOXP3 gene polymorphism in sarcoidosis patients.

BACKGROUND: FOXP3 is a critical regulator of the development and function of regulatory T (Treg) cells, which are capable of suppressing immune responses. A recent study showed that the presence of the (GT) n microsatellite polymorphism in the FOXP3 gene was associated with enhancer activity, resulting in an effect on type I diabetes mellitus. Furthermore, sarcoidosis reportedly increases the prevalence of Treg cells in bronchoalveolar lavage fluid and peripheral blood. Because Treg cells may play roles in immune responses in sarcoidosis, in this study we investigated whether the FOXP3 gene polymorphism affects sarcoidosis. METHODS: One hundred and eight sarcoidosis patients and 100 healthy control subjects were studied. PCR-based fragment analysis combined with fluorescent technology were used to determine the FOXP3 (GT)n genotype. RESULTS: We found that the genotype distribution did not differ between sarcoidosis patients and healthy controls. Among sarcoidosis patients, the prevalence of the (GT)15 allele was higher in patients without skin lesions than in patients with skin lesions (p = 0.037, odds ratio = 2.96, 95% confidence interval: 1.07-8.24). CONCLUSIONS: Although the FOXP3 gene polymorphism has no effect on susceptibility to sarcoidosis, the (GT)15 allele may exert protective effects against skin involvement.