A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer.

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).

Umbilical cord mesenchymal stem cells enhance the therapeutic effect of imipenem by regulating myeloid-derived suppressor cells in septic mice.

BACKGROUND: Umbilical cord mesenchymal stem cells (UC-MSCs), which possess potent immunomodulatory effects and low immunogenicity, are considered to be a promising stem cell-based therapy for sepsis. In the current study, we aimed to investigate whether the combined use of UC-MSCs and imipenem has a better effect than imipenem alone in treating Escherichia coli (E. coli)-induced sepsis and to explore the mechanism by which UC-MSCs exert their therapeutic effect in septic mice. METHODS: We randomly divided mice into five groups with 10 mice in each group: the normal control group (control group), the sepsis group (vehicle group), the MSCs treatment group (MSCs group), the imipenem treatment group (imipenem group), and the imipenem plus MSCs treatment group (imipenem + MSCs group). We monitored the survival rate in each group every 12 h for 3 days. After observing the survival rate, another 50 mice were also randomly divided into five groups, and the mice were sacrificed after 24 h. Bacterial colonies from the blood and peritoneal lavage fluid were counted in a blinded manner. Organ injury was analyzed by hematoxylin and eosin (HE) staining. Frequencies of myeloid-derived suppressor cells (MDSCs) in the blood, spleen, and bone marrow (BM) were determined by flow cytometry. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with imipenem treatment, the co-administration of UC-MSCs and imipenem dramatically improved the survival rate, decreased the bacterial load, and ameliorated organ injury. Furthermore, UC-MSCs treatment, either alone or in combination with imipenem, significantly increased plasma levels of IL-10 and the percentage of MDSCs by inducing arginase-1 in septic mice. CONCLUSIONS: Our results indicated that UC-MSCs protect mice against sepsis by acting on MDSCs. Combination therapy of UC-MSCs and imipenem may be a new approach for the future clinical treatment of sepsis.

Comparison of heart rate variability and classic autonomic testing for detection of cardiac autonomic dysfunction in patients with fibromyalgia.

AIM: Cardiac autonomic dysfunction (CAD) is frequently found in patients with fibromyalgia (FM). Thus, we evaluated whether heart rate variability (HRV) is superior to the Ewing tests in detecting CAD in FM patients. METHODS: We studied 35 females with FM and 25 age-matched healthy females. In Ewing tests, results were added to yield an overall score. An abnormal result on deep breathing, the Valsalva maneuver, or orthostatic standing was counted as 1 point. A change in systolic blood pressure (SBP) of > 10 mmHg while standing counted as 1 point, and a change of > 20 mmHg as 2 points. A score of 0 was regarded as no CAD, a score of ≥ 2 as severe CAD and a score of 1 as mild CAD. HRV was measured in two ways: by R-R intervals (time-domain analysis) and by spectral analysis of a series of successive R-R intervals (frequency-domain analysis). RESULTS: FM patients had significantly lower expiratory/inspiratory (E/I) ratios, lower Valsalva ratios and higher SBP values than healthy controls (P < 0.05, P < 0.05, P < 0.01, respectively). In the frequency domain, very low-frequency and low-frequency bands were also lower in FM patients than controls (both P < 0.05). Based on the discriminant analysis of the Ewing tests, 54.4% of cases were correctly classified. The addition of HRV parameters did not improve the reclassification. CONCLUSION: HRV does not improve detection of CAD in FM patients over classic autonomic testing.

Association between grip strength and hand and knee radiographic osteoarthritis in Korean adults: Data from the Dong-gu study.

OBJECTIVES: We assessed whether grip strength was related to various types of radiographic damage in Korean adults with osteoarthritis (OA). METHODS: Data from 2,251 subjects enrolled in the Dong-gu study, who had no hand joint pain, were analyzed to investigate the relationship between grip strength and OA. Hand grip strength was measured using a hand-held dynamometer, and radiographs of the hand and knee were scored according to a semi-quantitative grading system. Multiple linear regressions were used to explore associations between grip strength and radiographic features of OA. RESULTS: Grip strength in men and women was negatively related to hand (both p < 0.001) and knee (men, p < 0.001; women, p = 0.010) OA after adjusting for confounders. Hand (men, p < 0.001; women, p = 0.001) and knee (both p < 0.001) joint space narrowing (JSN) showed the strongest associations with low grip strength, regardless of gender. Moreover, the severity of hand osteophytes in women (p = 0.001), and subchondral cysts (men, p < 0.001) was correlated with low grip strength in both genders. CONCLUSIONS: Among subjects without hand joint pain, low grip strength was associated significantly with hand and knee radiographic OA, regardless of gender. Among all types of OA radiographic damage, low grip strength showed the strongest association with JSN.

Predictive significance of CCL21 and CXCL13 levels in the minor salivary glands of patients with Sjögren's syndrome.

OBJECTIVES: To investigate whether CCL21 and CXCL13 expression levels in the minor salivary gland are associated with the laboratory and clinical manifestations of Sjögren's syndrome (SS). METHODS: Sociodemographic data on 106 SS patients were obtained and the glandular and extraglandular manifestations of the disease were documented. In addition, minor salivary gland biopsies were performed and the patients' laboratory findings were analysed. European League Against Rheumatism SS disease activity index (ESSDAI) values of SS disease activity at the time of biopsy and the SS disease damage index (SSDDI) values were also recorded. An immunohistochemical approach was used to semiquantitatively measure the CCL21 and CXCL13 expression in the minor salivary glands. RESULTS: The minor salivary glands of SS patients stained positively for CCL21 and CXCL13 in 46.2% (49/106) and 70.7% (75/106) of all cases, respectively. Higher-level expression of CCL21 and CXCL13 was associated with increases in ESR, IgG and rheumatoid factor levels, as well as anti-SS-A and -SS-B titers. A higher focus score and ESSDAI value at the time of biopsy were also associated with these chemokines. In patients with extraglandular manifestations of SS, the prevalence of lymphadenopathy increased with increasing CCL21 levels. CONCLUSIONS: The expression levels of CCL21 and CXCL13 within the lymphocytic infiltrates of SS patients were associated with several laboratory features of the disease as well as lymphadenopathy and the extent of clinical disease activity. CCL21 and CXCL13 levels can therefore serve as useful markers to predict the disease activity and prognosis of patients with SS.

Predictors of a favourable outcome in patients with fibromyalgia: results of 1-year follow-up.

OBJECTIVES: To determine the outcomes of Korean patients with fibromyalgia (FM) and to identify prognostic factors associated with improvement at 1-year follow-up. METHODS: Forty-eight patients with FM were enrolled and examined every 3 months for 1 year. At the time of enrollment, we interviewed all patients using a structured questionnaire that recorded socio-demographic data, current or past FM symptoms, and current use of relevant medications. Tender point counts and scores were assessed by thumb palpation. Patients were asked to complete the Korean versions of the Fibromyalgia Impact Questionnaire (FIQ), the Brief Fatigue Inventory, the SF-36, the Beck Depression Inventory, the State-Trait Anxiety Inventory (STAI), the Self-Efficacy Scale, and the Social Support Scale. Tender points, FIQ scores, and the use of relevant medications were recorded during one year of follow-up. RESULTS: Of the 48 patients, 32 (66.7%) had improved FIQ scores 1 year after enrollment. Improved patients had higher baseline FIQ scores (68.4±13.9 vs. 48.4±20.8, p=0.001) and STAI-II scores (55.8±10.9 vs. 11.5±11.5, p=0.022). Patients treated with pregabalin were more likely to improve after 1 year, based on the FIQ scores (71.9% vs. 37.5%, p=0.031). On multivariate logistic regression analysis, a higher STAI-II score at the time of enrollment and pregabalin treatment during one year of follow-up were the predictors of improvement. CONCLUSIONS: Two-thirds of our Korean FM patients experienced some clinical improvement by 1-year follow-up. A high baseline STAI-II score and treatment with pregabalin were the important predictor of improved FM.

The Significance of Ectopic Germinal Centers in the Minor Salivary Gland of Patients with Sjögren's Syndrome.

We investigated the clinical and biological significance of germinal centers (GC) present in the minor salivary glands of patients with Sjögren's syndrome (SS). Minor salivary gland tissue biopsies from 93 patients with SS were used to identify GC-like structures, which were confirmed by CD21-positive follicular dendritic cell networks. Patients were compared based upon sociodemographics, glandular and extraglandular manifestations, and laboratory findings including autoantibody profiles, complement, and immunoglobulin levels; EULAR SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. GC-like structures were observed in 28 of 93 SS patients (30.1%). Mean focus scores and CRP levels were significantly higher in GC-positive patients than in GC-negative patients; GC-positive patients also exhibit a higher prevalence of rheumatoid factor and anti-SS-A/Ro antibodies compared to GC-negative patients. No differences in glandular or extra-glandular manifestations were evident between groups. In conclusion, SS patients with GC-like structures in the minor salivary glands exhibited laboratory profiles significantly different from those of their GC-negative counterparts. Long-term follow-up of these patients will be necessary to determine whether these laboratory abnormalities are predictive of clinical outcomes.

The relationships between bone mineral density and radiographic features of hand or knee osteoarthritis in older adults: data from the Dong-gu Study.

OBJECTIVE: The relationship between OA and osteoporosis has exhibited contradictory features over the past four decades. The aim of this study was to determine using separate analysis of the radiographic features of OA whether various radiographic features of OA were associated differently with BMD in the Korean elderly. METHODS: Data were derived from the Dong-gu cohort; 2354 subjects were enrolled in the present cross-sectional study. Baseline characteristics, the BMDs of the lumbar spine and femoral neck measured by DXA, and X-rays of knees and hands were collected. A semi-quantitative grading system was used to estimate the severities of individual radiographic features. We adjusted for confounders using multiple linear regression modelling to analyse the relationships. RESULTS: After adjustment for confounders, hand and knee OA total scores were negatively associated with the BMDs of the lumbar spine and femoral neck, except for the total knee OA score and lumbar spine BMD. In detail, hand osteophytes and sclerosis exhibited positive relationships with the BMDs of the lumbar spine and femoral neck, except for hand osteophytes and femoral neck BMD. On the contrary, however, knee joint space narrowing (JSN), hand JSN, and hand subchondral cysts were negatively associated with the BMD of the lumbar spine and femoral neck. Knee JSN and hand subchondral cysts exerted the greatest effects on BMD. CONCLUSION: Separate analysis of the radiographic features of OA better reveals associations of OA with the BMD of the lumbar spine and femoral neck.

Cross-cultural adaptation of the Revised Korean version of the Fibromyalgia Impact Questionnaire: its association with physical function and quality of life.

AIM: Despite its shortcomings, the Fibromyalgia Impact Questionnaire (FIQ) is widely used to assess clinical symptoms and measure therapeutic changes in patients with fibromyalgia (FM). Recently, the revised version of the FIQ (FIQR) was released. In this study, we validated the Korean version of the FIQR and evaluated whether the revised version is superior to the original version in reflecting the physical function and quality of life of these patients. METHODS: Seventy-nine patients with FM were invited to complete a questionnaire that included the original FIQ, FIQR, Multidimensional Health Assessment Questionnaire (MDHAQ), Rheumatology Attitudes Index (RAI), and Medical Outcome Study Short-Form 36 (SF-36). RESULTS: The test-retest reliability was assessed in 55 patients after 1 week, and the Spearman coefficients were 0.604-0.825 and Cronbach's alpha was 0.948 (95% confidence interval 0.930-0.964). The FIQR was significantly correlated with the pain visual analogue scale (VAS), fatigue VAS, RAI, MDHAQ, and physical and mental component summary scores of the SF-36. The FIQR was more strongly associated with the MDHAQ and SF-36 scores than with the original FIQ. CONCLUSION: Our study showed that the FIQR is a reliable, valid instrument for assessing patients with FM and performs better in the prediction of physical function and health status than the original version.

Exploring Genetic Susceptibility to Fibromyalgia.

Fibromyalgia (FM) affects 1% to 5% of the population, and approximately 90% of the affected individuals are women. FM patients experience impaired quality of life and the disorder places a considerable economic burden on the medical care system. With the recognition of FM as a major health problem, many recent studies have evaluated the pathophysiology of FM. Although the etiology of FM remains unknown, it is thought to involve some combination of genetic susceptibility and environmental exposure that triggers further alterations in gene expression. Because FM shows marked familial aggregation, most previous research has focused on genetic predisposition to FM and has revealed associations between genetic factors and the development of FM, including specific gene polymorphisms involved in the serotonergic, dopaminergic, and catecholaminergic pathways. The aim of this review was to discuss the current evidence regarding genetic factors that may play a role in the development and symptom severity of FM.

Predictors of Switching Anti-Tumor Necrosis Factor Therapy in Patients with Ankylosing Spondylitis.

The aim of this study was to investigate the potential predictors of switching tumor necrosis factor (TNF)-α inhibitors in Korean patients with ankylosing spondylitis (AS). The patients who had been treated with TNF-α inhibitors were divided into two groups depending on whether they had switched TNF-α inhibitors. Demographic, clinical, laboratory, and treatment data at the time of initiation of TNF-α inhibitor treatment were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Of the 269 patients, 70 (23%) had switched TNF-α inhibitors once; of these, 11 switched again. The median follow-up time was 52.7 months. Three- and five-year drug survival rates were 52%/48% for infliximab, 62%/42% for etanercept, and 71%/51% for adalimumab, respectively. Switchers were more likely to be prescribed disease-modifying anti-rheumatic drugs than non-switchers. A history of joint surgery and complete ankylosis of the sacroiliac joint was more frequent in switchers. Multivariate Cox's proportional hazard analysis showed that the use of adalimumab as the first TNF-α inhibitor was less likely to lead to switching and complete ankylosis of the sacroiliac joints was more likely to lead to switching. The principal reasons for switching were drug inefficacy and adverse events, but the differences in the clinical data of these two groups of switchers were not significant. In AS patients who are candidates for TNF-α inhibitor therapy, switching may improve the therapeutic outcome based on clinical information.

Anti-centromere antibody-positive Sjögren's syndrome: A distinct clinical subgroup?

AIM: To investigate whether patients with Sjögren's syndrome (SS) can be distinguished based on the positivity of anti-centromere antibody (ACA), and if so, whether the subgroups differ in their clinical and laboratory features. METHODS: Eleven patients with ACA-positive and 71 patients ACA-negative SS were examined. All patients had minor salivary gland biopsy; sociodemographic data, glandular and extraglandular manifestations, and laboratory findings, including autoantibodies, complement and immunoglobulin levels, were analyzed. European League Against Rheumatism SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. RESULTS: The prevalence of ACA among SS patients was 13.4%. ACA-positive SS patients had a higher prevalence of Raynaud's phenomenon, sclerodactyly and autoimmune thyroiditis and a lower prevalence of anti-SSA/Ro and anti-SSB/La antibodies compared to ACA-negative patients. Disease activity was higher in ACA-positive patients than in ACA-negative patients, but the damage index did not differ between the two groups. None of the patients who originally had ACA evolved to having full-blown systemic sclerosis. CONCLUSION: Patients with SS who have ACA differ from classic SS patients in several clinical and laboratory parameters. ACA should be considered one of the pathogenically relevant autoantibodies for SS.

Cost-effectiveness analysis of HLA-B5801 genotyping in the treatment of gout patients with chronic renal insufficiency in Korea.

OBJECTIVE: Allopurinol-induced severe cutaneous adverse reactions (SCARs) are relatively rare but cause high rates of morbidity and mortality. Studies have shown that the HLA-B5801 allele and renal impairment are strongly associated with SCARs. Recent American College of Rheumatology guidelines recommend that, prior to treatment with allopurinol, the HLA-B5801 genotype of gout patients at high risk for SCARs, including Korean patients with chronic renal insufficiency, should be determined. However, whether such genotyping is cost-effective is unknown. This study evaluated the cost-effectiveness of HLA-B5801 genotyping for the treatment of gout in patients with chronic renal insufficiency in Korea. METHODS: A decision analytical model over a time period of 12 months was employed to compare the cost and outcomes of treatment informed by HLA-B5801 genotyping with that of a conventional treatment strategy using a hypothetical cohort of gout patients with chronic renal insufficiency. Direct medical costs were obtained from real patients with SCARs from 2 tertiary hospitals. Outcomes were measured as a total expected cost and an incremental cost-effectiveness ratio. RESULTS: In the base model, the total expected cost and probability of continuation of gout treatment without SCARs for the conventional and HLA-B5801 screening strategies were $1,193 and 97.8% and $1,055 and 100%, respectively. The results were robust according to sensitivity analyses. CONCLUSION: Our model suggests that gout treatment informed by HLA-B5801 genotyping is less costly and more effective than treatment without genotyping, and HLA-B5801 genotyping could considerably reduce the occurrence of allopurinol-induced SCARs and related deaths.

Drug survival rates of tumor necrosis factor inhibitors in patients with rheumatoid arthritis and ankylosing spondylitis.

We investigated the compliance of Korean patients using tumor necrosis factor (TNF) inhibitors to treat rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and identified potential predictors associated with treatment discontinuation. The study population comprised 114 RA and 310 AS patients treated with TNF inhibitors at a single tertiary center for at least 1 yr from December 2002 to November 2011. Of the 114 RA patients, 64 (56.1%) discontinued their first TNF inhibitors with a mean duration of 18.1 months. By contrast, 65 of 310 patients (21.0%) with AS discontinued their first TNF inhibitors, with a mean duration of 84 months. Although the survival rate did not differ among the three TNF inhibitors in the AS patients, the etanercept group had a lower discontinuation rate than the infliximab group in the RA patients. In addition, RA patients who received corticosteroids in combination with TNF inhibitors were more likely to discontinue their TNF inhibitors. The independent predictors of drug discontinuation in AS patients were male gender and complete ankylosis on radiographs of the sacroiliac joint. Our results provide further evidence that real-life treatment outcomes of RA and AS patients may be different from those observed in randomized clinical trials.